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Baroreceptor reflex pathways and neurotransmitters: 10 Years on
Abstract
The central nervous system plays a critical role in the management of blood flow to the tissues and its return to the heart and lungs. This is achieved by a complex interplay of neural efferent pathways, humoral mechanisms and afferent pathways. In this review, we focus on recent progress (within the past 10 years) that has been made in the sympathetic control of arterial blood pressure with a special emphasis on the role of baroreceptor mechanisms and central neurotransmitters. In particular, we focus on new features since 1991, such as neurotransmission in the nucleus tractus solitarius, the role of neurons in the most caudal part of the ventrolateral medulla oblongata and the increasing understanding of the exquisite control of different sympathetic pathways by different neurotransmitter systems.
... Gravitational effects on invertebrate cardiovascular and respiratory systems are likely to be widely distributed among invertebrates and to have broad influence on morphological and physiological evolution. gravity | invertebrate | insect | cardiovascular system | respiratory system I n vertebrates, gravity effects are commonly experienced when an animal changes body orientation, resulting in changing pressures throughout the body governed by principles of fluid mechanics, with pressure differences directly proportional to vertical height (1)(2)(3)(4)(5). Many insects change body positions routinely and often, especially during locomotion; for example, ants and roaches routinely walk up and down trees and walls (6). ...
... Vertebrates counteract gravity effects on blood partly by varying heart rates in response to baroreceptor cardiac reflexes (1). Because the heart of grasshoppers pumps primarily in a cranial direction (12), we hypothesized that heart rates would be higher in head-up than head-down positions to counteract gravity effects on hemolymph. ...
... Each data point represents the maximum pressure for pressure pulsations measured at two locations in the body (points 1 and 2). The red line represents a fit using the total least square method as calculated in (1). Slopes, intercepts, and confidence limits for these plots are in Table S11. ...
... Enhanced respiratory drive appears to induce a form of neural plasticity in RVLM neurons, leading to hyper-sensitisation of the sympathetic-respiratory response. Throughout this process, the co-ordinated post-synaptic release of various neuropeptides may play a critical role in shaping cardiovascular disease outcomes (Pilowsky et al., 1996;Pilowsky and Goodchild, 2002). ...
... Autonomic reflexes comprise a series of regulatory responses following changes induced by a challenge to an organism. Notable stimuli include rapid increase or decreases in blood pressure (baroreceptor activation or silencing) (Pilowsky and Goodchild, 2002), reductions in blood glucose levels (glucose counter-regulatory response) , and reductions in arterial O 2 and/or increased CO 2 levels (peripheral/central chemoreflexes) (Guyenet, 2000;Prabhakar, 2006). Impairments in autonomic reflex function are present in certain diseases and conditions including OSA, 'hypoglycaemia-associated autonomic failure' (HAAF-see later section), and hypertension. ...
... Respiratory Physiology & Neurobiology xxx (xxxx) xxx-xxx behaviour arises from the activation of receptors belonging to a wide array of neuropeptides. These receptors are typically located pre-or post-synaptically on presympathetic RVLM neurons/fibres, or on sympathetic preganglionic neurons of the spinal cord (Pilowsky and Goodchild, 2002;Pilowsky et al., 2009). It is difficult to trace and identify the root source of neuropeptides activating these specific receptors. ...
Autonomic reflex responses are critical in restoring changes to circulatory factors reduced beyond the domain of homeostasis. Intermittent hypoxia triggers repeated activation of chemoreflexes, resulting in baroreflex dysfunction and widespread changes in cellular and neuronal activity regulated by sensory/motor pathways. Hypoglycaemia initiates a rapid neurally-mediated counter-regulatory response. This counter-regulatory response to hypoglycaemia increases plasma adrenaline levels, liver glycogenolysis, and thus blood glucose levels. Context-dependent activation of rostral ventral medullary neurons initiates baroreceptor unloading, peripheral chemoreflex firing and the counter-regulatory response to hypoglycaemia. In this review, we briefly focus on the functional integration between peripheral and medullary pathways comprising the sympathetic baroreflex, chemoreflexes, and the counter-regulatory response to hypoglycaemia.
... A crucial central area for cardiovascular regulation is the NTS, the main area receiving inputs from interoceptive viscerosensory afferents, including those from peripheral baro-and chemoreceptors [20,21]. In SHRs, ROS increases were detected in the intermediate NTS (iNTS), the primary central site receiving inputs from baroreceptors [21]. ...
... A crucial central area for cardiovascular regulation is the NTS, the main area receiving inputs from interoceptive viscerosensory afferents, including those from peripheral baro-and chemoreceptors [20,21]. In SHRs, ROS increases were detected in the intermediate NTS (iNTS), the primary central site receiving inputs from baroreceptors [21]. In addition, SOD overexpression in the iNTS also reduced arterial pressure and HR in SHRs [22]. ...
Background:
A growing body of evidence suggests that oxidative stress plays a role in the pathophysiology of hypertension. However, the involvement of the reactive oxygen species (ROS) in the commissural nucleus of the solitary tract (commNTS) in development the of hypertension remains unclear.
Method:
We evaluated the hemodynamic and sympathetic responses to acute inhibition of NADPH oxidase in the commNTS in renovascular hypertensive rats. Under anesthesia, male Holtzman rats were implanted with a silver clip around the left renal artery to induce 2-kidney 1-clip (2K1C) hypertension. After six weeks, these rats were anesthetized and instrumented for recording mean arterial pressure (MAP), renal blood flow (RBF), renal vascular resistance (RVR), and renal sympathetic nerve activity (RSNA) during baseline and after injection of apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor), NSC 23766 (RAC inhibitor) or saline into the commNTS.
Results:
Apocynin into the commNTS decreased MAP, RSNA, and RVR in 2K1C rats. NSC 23766 into the commNTS decreased MAP and RSNA, without changing RVR in 2K1C rats.
Conclusion:
These results demonstrate that the formation of ROS in the commNTS is important to maintain sympathoexcitation and hypertension in 2K1C rats and suggest that NADPH oxidase in the commNTS could be a potential target for therapeutics in renovascular hypertension.
... The endocannabinoid system consists of G-protein coupled receptors (CB1 and CB2 receptors), endogenous ligands (called endocannabinoids) and proteins involved in endocannabinoid synthesis and inactivation [10,11,42]. Studies have shown that the CB1 receptor is the most abundant G protein-coupled receptor in the CNS, and it is expressed in areas involved in the respiratory control and thermorregulation [24,41,49,52]. In contrast, CB2 receptors are expressed almost exclusively by peripheral immune cells [9]. ...
... The same was observed in mice [32]. Other studies confirm that endocannabinoids have no tonic role in the regulation of Tb [8,30,41]. It is well established that besides to increase ventilation, hypoxia also reduces Tb [1,46], a response that has been called anapyrexia [1,46] or regulated hypothermia [22]. ...
The anteroventral preoptic region (AVPO) of the hypothalamus is involved in both temperature and breathing regulation. This area densely express cannabinoid receptors type 1 (CB1) that modulates both excitatory and inhibitory synaptic transmission. However, it is still unknown if the endocannabinoid system located in the AVPO participates in breathing control and thermoregulation. Therefore, we tested the participation of CB1 in the AVPO in the modulation of ventilation and thermal control during normoxia and hypoxia. To this end, body temperature (Tb) of Wistar rats was monitored by datallogers and ventilation (VE) by whole body plethysmography before and after intra-AVPO microinjection of AM-251 (CB1 antagonist, 50 and 100 pmol) followed by 60 min of hypoxia exposure (7% O2). Intra-AVPO microinjection of the higher dose of AM-251 increased ventilation but did not change Tb under resting conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced anapyrexia and hyperventilation after vehicle microinjection. The higher dose of the cannabinoid antagonist increased the hypoxia-induced hyperventilation, in the same magnitude as observed under normoxic condition, whereas the drop in Tb elicited by hypoxia was attenuated. Therefore, the present results demonstrate that the endocannabinoid system acting on CB1 receptors in the AVPO exerts a tonic inhibitory modulation on breathing but seem not be involved in thermoregulation during restingconditions. In addition, activation of CB1 receptors in the AVPO stimulate thermal response during hypoxia, reducing energetically expensive responses, such as the hypoxic hyperventilation.
... The rostral ventrolateral medulla (RVLM) is a key brain region involved in regulating sympathetic nerve activity and BP (Madden and Sved, 2003;Guyenet et al., 2018). RVLM neurons send axons directly to the intermediolateral cell column (IML) neurons connecting with the peripheral sympathetic function and BP (Deuchars and Lall, 2015;Deuchars et al., 1995;Oshima et al., 2008;Pilowsky and Goodchild, 2002). Therefore, this study examined the effects of Klotho on RVLM neurons. ...
... The RVLM contains neurons that play a key role in controlling sympathetic vasomotor tone and BP. Increased activity of the RVLM presympathetic neurons is transmitted to the IML in the spinal cord, where peripheral sympathetic nerves activated, thus causing BP elevation (Pilowsky and Goodchild, 2002) and decreased activity of these neurons leads to BP reduction (Zanzinger et al., 1995). In this study, we examined how Klotho or FGF23 changes the activities of RVLM neurons. ...
Hypertension often occurs in patients with chronic kidney disease (CKD). Considering the decrease in serum Klotho and increase in serum FGF23 levels in such patients, decreased Klotho and increased FGF23 levels were thought to be associated with hypertension. Presympathetic neurons at the rostral ventrolateral medulla (RVLM) contribute to sympathetic activity and regulation of blood pressure. Therefore, we hypothesized that Klotho would reduce the activities of RVLM neurons and FGF23 would stimulate them. Accordingly, this study examined the effects of Klotho and FGF23 on bulbospinal neurons in the RVLM. We used a brainstem-spinal cord preparation to record from RVLM presympathetic neurons and to evaluate the effects of Klotho and FGF23 on firing rate and membrane potentials of these neurons. Our results showed that Klotho-induced RVLM neuron hyperpolarization, while ouabain, a Na+/K+-ATPase inhibitor, suppressed the effects of Klotho on such neurons. Moreover, FGF23 induced RVLM neuron depolarization, while SU5402, an FGF23 receptor (FGFR1) antagonist, induced RVLM neuron hyperpolarization. Histological examinations revealed that Klotho, Na+/K+-ATPase, FGF23, and FGFR1 were present in RVLM neurons and that Klotho was localized in the same neurons as FGFR1. These results suggest that Klotho and FG23 regulate the activity of RVLM neurons. Klotho may reduce the activity of RVLM neurons via stimulating Na+/K+-ATPase on those neurons while FGF23 may activate those neurons via FGFR1.
... Gravitational effects on invertebrate cardiovascular and respiratory systems are likely to be widely distributed among invertebrates and to have broad influence on morphological and physiological evolution. gravity | invertebrate | insect | cardiovascular system | respiratory system I n vertebrates, gravity effects are commonly experienced when an animal changes body orientation, resulting in changing pressures throughout the body governed by principles of fluid mechanics, with pressure differences directly proportional to vertical height (1)(2)(3)(4)(5). Many insects change body positions routinely and often, especially during locomotion; for example, ants and roaches routinely walk up and down trees and walls (6). ...
... Vertebrates counteract gravity effects on blood partly by varying heart rates in response to baroreceptor cardiac reflexes (1). Because the heart of grasshoppers pumps primarily in a cranial direction (12), we hypothesized that heart rates would be higher in head-up than head-down positions to counteract gravity effects on hemolymph. ...
Significance
While it has long been known that vertebrates rely on compensatory responses to gravity with changing body orientation, this topic has not been previously studied in invertebrates. Here, we use synchrotron X-ray imaging and radio-tracing to demonstrate that body orientation has dramatic effects on hemolymph and air distribution in grasshoppers, and that grasshoppers exhibit similar physiological responses to gravity as vertebrates. Our findings suggest that gravity-driven cardiovascular responses may be ancient and widely shared among animals, opening the door for invertebrates as model systems for investigation of cellular and systemic mechanisms of gravity responses. Furthermore, future physiological studies of arthropods should control for body position.
... in the nucleus tractus solitarius and rostral ventrolateral medulla. 100 Hypertensive rats exhibit neurochemical markers of elevated opioid activity in the spinal cord and other CNS nuclei. 41, 101 Interestingly, it has been proposed that in the presence of essential hypertension, there is reduced hypothalamic sensitivity to endogenous opioids, which leads to: (1) a reduction in baroreflex inhibition of the sympathetic output; (2) an increase and prolongation of arterial pressure response to environmental stimuli; (3) prolonged baroreceptor stimulation; and finally, (4) an excessive release of endogenous opioids. ...
... Noteworthy, nucleus tractus solitarius, rostral ventrolateral medulla, and caudal ventrolateral medulla contain noradrenergic and adrenergic neurons. 100,107 Microinjection of the α 2 -adrenergic receptor agonist clonidine into nucleus tractus solitarius produces analgesia mediated by opioid receptors in normotensive rats and spontaneously hypertensive rats. 108 Of note, morphine administration to the region of the nucleus tractus solitarius produces naloxone-reversible analgesia in rats. ...
Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain homeostasis by coordinating physiologic responses to external and internal stimuli. While it is recognized that carotid and cardiopulmonary baroreceptor reflexes modulate autonomic output to mitigate excessive fluctuations in arterial blood pressure and to maintain intravascular volume, increasing evidence suggests that baroreflex pathways also project to key regions of the central nervous system that regulate somatosensory, somatomotor, and central nervous system arousal. In addition to maintaining autonomic homeostasis, baroreceptor activity modulates the perception of pain, as well as neuroimmune, neuroendocrine, and cognitive responses to physical and psychologic stressors. This review summarizes the role that baroreceptor pathways play in modulating acute and chronic pain perception. The contribution of baroreceptor function to postoperative outcomes is also presented. Finally, methods that enhance baroreceptor function, which hold promise in improving postoperative and pain management outcomes, are presented.
... Over the last 20 years, in several reviews of sympathetic control of the cardiovascular system and the integration mechanisms of baroreceptor and chemoreceptor reflexes and the central pathways that support them, both in conscious animals and under anaesthesia, several authors agree in assigning an important role to area A5 in sympathoexcitatory control [58][59][60][61][62]. In addition, recent work by our research group [8,28,32,62,63] highlights this sympathoexcitatory activity by demonstrating the involvement of area A5 in the defence response elicited by the hypothalamic defence area and the dorsolateral periaqueductal grey matter. ...
Area A5 is a noradrenergic cell group in the brain stem characterised by its important role in triggering sympathetic activity, exerting a profound influence on the sympathetic outflow, which is instrumental in the modulation of cardiovascular functions, stress responses and various other physiological processes that are crucial for adaptation and survival mechanisms. Understanding the role of area A5, therefore, not only provides insights into the basic functioning of the sympathetic nervous system but also sheds light on the neuronal basis of a number of autonomic responses. In this review, we look deeper into the specifics of area A5, exploring its anatomical connections, its neurochemical properties and the mechanisms by which it influences sympathetic nervous system activity and cardiorespiratory regulation and, thus, contributes to the overall dynamics of the autonomic function in regulating body homeostasis.
... The mechanisms of acute hypertensive response are different from that of HD after carotid revascularization. Acute hypertensive responses can be caused by a Cushing response to the mass effect of brain [15][16][17][18][19] In the current study, the following did not affect HD: old age, a past history of heart failure, coronary artery disease, severe stenosis of the carotid artery, high level carotid stenosis, and opposite carotid occlusion. To date, risk factors of HD include old age, heart failure, previous myocardial infarction, absence of chronic obstructive pulmonary dis- Fourth, we had no access to data regarding preoperative cardiology evaluation, 33 HD duration, and clinical events. ...
Background Carotid revascularization is frequently complicated by hemodynamic depression (HD), which can increase the risk of stroke or vascular death. However, no studies yet exist describing the correlation between the timing of carotid revascularization and HD. The present study investigated whether carotid revascularization in the early phase of a stroke had an impact on the incidence of HD. Methods A retrospective study of consecutive ischemic stroke patients who underwent carotid revascularization was designed to compare the incidence of HD between early and late carotid revascularization. Early carotid revascularization was defined as carotid artery stenting or endarterectomy within two weeks of stroke onset. HD was defined as hypotension or bradycardia within five days of carotid revascularization. Results Of 69 carotid revascularizations, HD occurred in 29 (42.0%). The incidence of HD did not differ significantly between the early and late phase groups (48.0% vs. 38.6%, respectively, P=0.449). Patients with HD had undergone more carotid artery stenting than those without HD (79.3% vs. 35%, respectively, P
... The action potentials generated in the periphery depolarizes the afferent nerves towards the nucleus of the solitary tract (NTS) [141], which is an integrative region [28]. NTS stimulates the dorsal nucleus and ambiguous nucleus of the vagus, two areas containing parasympathetic preganglionic cell bodies capable of increasing cardiac vagal tone [76,146]. This stimulus inhibits sympathetic premotor neurons located in rostral ventrolateral medulla, resulting in sympathetic activity reduction on heart and blood vessels [145]. ...
The cardiac baroreflex is an autonomic neural mechanism involved in the modulation of the cardiovascular system. It influences the heart rate and peripheral vascular resistance to preserve arterial blood pressure within a narrow variation range. This mechanism is mainly controlled by medullary nuclei located in the brain stem. However, supramedullary areas, such as the ventral portion of medial prefrontal cortex (vMPFC), are also involved. Particularly, the glutamatergic NMDA/NO pathway in the vMPFC can facilitate baroreflex bradycardic and tachycardic responses. In addition, cannabinoid receptors in this same area can reduce or increase those cardiac responses, possibly through alteration in glutamate release. This vMPFC network has been associated to cardiovascular responses during stressful situations. Recent results showed an involvement of glutamatergic, nitrergic, and endocannabinoid systems in the blood pressure and heart rate increases in animals after aversive conditioning. Consequently, baroreflex could be modified by the vMPFC neurotransmission during stressful situations, allowing necessary cardiovascular adjustments. Remarkably, some mental, neurological and neurodegenerative disorders can involve damage in the vMPFC, such as posttraumatic stress disorder, major depressive disorder, Alzheimer’s disease, and neuropathic pain. These pathologies are also associated with alterations in glutamate/NO release and endocannabinoid functions along with baroreflex impairment. Thus, the vMPFC seems to play a crucial role on the baroreflex control, either during pathological or physiological stress–related responses. The study of baroreflex mechanism under such pathological view may be helpful to establish causality mechanisms for the autonomic and cardiovascular imbalance found in those conditions. It can explain in the future the reasons of the high cardiovascular risk some neurological and neurodegenerative disease patients undergo. Additionally, the present work offers insights on the possible contributions of vMPFC dysfunction on baroreflex alterations, which, in turn, may raise questions in what extent other brain areas may play a role in autonomic deregulation under such pathological situations.
... This observation is consistent with previous works speculating on a chemoreceptor role for the A5 region due to its connectivity with the retrotrapezoid nucleus (RTN), a nucleus that is involved in chemoreception. Therefore, the inhibition of these projections could lead to the decrease of respiratory rate at rest after inhibiting or lesioning the A5 region [26,27]. ...
Stimulation of the dorsolateral periaqueductal grey matter (dlPAG) in rats evokes an active defensive behaviour together with a cardiorespiratory response characterised by tachypnoea, tachycardia and hypertension. The dlPAG neurons involved in these responses are excitatory, presumably glutamatergic, due to the presence of vesicular glutamate transporter VGLUT2 within their axon terminals. Previously, our group described a functional interaction between dlPAG and the pontine A5 region. Accordingly, in the present work, in order to characterize the role of glutamate within this interaction, experiments were carried out in spontaneously breathing anaesthetized rats (sodium pentobarbitone 60 mg/kg i.p., suplemented with 20 mg/kg i.p.). The cardiorespiratory response evoked by electrical stimulation of the dlPAG (1 ms pulses, 20–50 μA, given at 100 Hz, during 5 s) was analysed before and after the microinjection, within the A5 region, of either kynurenic acid (non-specific glutamate receptor antagonist; 5–10 nmol), DAP-5 (NMDA antagonist; 1 pmol), CNQX (non-NMDA antagonist; 1 pmol) or MCPG (metabotropic antagonist; 0,1 nmol). Kynurenic acid decreased the intensity of both the tachypnoea (p < 0,001) and tachycardia (p < 0,001) induced by dl-PAG stimulation. Blockade of no-NMDA receptors reduced the increase of respiratory frequency, heart rate and pressor response to dl-PAG stimulation (p < 0,01, p < 0,001, p < 0,05 respectively). Blockade of either NMDA or metabotropic receptors reduced the dlPAG-evoked tachycardia and pressor response (p < 0,01; p < 0,05 respectively). These results suggest a neuromodulatory role for A5 region via glutamate neurotransmission of the dlPAG-evoked cardiorespiratory response, confirming the role of the ventrolateral pons in the neuronal circuits involved in respiratory and heart rate control.
... Mechanoreceptors present in the aortic and carotid sinuses respond to blood pressure, increasing firing rates in response to increased pressure and hypertension Ghitani and Chesler, 2019;Min et al., 2019). This signal, carried through either cranial nerve IX (glossopharyngeal nerve) or X (vagus nerve), synapses onto the nucleus of the solitary tract (NST) in the brainstem (Pilowsky and Goodchild, 2002). Activation of the NST both decreases sympathetic activity through brainstem projections to the intermediolateral nucleus of the spinal cord and increases vagal outflow. ...
The central nervous system (CNS) exerts a strong regulatory influence over the cardiovascular system in response to environmental demands. Floatation-REST (Reduced Environmental Stimulation Therapy) is an intervention that minimizes stimulation from the environment, yet little is known about the autonomic consequences of reducing external sensory input to the CNS. We recently found that Floatation-REST induces a strong anxiolytic effect in anxious patients while paradoxically enhancing their interoceptive awareness for cardiorespiratory sensations. To further investigate the physiologic nature of this anxiolytic effect, the present study measured acute cardiovascular changes during Floatation-REST using wireless and waterproof equipment that allowed for concurrent measurement of heart rate, heart rate variability (HRV), breathing rate, and blood pressure. Using a within-subjects crossover design, 37 clinically anxious participants with high levels of anxiety sensitivity and 20 non-anxious comparison participants were randomly assigned to undergo a 90-min session of either Floatation-REST or an exteroceptive comparison condition that entailed watching a relaxing nature film. Measures of state anxiety and serenity were collected before and after each session, while indices of autonomic activity were measured throughout each session. HRV was calculated using both time-series and frequency domain analyses. Linear mixed-effects modeling revealed a significant main effect of condition such that relative to the film condition, Floatation-REST elicited significant decreases (p < 0.001) in diastolic blood pressure, systolic blood pressure, breathing rate, and certain metrics of HRV including the standard deviation of the interbeat interval (SDNN), low-frequency HRV, and very low-frequency HRV. Heart rate showed a non-significant trend (p = 0.073) toward being lower in the float condition, especially toward the beginning of the session. The only metric that showed a significant increase during Floatation-REST was normalized high-frequency HRV (p < 0.001). The observed physiological changes were consistent across both anxious and non-anxious participants, and there were no significant group by condition interactions. Blood pressure was the only cardiac metric significantly associated with float-related reductions in state anxiety and increases in serenity. These findings suggest that Floatation-REST lowers sympathetic arousal and alters the balance of the autonomic nervous system toward a more parasympathetic state.
Clinical trial registration
[https://clinicaltrials.gov/show/NCT03051074], identifier [NCT03051074].
... This observation is consistent with previous works speculating on a chemoreceptor role for the A5 region due to its connectivity with the retrotrapezoid nucleus (RTN), a nucleus that is involved in chemoreception. Therefore, the inhibition of these projections could lead to the decrease of respiratory rate at rest after inhibiting or lesioning the A5 region [27,28]. ...
Stimulation of the dorsolateral periaqueductal grey matter (dlPAG) in rats evokes an active defensive behaviour together with a cardiorespiratory response characterised by tachypnoea, tachycardia and hypertension. The dlPAG neurons involved in these responses are excitatory, presumably glutamatergic, due to the presence of vesicular glutamate transporter VGLUT2 within their axon terminals. Previously, our group described a functional interaction between dlPAG and the pontine A5 region. Accordingly, in the present work, in order to characterize the role of glutamate within this interaction, experiments were carried out in spontaneously breathing anaesthetized rats (sodium pentobarbitone 60 mg/kg i.p., suplemented with 20 mg/kg i.p.). The cardiorespiratory response evoked by electrical stimulation of the dlPAG (1ms pulses, 20-50 mA, given at 100 Hz, during 5s) was analysed before and after the microinjection, within the A5 region, of either kynurenic acid (non-specific glutamate receptor antagonist; 5-10 nmol), DAP-5 (NMDA antagonist; 1 pmol), CNQX (non-NMDA antagonist; 1 pmol) or MCPG (metabotropic antagonist; 0,1 nmol). Kynurenic acid decreased the intensity of both the tachypnoea (p<0,001) and tachycardia (p<0,001) induced by dl-PAG stimulation. Blockade of no-NMDA receptors reduced the increase of respiratory frequency, heart rate and pressor response to dl-PAG stimulation (p<0,01, p<0,001, p<0,05 respectively). Blockade of either NMDA or metabotropic receptors reduced the dlPAG-evoked tachycardia and pressor response (p<0,01; p<0,05 respectively). These results suggest a neuromodulatory role for A5 region via glutamate neurotransmission of the dlPAG-evoked cardiorespiratory response, confirming the role of the ventrolateral pons in the neuronal circuits involved in respiratory and heart rate control.
... The OB connects with different telencephalic, midbrain, diencephalic and brainstem regions, some of which are closely involved in the regulation of cardiovascular activity [12,13]. In this sense, a relevant projection is that to the nucleus tractus solitarius, at the level of the brainstem, which is considered the primary site for the integration of visceral afferents such as those arising from the baroreflex [14,15]. In addition, limbic system areas like the amygdala, septum, piriformis, and orbitofrontal cortex also receive inputs from the OB [4,16]. ...
Numerous studies have addressed the participation of the central nervous system in the physiological regulation of blood pressure and in the development and/or maintenance of hypertension. The central nervous system plays a key role in the short-term regulation of blood pressure although recent investigations also support its participation in the long-term modulation. Diverse brain regions and areas like the rostral ventrolateral medulla, the nucleus of the solitary tract, the locus coeruleus, amygdala and hypothalamus are
intimately involved in the control of cardiovascular activity. Nevertheless, little is known about the role of the olfactory bulb. This mini review summarizes current knowledge regarding the participation of this telencephalic region in the regulation of cardiovascular
activity in physiological and pathophysiological conditions.
... From here, inhibitory and excitatory neurons synapse to the caudal and rostral ventrolateral medulla to control preganglionic excitatory neurons located in the intermediolateral nucleus at the spinal cord. The ultimate target is the postganglionic neurons residing in the sympathetic cervical and stellate ganglia [49,50]. These postganglionic neurons directly innervate the pacemaker cells and release the noradrenaline that accelerates the pacemaker intrinsic firing rate. ...
The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life. Pacemaker rate is constantly tuned by the autonomous nervous system to maintain body homeostasis. Sympathetic and parasympathetic terminals act over the pacemaker cells as the accelerator and the brake pedals, increasing or reducing the firing rate of pacemaker cells to match physiological demands. Despite the remarkable reliability of this tissue, the pacemaker is not exempt from the detrimental effects of aging. Mammals experience a natural and continuous decrease in the pacemaker rate throughout the entire lifespan. Why the pacemaker rhythm slows with age is poorly understood. Neural control of the pacemaker is remodeled from birth to adulthood, with strong evidence of age-related dysfunction that leads to a downshift of the pacemaker. Such evidence includes remodeling of pacemaker tissue architecture, alterations in the innervation, changes in the sympathetic acceleration and the parasympathetic deceleration, and alterations in the responsiveness of pacemaker cells to adrenergic and cholinergic modulation. In this review, we revisit the main evidence on the neural control of the pacemaker at the tissue and cellular level and the effects of aging on shaping this neural control.
... However, the direct administration of the α2-adrenergic receptor agonist clonidine into the NTS results in naloxone-sensitive hypotension, bradycardia, and analgesia in spontaneously hypertensive rats and some normotensive rat strains (286). Finally, the NTS, RVLM, and CVLM, which are relay nuclei for baroreflexes, contain noradrenergic and adrenergic neurons (414,521). Although there is no direct evidence in human subjects, elevated AP within the normotensive range is associated with increased pain tolerance along with higher circulating levels of norepinephrine (453). ...
Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain cardiovascular homeostasis by coordinating the responses to external and internal environmental stressors. While it is well known that carotid and cardiopulmonary baroreceptors modulate sympathetic vasomotor and parasympathetic cardiac neural autonomic drive, to avoid excessive fluctuations in vascular tone and maintain intravascular volume, there is increasing recognition that baroreceptors also modulate a wide range of non-cardiovascular physiological responses via projections from the nucleus of the solitary tract to regions of the central nervous system, including the spinal cord. These projections regulate pain perception, sleep, consciousness, and cognition. In this article, we summarize the physiology of baroreceptor pathways and responses to baroreceptor activation with an emphasis on the mechanisms influencing cardiovascular function, pain perception, consciousness, and cognition. Understanding baroreceptor-mediated effects on cardiac and extra-cardiac autonomic activities will further our understanding of the pathophysiology of multiple common clinical conditions, such as chronic pain, disorders of consciousness (e.g., abnormalities in sleep-wake), and cognitive impairment, which may result in the identification and implementation of novel treatment modalities. © 2021 American Physiological Society. Compr Physiol 11:1373-1423, 2021.
... This increased cardiac output has stimulated baroreceptor, as a result of which sympathetic discharge had decreased. [13,14] Another reason may be a person's anxiety level was less as this procedure was done using a tilt table. ...
Context: Sirshasan is supposed to increase blood flow to the brain and considered to be beneficial for intellectual function, however
mastering these techniques may be difficult. Aims: To see the effect of headstand using a tilt table on heart rate variability (HRV).
Settings and Design: A cross‑sectional study that was done on 26 healthy volunteers. Methods and Material: HRV was assessed in
the supine position and 30° head tilt position for 5 min. HRV recording was done on the power lab (AD Instruments P Ltd, Castle
Hill Australia). The tilt table used was Medica Podium, New Delhi, HLT‑200. Statistical analysis used: Paired t‑test. Results: All the
HRV parameters showed non‑significant change except low‑frequency parameters which showed significant change during head
tilt. Conclusions: Headstand to a 30° using tilt table cause a decrease in the autonomic activity which is mainly because of decrease
in sympathetic activity
... This increased cardiac output has stimulated baroreceptor, as a result of which sympathetic discharge had decreased. [13,14] Another reason may be a person's anxiety level was less as this procedure was done using a tilt table. ...
Abstract
Context: Sirshasan is supposed to increase blood flow to the brain and considered to be beneficial for intellectual function, however
mastering these techniques may be difficult. Aims: To see the effect of headstand using a tilt table on heart rate variability (HRV).
Settings and Design: A cross‐sectional study that was done on 26 healthy volunteers. Methods and Material: HRV was assessed in
the supine position and 30° head tilt position for 5 min. HRV recording was done on the power lab (AD Instruments P Ltd, Castle
Hill Australia). The tilt table used was Medica Podium, New Delhi, HLT‐200. Statistical analysis used: Paired t‐test. Results: All the
HRV parameters showed non‐significant change except low‐frequency parameters which showed significant change during head
tilt. Conclusions: Headstand to a 30° using tilt table cause a decrease in the autonomic activity which is mainly because of decrease
in sympathetic activity.
Keywords: Headtilt, heart rate variability, Yoga
... Baroreceptor oscillations around 0.1 Hz contribute to the lowfrequency component of HRV (Swenne, 2013). Damage to the NST and denervation of vagal fibers carrying baroreceptor information eliminates baroreflex oscillations and results in an increase in average arterial blood pressure and large fluctuations in blood pressure variability (Lanfranchi & Somers, 2002;Pilowsky & Goodchild, 2002). Furthermore, beat-by-beat fluctuations in blood pressure (diastolic versus systolic) cause opposing changes in muscle sympathetic nerve activity (MSNA), highlighting the role that the baroreceptor circuit has on both the cardiac pulse synchronous and slower-scale responses (Eckberg, 2004;Macefield, et al., 2013). ...
Interoception concerns the afferent vagal and spinothalamic lamina I systems, and their projection to regions of the brain comprising the central autonomic network (CAN). At the level of the cortex, the CAN includes regions such as the insula, medial prefrontal and cingulate
cortices, which interact with subcortical and brainstem networks to regulate autonomic, neuroendocrine, immune, and other visceral functions of the body. Interoception is an important
concept linking ‘primitive’ homeostatic functions of the brain to its ‘high-order’ cognitive functions. This view is supported by an increasing body of experimental evidence indicating the
relevance of interoceptive neural systems to motivational drives, mood, emotion, self-awareness, body-ownership, somatic disorders and psychopathology. However, constructs, paradigms and
other methodology for investigating neural interoception in humans require additional development and validation. Additionally, neural interoceptive processing in psychopathology has not been thoroughly characterized, hence limiting the translational relevance of findings
from this field. Given the emerging role of interoception in many psychological functions, a key question would be whether we could access and modulate neural interoceptive systems in
humans. Hence, the first aim of this thesis was to investigate whether interoceptive neural processing can be modulated through non-invasive stimulation of the cortex or through peripheral nerve stimulation. To accomplish these aims, transcranial magnetic stimulation (TMS) and transcutaneous vagus nerve stimulation (tVNS) were used to modulate heart-brain interactions. A second aim of this thesis was to determine whether traumatic stress exposure in
female psychiatric patients alters the degree to which neural interoceptive systems are engaged when asked to attend to somatic and visceral feelings during mindful breathing.
**STUDY 1** is a randomized, sham-controlled investigation to determine whether tVNS affects cardiovagal responses and neurocardiac integration in interoceptive cortices. The ability of tVNS to evoke cardiovagal responses was mixed. tVNS was found to increase baroreceptor sensitivity, but not heart rate variability, whereas both sham and tVNS elicited reductions in heart rate. At the level of the brain, tVNS increased electroencephalographic (EEG) functional
connectivity between regions of the CAN. In particular, stronger functional connectivity was obtained for the right somatosensory and anterior insula in the beta frequency band. The effect of
tVNS on an evoked potential reflecting neural cardiac interoceptive processing (the heart-evoked potential or ‘HEP’) was also assessed. At the sensor-levels, tVNS was associated with greater HEP negativity in left-lateralized frontal, temporal, parietal and central electrodes. Source localized functional connectivity between regions where HEPs have been observed intracranially revealed patterns of greater and lesser connectivity in several frequency bands. Insula-prefrontal
connectivity features correlated with heart rate during tVNS. Altogether, the results indicate that tVNS modulates neural systems relevant to cardiac interoceptive processing, which may be
relevant to the mechanisms of action by which tVNS improves cardiovascular autonomic function in somatic and psychiatric conditions.
**STUDY 2** applied transcranial magnetic stimulation to the right frontotemporal cortex to test whether modulating cortical excitability within regions putatively accessing the CAN alters cardiovascular autonomic responses. Intermittent theta-burst stimulation increased vagally mediated heart rate variability, but this effect appears to have been confounded by stimulation induced state anxiety. However, continuous theta-burst stimulation increased pulse-transit time
latency, an effect that was not explained by stimulation-induced anxiety. This study supports the use of TMS for modulating ‘top-down’ neurocardiac integration, and discusses approaches for optimizing TMS for investigating neural interoceptive and visceromotor processing, and its translational relevance.
**STUDY 3** investigated the functional MRI correlates of respiratory interoception in women in residential treatment for stimulant dependence (SUD) who have varying histories of physical,
psychological and/or sexual trauma. A subset of patients had a concurrent diagnosis of posttraumatic stress disorder (PTSD). Reduced functional connectivity of an interoception-linked
network was found in women with SUD-PTSD comorbidity. Specifically, an orbitofrontal network showed diminished strength of correlation with the insular, somatosensory and cognitive control regions during a mindfulness-based breathing task. Additionally, orbitofrontal network
strength was negatively associated with sexual violence exposure beyond the contribution of PTSD diagnosis alone. This study contributes to scientific understanding concerning interoceptive dysfunction in psychopathology and potential mechanisms through which psychobehavioral techniques such as mindfulness may improve mental health.
OVERALL, these results of this dissertation support the utility of non-invasive cortical or peripheral nerve stimulation in accessing and modulating neural interoceptive systems related to cardiovascular autonomic regulation. The results also support the utility of using certain psychobehavioral techniques, such as mindfulness, to engage interoceptive brain systems, and they highlight how different psychopathological conditions may respond differently to treatment
modalities involving interoceptive manipulations. Altogether, this work enhances basic understanding of brain-body interactions, and advances the translational value that can be derived from interoceptive theoretical frameworks.
... Sensory afferents from the pulmonary stretch receptors, chemoreceptors, and arterial baroreceptors terminate in the nucleus of the solitary tract which controls the autonomic outflow via nucleus ambiguus and caudal ventrolateral medulla[96,221]. Findings from studies on lung transplant patients (i.e. with denervated lung) suggest that vagal afferent signals from the pulmonary stretch receptors may contribute to RSA during breathing at a normal frequency[111][112][113]. ...
Pain is the most common symptom for which people seek medical care. Chronic pain is common worldwide, and often not treated adequately, thereby leading to reduced quality of life and high healthcare costs. Recently, there has been increasing attention toward the complexity and biopsychosocial nature of pain, and the need for multidisciplinary pain management has been increasingly acknowledged. Various mind-body interventions are being used for pain management, and some of them have been found to be effective. Slow, deep breathing is a commonly applied mind-body intervention for the management of pain. Some of the previous experimental studies found an influence of slow, deep breathing on pain outcomes. However, the results have not been consistent across studies and the underlying mechanisms are largely unknown. Some of the proposed mechanisms are emotional and cognitive modulation of pain perception and stimulation of the arterial baroreceptors and pulmonary vagal afferents. The aim of this Ph.D. project was to evaluate the effect of slow, deep breathing on pain perception in healthy subjects and to investigate the underlying psychophysiological mechanisms. To further investigate the arterial baroreceptors and pulmonary vagal afferents as possible mechanisms for the hypoalgesic effects of slow, deep breathing, we first determined whether adding an inspiratory threshold load to slow, deep breathing can enhance its effects on the cardiovascular responses (Chapter 3). We found an increase in the amplitude of blood pressure variation accompanied by an increase in respiratory sinus arrhythmia in response to increasing loads, suggesting that applying inspiratory threshold loads during slow, deep breathing results in stronger stimulation of the arterial baroreceptors. In a complementary study (Chapter 4) we compared four slow, deep breathing techniques (loaded slow, deep breathing, left and right unilateral nostril breathing, and pursed-lips breathing) with regards to psychophysiological responses. We found that loaded slow, deep breathing and pursed-lips breathing techniques are associated with a larger amplitude of blood pressure variation and respiratory sinus arrhythmia, suggesting stronger stimulation of the arterial baroreceptors with these techniques. Moreover, the pursed-lips breathing technique was associated with lower emotional arousal and more pleasantness and a sense of control. Based on these two studies, we investigated the effect of loaded slow, deep breathing and pursed-lips breathing on somatic pain perception (Chapter 5). We found that loaded slow, deep breathing, but not pursed-lips breathing, reduces pain intensity compared with a control condition. However, physiological responses to loaded slow, deep breathing did not mediate its effect on pain perception. Finally, we evaluated the effect of slow, deep breathing on visceral pain perception. We found that slow, deep breathing reduces visceral pain intensity compared with uncontrolled breathing, but the effect is similar to controlled breathing at normal breathing frequency. Physiological and emotional responses to slow, deep breathing did not mediate its effects on visceral pain perception. The studies in this PhD project helped us to better test and understand the role of different psychophysiological mechanisms in somatic and visceral pain modulation by slow, deep breathing. Overall, our studies do not support the role of baroreceptors and vagal afferents stimulation as possible mechanisms mediating the effect of slow, deep breathing on pain perception, suggesting other potential mechanisms, notably attentional modulation may be at play. Further experimental studies are required to better investigate the role of attentional and emotional modulation on pain inhibition by breathing exercises. Also, clinical studies are required to test whether breathing exercises can modulate pain perception in various patient populations and if so, the underlying mechanisms will need elucidation.
... Nevertheless, we checked whether the nucleus of the solitary tract (NTS), the baroreflex control center (40), would provide inputs to the LPB to modulate vasodilation. Activation of glutamatergic NTS→LPB pathway indeed induced hypothermia but did not affect tail vasodilation ( fig. ...
Heat defense is crucial for survival and fitness. Transmission of thermosensory signals into hypothalamic thermoregulation centers represents a key layer of regulation in heat defense. Yet, how these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that lateral parabrachial nucleus (LPB) glutamatergic prodynorphin and cholecystokinin neuron populations are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuits with downstream preoptic hypothalamic neurons to inhibit the thermogenesis of brown adipose tissues (BATs) and activate tail vasodilation, respectively. Both circuits are activated by warmth and can limit fever development. The prodynorphin circuit is further required for regulating energy expenditure and body weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, inhibition of BAT thermogenesis and activation of vasodilation.
... Nevertheless, we checked whether the nucleus of the solitary tract (NTS), the baroreflex control center (40), would provide inputs to the LPB to modulate vasodilation. Activation of glutamatergic NTS→LPB pathway indeed induced hypothermia but did not affect tail vasodilation ( fig. ...
Heat defense is crucial for survival and fitness. Transmission of thermosensory signals into hypothalamic thermoregulation centers represents a key layer of regulation in heat defense. Yet, how these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that lateral parabrachial nucleus (LPB) glutamatergic prodynorphin and cholecystokinin neuron populations are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuits with downstream preoptic hypothalamic neurons to inhibit the thermogenesis of brown adipose tissues (BATs) and activate tail vasodilation, respectively. Both circuits are activated by warmth and can limit fever development. The prodynorphin circuit is further required for regulating energy expenditure and body weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, inhibition of BAT thermogenesis and activation of vasodilation.
... Similarly, the area postrema (AP) in the brainstem is another circumventricular organ that projects to the preautonomic neurons of the RVLM [58,59]. Finally, the nucleus of the solitary tract (NTS) in the brainstem can directly sense cardiovascular function through afferents arising from the aortic arch and the carotid sinus which input on the NTS [60]. Those autonomic brain regions that sense, control, and regulate cardiovascular physiology are known as cardiovascular control centers, where Ang II can regulate cardiovascular physiology via acting on those regions [4,61]. ...
Purpose of review:
To review recent data that suggest opposing effects of brain angiotensin type-1 (AT1R) and type-2 (AT2R) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of AT1R and anti-hypertensive and anti-inflammatory actions of AT2R. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension.
Recent findings:
The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain AT1R and AT2R, both of which are expressed in or adjacent to brain regions that control BP. Activation of AT1R within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that AT1R and AT2R have opposing actions on BP suggests that AT1R and AT2R may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain AT1R and AT2R mediate neuroinflammatory responses remain unclear. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.
... Indeed, decreased pain sensitivity can be reversed by lowering BP in genetically hypertensive rats [13][14][15], although some evidence suggests that decreased pain sensitivity in hypertensive humans may not be reversed following anti-hypertensive treatment [16]. There is also a role for endogenous opioid activity in hypertension-related reductions in pain sensitivity [13,15,17,18], including evidence of increased endogenous opioid activity associated with baroreceptor stimulation [19]. ...
PurposeAcute pain and resting arterial blood pressure (BP) are positively correlated in patients with chronic pain. However, it remains unclear whether treatment for chronic pain reduces BP. Therefore, in a retrospective study design, we tested the hypothesis that implantation of an epidural spinal cord stimulator (SCS) device to treat chronic pain would significantly reduce clinic pain ratings and BP and that these reductions would be significantly correlated.Methods
Pain ratings and BP in medical records were collected before and after surgical implantation of a SCS device at the University of Iowa Hospitals and Clinics between 2008 and 2018 (n = 213).ResultsReductions in pain rating [6.3 ± 2.0 vs. 5.0 ± 1.9 (scale: 0–10), P < 0.001] and BP [mean arterial pressure (MAP) 95 ± 10 vs. 89 ± 10 mmHg, P < 0.001] were statistically significant within 30 days of SCS. Interestingly, BP returned toward baseline within 60 days following SCS implantation. Multiple linear regression analysis showed that sex (P = 0.007), baseline MAP (P < 0.001), and taking hypertension (HTN) medications (P < 0.001) were significant determinants of change in MAP from baseline (Δ MAP) (model R2 = 0.33). After statistical adjustments, Δ MAP was significantly greater among women than among men ( − 7.2 ± 8.5 vs. − 3.9 ± 8.5 mmHg, P = 0.007) and among patients taking HTN medications than among those not taking hypertension medications ( − 10.1 ± 8.7 vs. − 3.9 ± 8.5 mmHg, P < 0.001), despite no group differences in change in pain ratings.Conclusions
Together, these findings suggest that SCS for chronic pain independently produces clinically meaningful, albeit transient, reductions in BP and may provide a rationale for studies aimed at reducing HTN medication burden among this patient population.
... The RVLM is a major brainstem nucleus and considered to be a common projection pathway of presympathetic neurons descending to the spinal cord to regulate sympathetic outflow and cardiovascular function (10,25). In addition, the RVLM receives inhibitory projections from the nucleus tractus solitarius and the caudal ventrolateral medulla, which modulates arterial baroreflex regulation of HR, peripheral resistance, and sympathetic nerve activity (43). We have previously shown that selective deletion of the Nrf2 gene in the RVLM of normal Nrf2 floxed mice leads to an increase in RVLM reactive oxygen species (ROS) concomitant with a downregulation of antioxidant enzymes (23). ...
CHF is associated with global oxidative stress, which contributes to sympatho-excitation. Increased reactive oxygen species (ROS) in the brain accumulate within neurons and lead to enhanced neuronal excitability. Exercise training (ExT) is associated with a reduction of oxidative stress by upregulation of antioxidant enzymes. The link between ExT and antioxidant enzyme expression in the brain of animals with CHF is not clear. We hypothesized that ExT enhances transcription and translation of the Nuclear Factor (Erythroid derived 2)-Like 2 (Nrf2) gene, a master transcription factor that modulates antioxidant enzyme gene expression, in the rostral ventrolateral medulla (RVLM) of mice with CHF. Mice were divided into the following groups: Sham sedentary (Sham-Sed), Sham-ExT, CHF-Sed and CHF-ExT. After 8 weeks of ExT, we measured Nrf2 and NAD(P)H dehydrogenase [quinone] 1 (NQO-1) message and protein expression along with maximal exercise tolerance and urinary norepinephrine (NE) excretion. We found that Nrf2 and NQO-1 mRNA and protein expression in the RVLM were lower in CHF-Sed mice compared with Sham-Sed. ExT attenuated the CHF-induced reduction of Nrf2 and NQO-1 mRNA and protein expression in the RVLM. NE excretion was higher in CHF-Sed mice compared with Sham-Sed (666.8 ± 79.3 ng/24 h, n=6 versus 397.8 ± 43.7 ng/24 h, p=0.04). CHF-ExT mice exhibited reduced urinary NE excretion compared with CHF-Sed (360.7 ± 41.7 ng, n=4 versus 666.8 ± 79.3 ng, n=6; p=0.03). We conclude that ExT-induced upregulation of Nrf2 in the RVLM contributes to the beneficial effects of ExT on sympathetic function in the heart failure state.
... A recent study using pharmacological autonomic blockade (i.e., with antimuscarinic, anticholinergic, and beta blocker) supports the idea that the increase in RSA during SDB reflects an increase in cardiac vagal modulation (Kromenacker et al., 2018). Sensory afferents from the pulmonary stretch receptors, chemoreceptors, and arterial baroreceptors terminate in the nucleus tractus solitarius which controls the autonomic outflow via nucleus ambiguus and caudal ventrolateral medulla (Kubin, Alheid, Zuperku, & McCrimmon, 2006;Pilowsky & Goodchild, 2002). Findings from studies on lung transplant patients (i.e., with denervated lung) suggest that vagal afferent signals from the pulmonary stretch receptors may contribute to RSA during breathing at a normal frequency (Fontolliet et al., 2018;Khayat, Przybylowski, Meyer, Skatrud, & Morgan, 2004;Taha, Simon, Dempsey, Skatrud, & Iber, 1995). ...
Slow, deep breathing is being used as a self-management intervention for various health conditions including pain and hypertension. Stimulation of the arterial baroreceptors and increased vagal modulation are among the proposed mechanisms for the therapeutic effects of slow, deep breathing. We investigated whether adding inspiratory threshold load can enhance the cardiovascular responses to controlled breathing at the frequency of 0.1 Hz, a common form of slow, deep breathing. Healthy volunteers (N = 29) performed controlled breathing at 0.1 Hz (6 breaths/minute) without load and with inspiratory threshold loads of 5 cmH2 O and 10 cmH2 O. Respiratory airflow, heart rate, and blood pressure were continuously recorded. The amplitude of the systolic blood pressure variation during respiratory cycles increased with increasing loads. Respiratory sinus arrhythmia was higher during controlled breathing at 0.1 Hz with the load of 10 cmH2 O compared to without load. Baroreflex sensitivity was not affected by loads. The effect of loads on respiratory sinus arrhythmia was mediated by increasing the amplitude of systolic blood pressure variation during respiratory cycles. These results suggest that applying small inspiratory threshold loads during controlled breathing at 0.1 Hz increases cardiac vagal modulation by this breathing exercise. This effect seems to be mediated by stronger stimulation of the arterial baroreceptors because of larger systolic blood pressure swings along the respiratory cycle. The potential benefit of long-term practice of controlled breathing at 0.1 Hz with inspiratory threshold loads on baroreflex function and cardiac vagal control needs to be investigated, particularly in pain and hypertension patients.
... The NTS acts as a key cardiovascular integration center, and functions to activate inhibitory interneurons through glutamate release within the caudal ventrolateral medulla (CVLM). The CVLM elicits an inhibitory effect through release of the neurotransmitter Gamma-Aminobutyric Acid (GABA) on the rostral ventrolateral medulla (RVLM) (Kumagai, Oshima et al. 2012), the location of many pre-sympathetic neurons and a key center for sympathetic output (Pilowsky and Goodchild 2002). This pathway causes a cessation of sympathetic efferent output, and an increase in PNS activity. ...
Orexin is a neuropeptide with a large range of functions, with a recently discovered role in blood pressure (BP) regulation. Although the role of brain orexin system in hypertension has been investigated in several hypertensive animals, it remains unclear whether activation of the orexin system contributes to the development of Deoxycorticosterone-acetate (DOCA) hypertension, an animal model of human salt sensitive hypertension. In this study, we investigated the hypothesis that Orexin-1 receptor (OX1R) expression is increased in the paraventricular nucleus (PVN), a critical brain area controlling cardiovascular function, which subsequently increases vasopressin (AVP) expression and peripheral secretion, resulting in hypertension development in this model. Seven to eight-week-old male Sprague Dawley (SD) rats were split into three groups including DOCA-salt, untreated controls, and OX1RshRNA-DOCA rats. Following knockdown of OX1R in the PVN via viral infection in the OX1RshRNA-DOCA rats, they, as well as the DOCA-salt group, were implanted with a 75mg DOCA pellet and treated with 1%NaCl/0.2%KCl drinking water, while the control group remained untreated. Blood pressure of each rat was measured using tail-cuff plethysmography. Three weeks following DOCA-salt or sham treatment, all rats were sacrificed, and brains were subjected to either real-time PCR or immunostaining to assay mRNA level and protein expression of Orexin A, OX1R, and AVP in the PVN. Their blood was collected for plasma AVP measurement, and their hearts were weighed for measurement of their heart weight/body weight (BW/HW) ratio. Our results showed that chronic knockdown of the PVN OX1R effectively attenuated hypertension induced by DOCA-salt treatment (control: 107.91±5.99 vs. DOCA-salt: 142.43±7.73 vs. DOCA+OX1RshRNA: 115.69±8.23 mmHg; P
... One of the brainstem nuclei regulating blood pressure is the rostral ventrolateral medulla (RVLM). This is a critical relay nucleus in the sympathetic baroreflex, which maintains arterial blood pressure through a series of feedback loops (Pilowsky & Goodchild, 2002;Ito & Sved, 1997;Lipski et al., 1996). In models of essential hypertension, neurons in the RVLM projecting to the spinal cord are persistently overactive, leading to a sustained increase in blood pressure via the excessive constriction of resistance arterioles and release of noradrenaline from the adrenal medulla (Minson et al., 1996;Geraldes et al., 2014). ...
The RVLM of spontaneously hypertensive rats (SHR) contains over-active C1 neurons, which model the pathology of essential hypertension. Hypertension involves chronic low-grade neuroinflammation. Inflammation in the brain is produced and maintained primarily by microglia. We assessed microglial gene expression (P2Y12R and CX3CR1) and morphology in the RVLM of SHR compared to normotensive Wistar-Kyoto rats (WKY). The gene expression of the metabotropic purinergic receptor P2Y12 and the fractalkine receptor CX3CR1 was downregulated in the RVLM of SHR compared to WKY (by 37.3% and 30.9% respectively). P2Y12R and CX3CR1 are required for normal microglial function, and reduced P2Y12R expression is associated with changes in microglial activity. Histological analysis showed a 22.9% reduction in microglial cell density, along with 18.7% shorter microglial processes, a phenotypic indicator of activation, in the RVLM of SHR compared to WKY. These results indicate a subtle loss of function, or a mild state of inflammation, in the RVLM microglia of SHR.
... The differences were significant ( P \ 0.05 between groups, *P \ 0.05 at the given frequency). solitary tract, nucleus ambiguus, dorsal motor nucleus of the vagus nerve, paraventricular nucleus of the hypothalamus, caudal ventrolateral medulla, and rostral ventrolateral medulla [17][18][19][20]. Thus, we reasoned that the increased signaling from the ADN nerves to the brainstem is buffered by other neural components of the baroreflex circuitry. ...
Excessive reactive oxygen species (ROS) (such as the superoxide radical) are commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1 (SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1 (hSOD1) overexpression does not change baroreflex bradycardia and tachycardia but rather increases aortic depressor nerve activity in response to arterial pressure changes in C57B6SJL-Tg (SOD1)2 Gur/J mice. Since the baroreflex arc includes afferent, central, and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of heart rate (HR) responses. Our data indicate that SOD1 overexpression decreased the HR responses to vagal efferent nerve stimulation but did not change the HR responses to aortic depressor nerve (ADN) stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves normal baroreflex function but may differentially alter the functions of the ADN, vagal efferents, and central components. While SOD1 overexpression likely enhanced ADN function and the central mediation of bradycardia, it decreased vagal efferent control of HR.
... Both mechanisms involve the parasympathetic nervous system but with different pathways. It is well known that increased blood pressure can excite the baroreceptor by increasing its basal rate of action potential generation and send the signal to the nucleus of the tractus solitarius (NTS), which in turn inhibits the vasomotor center and stimulates the vagal nuclei [24,25]. The end-result is to reduce the heart rate and cardiac contractility, which keeps the blood pressure in a narrow fluctuation range. ...
Background:
Heart rate variability (HRV) as a marker reflects the activity of the autonomic nervous system. The prognostic significance of HRV for cardiovascular disease has been reported in clinical and epidemiological studies. Our laboratory has reported alterations in rat heart rate variability (HRV) due to increasing activity of both sympathetic and parasympathetic nervous system after pulmonary exposure to multi-walled carbon nanotubes (MWCNTs). This suggests that pulmonary inhalation of engineered nanoparticles (ENs) may lead to functional changes in the cardiovascular system. The present study further investigated the effects of inhaled MWCNTs on the cardiovascular system and evaluated the correlation between the alterations in HRV and changes in cardiovascular function.
Methods:
Male Sprague-Dawley rats were pre-implanted with a telemetry device and exposed by inhalation to MWCNTs for 5 h at a concentration of 5 mg/m3. The electrocardiogram (EKG) and blood pressure were recorded in real time by the telemetry system at pre-exposure, during exposure, and 1 and 7 days post-exposure. In vivo cardiac functional performance in response to dobutamine was determined by a computerized pressure-volume loop system.
Results:
Inhalation of MWCNTs significantly increased both systolic and diastolic blood pressure and decreased heart rate in awake freely moving rat. Additionally, inhalation of MWCNTs also reduced cardiac stroke work, stroke volume, and output in response to dobutamine in anesthetized rats.
Conclusions:
Inhalation of MWCNTs altered cardiovascular performance, which was associated with MWCNT exposure-induced alterations in the sympathetic and parasympathetic nervous system. These findings suggest the need to further investigate the cardiovascular effects of inhaled MWCNTs.
... Classically, the A5 has been defined as a catecholaminergic region. It is known to provide the major component of the noradrenergic input to the sympathetic preganglionic neurons of IML [75][76][77], whereby it is implicated in cardiovascular control [41,65,[78][79][80][81][82]. It also contains noncatecholaminergic neurons, which are mainly located at the level of the most caudal part of the A5 region [83]. ...
Stimulation of discrete sites throughout the hypothalamus elicits autonomic and somatic responses. This chapter will stand out the cardiorespiratory changes evoked from stimulation of specific areas within the caudal hypothalamus: the perifornical area and the dorsomedial nucleus. The stimulation of these regions, known as the hypothalamic defense area (HDA), produces a pattern of visceral and somatic changes characteristic of the defense reaction, which includes tachypnoea, tachycardia and a pressor response. A close review of the literature demonstrates that the changes observed during this defensive behavioral response are partially mediated by the interactions with pontine regions. These include the parabrachial complex, located in the dorsolateral pons, and the A5 region, located in the ventrolateral pons. Specific glutamatergic stimulation of cell bodies located within the parabrachial complex and A5 region evokes cardiorespiratory responses similar to those observe during stimulation of the HDA. This functional interaction suggests a possible role of glutamate pontine receptors in the modulation of the HDA response. This chapter describes the most important evidences confirming the implication of the dorso and ventrolateral pons in the control of cardiorespiratory autonomic responses evoked from the perifornical and dorsomedial hypothalamus and the role of glutamate in this interaction
... The OB makes contact with different telencephalic, mesencephalic, diencephalic, and brainstem regions [26], some intimately involved in the control of the cardiovascular function. For instance, the OB interacts with the nucleus of the solitary tract, which is the primary site for the integration of baroreflex input [56,57]. In addition, areas like the amygdala, the septum, the piriform, and orbitofrontal cortex, as well as the ventromedial and posterior nucleus of hypothalamus, connect with the OB. ...
Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ET A) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ET A blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ET A blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ET A are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.
... This finding suggests that the rapid normalization of blood pressure may not relate to circulating concentrations, but other factors, such as receptor desensitization or the baroreflex, which liberates vasoconstrictor agents such as catecholamines. 60 To evaluate the ability of new analogues to modulate cardiac function in the Langendorff model, the heart of Sprague− Dawley rats was isolated and perfused with different concentrations of macrocyclic analogues, with doses ranging from 0.001 to 0.3 nM. In this experiment, the increase in left ventricular developed pressure is recorded as a measure of inotropic effect. ...
The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life > 3 h versus 24 min for Pyr-apelin-13), accompanied with improved affinity (analogue 15, Ki 0.15 nM and t1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.
Oxytocin (OXT), a neuropeptide originating from the hypothalamus and traditionally associated with peripheral functions in parturition and lactation, has emerged as a pivotal player in the central regulation of the autonomic nervous system (ANS). This comprehensive ANS, comprising sympathetic, parasympathetic, and enteric components, intricately combines sympathetic and parasympathetic influences to provide unified control. The central oversight of sympathetic and parasympathetic outputs involves a network of interconnected regions spanning the neuroaxis, playing a pivotal role in the real-time regulation of visceral function, homeostasis, and adaptation to challenges. This review unveils the significant involvement of the central OXT system in modulating autonomic functions, shedding light on diverse subpopulations of OXT neurons within the paraventricular nucleus of the hypothalamus and their intricate projections. The narrative progresses from the basics of central ANS regulation to a detailed discussion of the central controls of sympathetic and parasympathetic outflows. The subsequent segment focuses specifically on the central OXT system, providing a foundation for exploring the central role of OXT in ANS regulation. This review synthesizes current knowledge, paving the way for future research endeavors to unravel the full scope of autonomic control and understand multifaceted impact of OXT on physiological outcomes.
Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits towards a state of dysfunction. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY) rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, the nucleus of the solitary tract (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 weeks of age, spanning the pre-hypertensive stage through extended chronic hypertension. RNAseq data was analyzed using an unbiased, dynamic pattern-based approach that uncovered a dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development, as well as a cascade of transient dysregulation beginning in the RVLM at the pre-hypertensive stage that shifts towards the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occuring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.
Hypertension is well-known to often coexist with diabetes mellitus (DM) in humans. Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors has been shown to decrease both the blood glucose and the blood pressure (BP) in such patients. Some reports show that SGLT2 inhibitors improve the BP by decreasing the activities of the sympathetic nervous system. Therefore, we hypothesized that SGLT2 inhibitors might alleviate hypertension via attenuating sympathetic nervous activity. Combined SGLT2/SGLT1 inhibitor therapy is also reported as being rather effective for decreasing the BP. In this study, we examined the effects of SGLT2 and SGLT1 inhibitors on the bulbospinal neurons of the rostral ventrolateral medulla (RVLM). To investigate whether bulbospinal RVLM neurons are sensitive to SGLT2 and SGLT1 inhibitors, we examined the changes in the neuronal membrane potentials (MPs) of these neurons using the whole-cell patch-clamp technique during superfusion of the cells with the SGLT2 and SGLT1 inhibitors. A brainstem-spinal cord preparation was used for the experiments. Our results showed that superfusion of the RVLM neurons with SGLT2 and SGLT1 inhibitor solutions induced hyperpolarization of the neurons. Histological examination revealed the presence of SGLT2s and SGLT1s in the RVLM neurons, and also colocalization of SGLT2s with SGLT1s. These results suggest the involvement of SGLT2s and SGLT1s in regulating the activities of the RVLM neurons, so that SGLT2 and SGLT1 inhibitors may inactivate the RVLM neurons hyperpolarized by empagliflozin. SGLT2 and SGLT1 inhibitors suppressed the activities of the bulbospinal RVLM neurons in the brainstem-spinal preparations, suggesting the possibilities of lowering BP by decreasing the sympathetic nerve activities. RVLM, rostral ventrolateral medulla. IML, intralateral cell column. aCSF, artificial cerebrospinal fluid.
Sympathoexcitation, under the regulatory control of the brain, plays a pivotal role in the etiology of hypertension. Within the brainstem, significant structures involved in the modulation of sympathetic nerve activity include the rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla (CVLM), nucleus tractus solitarius (NTS), and paraventricular nucleus (paraventricular). The RVLM, in particular, is recognized as the vasomotor center. Over the past five decades, fundamental investigations on central circulatory regulation have underscored the involvement of nitric oxide (NO), oxidative stress, the renin-angiotensin system, and brain inflammation in regulating the sympathetic nervous system. Notably, numerous significant findings have come to light through chronic experiments conducted in conscious subjects employing radio-telemetry systems, gene transfer techniques, and knockout methodologies. Our research has centered on elucidating the role of NO and angiotensin II type 1 (AT1) receptor-induced oxidative stress within the RVLM and NTS in regulating the sympathetic nervous system. Additionally, we have observed that various orally administered AT1 receptor blockers effectively induce sympathoinhibition by reducing oxidative stress via blockade of the AT1 receptor in the RVLM of hypertensive rats. Recent advances have witnessed the development of several clinical interventions targeting brain mechanisms. Nonetheless, Future and further basic and clinical research are needed.
Cardiac physiology is the underlying mechanism of the cardiovascular system which works in a beat-to-beat manner, especially in patients with congenital heart diseases. This field has improved significantly as a result of the developments in cellular and molecular medicine. In this chapter, after an introductory discussion about the evolutional transition in cardiac physiology from fetal to neonatal, childhood, and adulthood, the myocardial function has been presented with its three main ingredients: electrical function of the myocardium, excitation-contraction coupling, and mechanical function of the myocardium. Control mechanisms of cardiac function including receptors, signals, and neurohormonal pathways are among the most important controlling mechanisms in the human body which are described afterward. Developmental changes in fetal cardiac muscle are mandatory for anyone who wants to work with patients having congenital heart disease; a full discussion could be reached in the previous chapter of the book. Cardiac work includes the normal sequences in the cardiac cycle, the Frank-Starling relationship, and the factors involved in cardiac work which are described next. And finally, the cardiac reflexes are described which are another main controller of cardiovascular physiologic response.
Hypertension is a cardiovascular disease that is related to different physiological parameters. Several pathways are involved in regulation of blood pressure, such as a sympathetic reflex pathway, renin–angiotensin–aldosterone system, cardiac contractility and vascular physiology. Induction of stress, change in food consumption behavior, sedentary lifestyle are precursors of hypertension nowadays. If untreated for a prolong period, it can damage vascular curvature, cardiac wall, renal perfusion, and several other physiological problems. In this context, we are trying to understand pathophysiological condition of hypertension and agents that can reduce it clinically through different pathways.
Objectives
The aim of this study is to identify the peri-procedural risk factors and outcomes of hemodynamic instability (HI) after carotid artery stenting (CAS).
Methods
A single-center, retrospective study was performed in 168 patients who underwent CAS procedure between September 2017 and September 2020. The presence of HI, as defined by hypertension (systolic blood pressure >160 mmHg), hypotension (systolic blood pressure <90 mmHg), and/or bradycardia (heart rate <60 bpm), was recorded. Long-period HI was defined as persistent HI lasting more than 24 h. Patient demographics, comorbidities, peri-procedural variables, and risk factors were recorded. Clinical outcomes including cerebral hyperperfusion syndrome, hemorrhage, transient ischemic attack (TIA), stroke, myocardial infarction, and mortality within 30 days of the procedure were evaluated. Logistic regression was used to analyze the independent risk factors of long-period HI following CAS.
Results
Among 168 patients (mean age, 68.2 ± 8.3 years; 81.5% male), the frequency of post-procedural long-period HI was noted in 42 patients (25.0%). Male was prone to experience HI (odds ratio, 9.156, p = 0.021). Aggressive inflation pressure (>7 atm) and 5 mm balloon for pre-dilatation were risk factors of long-period HI (OR, 7.372, p = 0.035; OR, 3.527, p = 0.023). Intraoperative peak blood pressure and larger-sized stents remained independent predictors for the development of HI (OR, 1.043, p = 0.027, and OR, 1.973, p = 0.015). Patients with prolonged HI were more likely to suffer TIA and stroke compared to other patients and significant difference was found in the occurrence of TIA ( p < 0.05). Non-significance was found in mortality rate and other outcomes.
Conclusions
CAS-induced HI occurs in a considerable percentage while several peri-procedural variables are determined as independent predictors to develop long-period HI. Patients with prolonged HI are associated with increased risk of neurologic events and thus standardized intervention as well as management of long-period HI are of critical importance during clinical process.
Objectives:
We aimed to assess the incidence and predictors of prolonged hemodynamic depression (PHD) after carotid artery stenting (CAS).
Methods:
We retrospectively analyzed data from 216 CAS procedures performed in 207 patients (156 male; median and interquartile range (IQR) of age 68 (62-73) yr) between July 2012 and October 2020. PHD was defined as hypotension (systolic blood pressure ≤ 90 mmHg) and/or bradycardia (heart rate < 60 bpm) lasting >1 h.
Results:
The incidence of PHD was 25.9%. At multivariate analysis, asymptomatic lesions (OR: 2.43, 95% CI (1.16-5.06), p: 0.018), the stenosis proximity (<10 mm) to bifurcation (OR: 2.94, 95% CI (1.34-6.43), p: 0.007) and implantation of a Protege stent (OR: 2.93, 95% CI (1.14-7.53), p: 0.025) were independent risk factors, while statin usage (OR: 0.48, 95% CI (0.24-0.95), p: 0.036) was an independent protective factor for PHD after CAS.
Conclusions:
Patients with asymptomatic lesions and stenosis close to the bifurcation are more prone to PHD. The type of the stent selected significantly influences the risk of PHD. Further prospective randomized studies are warranted to investigate the possible protective role of statins against PHD after CAS.
Synopsis
The vestibular system influences blood pressure, heart rate, respiration, and gastrointestinal motility through connections with the autonomic nervous system. This chapter summarizes current scientific knowledge derived from studies in human subjects and experimental animals. The overall conclusions are (i) the vestibular system commands rapid alterations in blood pressure and heart rate in response to postural changes, particularly those involving orthostatic challenge; (ii) polysynaptic vestibular input assists in modulating the rate and depth of respiration during movement; and (iii) vestibular input to autonomic nuclei is necessary to elicit motion sickness.
Tuning of the cardiovascular response is crucial to maintain performance during high-intensity exercise. It is well known that the nucleus of the solitary tract (NTS) in the brainstem medulla plays a central role in cardiovascular regulation; however, where and how upper brain regions form circuits with NTS and coordinately control cardiovascular responses during high-intensity exercise remain unclear. Here focusing on the amygdala and claustrum, we investigated part of the mechanism for regulation of the cardiovascular system during exercise. In rats, c-Fos immunostaining was used to examine whether the amygdala and claustrum were activated during treadmill exercise. Further, we examined arterial pressure responses to electrical and chemical stimulation of the claustrum region exhibiting exercise intensity-dependent activation. We also confirmed the anatomical connections between the amygdala, claustrum, and NTS by retrograde tracer injections. Finally, we performed simultaneous electrical stimulation of the claustrum and amygdala to examine their functional connectivity. c-Fos expression was observed in the amygdala and the posterior part of the claustrum (pCL), but not in the anterior part, in an exercise intensity-dependent manner. pCL stimulation induced a depressor response. Using a retrograde tracer, we confirmed direct projections from the amygdala to the pCL and NTS. Simultaneous stimulation of the central nucleus of the amygdala and pCL showed a greater pressor response compared with the stimulation of the amygdala alone. These results suggest the amygdala and pCL are involved in different phases of exercise. More speculatively, these areas might coordinately tune cardiovascular responses that help maintain performance during high-intensity exercise.
PurposePostprandial hypotension (PPH) is a common but poorly understood etiology for fainting in older adults. One potential mechanism is age-related baroreflex dysfunction. We examined baroreflex function in older adults with PPH and without PPH (noPPH) during a standardized meal test.Methods57 adults (age ≥ 65; 24 PPH, 33 noPPH, mean age 77.9 ± 0.9 years, 54% female) were recruited and had meal tests performed. The baroreflex effectiveness index (BEI, %) and baroreflex sensitivity (BRS, ms/mm Hg) were calculated using the sequence method.ResultsBaseline BEI (22 ± 2 versus 23 ± 2 percent, t = − 0.411, p = 0.682) and BRS (14.1 ± 2.4 versus 13.8 ± 2.5 ms/mm of Hg, t = − 0.084, p = 0.933) were similar in PPH and noPPH subjects. During the meal test PPH subjects showed significantly lower BEI as compared to noPPH subjects (time × PPH, F = 2.791, p = 0.042), while there was no difference in the postprandial change in BRS (time, F = 0.618, p = 0.605).Conclusion
Patients with PPH demonstrated an acute postprandial decrease in baroreflex effectiveness during meal testing as compared with normal subjects, suggesting a potential contributing mechanism for this condition.
La suppression du vecteur gravité lors des vols spatiaux normalement orienté de la tête vers les pieds en position debout agit sur les fluides de l’organisme par la perte du gradient de pression hydrostatique, ce qui aboutit à un syndrome de déconditionnement cardio-vasculaire. Cette absence de gravité perturbe également le système vestibulaire, particulièrement les otolithes qui perdent leur capacité à détecter les inclinaisons de la tête. Nous avons conduit nos études chez l’homme à l’aide du modèle d’immersion sèche durant 3 jours ainsi que du modèle d’alitement anti-orthostatique durant 60 jours.Le but de notre premier travail de recherche est d’étudier l’influence du système otolithique sur la régulation du système cardio-vasculaire au travers du réflexe vestibulo-sympathique. Il a pour cela été utilisé des expérimentations de stimulation galvanique pour évaluer la sensibilité otolithique ainsi que des manœuvres de flexion de cou associées à des mesures cardio-vasculaires conventionnelles et de pléthysmographie. Un accéléromètre a, de plus, été utilisé pour quantifier les phases d’activité et d’inactivité.Le but de notre second travail de recherche est d’étudier l’évolution du baroréflexe carotidien au cours des modèles de stimulation d’impesanteur et d’établir d’éventuelles hypothèses d’interaction avec les afférences otolithiques. Il a pour cela été utilisé des mesures de pression artérielle et de fréquence cardiaque en réponse à des stimulations mécaniques des barorécepteurs carotidiens appliquées de façon directe via la technique du collier de pression.Nos résultats ont confirmé que la manœuvre de flexion du cou est bien une stimulation otolithique avec l’apparition des modifications de réactivité otolitiques seulement en décubitus ventral et non en décubitus latéral. Néanmoins le rôle du réflexe vestibulo-sympathique sur la régulation cardio-vasculaire n’est pas clairement mis en évidence. Par ailleurs, la sensibilité du baroréflexe carotidien au cours de ces protocoles n’est pas modifiée.Notre hypothèse générale d’une modification du contrôle cardio-vasculaire en lien avec la réduction de la stimulation otolithique au cours de protocoles de simulation d’impesanteur n’est pas vérifiée. Il reste à comprendre la signification réelle de la manœuvre du head-down neck flexion et son lien avec l’authentique stimulation otolithique qu’elle provoque. Il est vraisemblable que de multiples systèmes sensoriels interviennent dans la régulation cardio-vasculaire en lien avec la gravité. Le rôle spécifique du système vestibulaire sera vraisemblablement mieux appréhendé dans des situations où sa plasticité est le mieux mise en jeu c’est-à-dire en impesanteur réelle.
Background:
Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP.
Aim:
To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis.
Methods:
CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected via pharmacological approach and chemogenetics in CP rats.
Results:
TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats vs 2.55 ± 0.44 Hz in sham rats, P < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats vs 14.71 ± 1.07 pA in sham rats; P < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission via the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, P < 0.001). Inhibiting the excitability of NTS neurons via chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, P < 0.01).
Conclusion:
Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.
Cardiac physiology is one of the most interesting discussions both in basic science and clinic. Anatomy and physiology of the heart directly affect the clinical presentations of disease states. The heart is composed of pericardium (outmost layer), endocardium (innermost layer), and myocardium (middle layer), the last being more discussed here and consists of: Cardiac connective tissue cells Cardiomyocytes (which have contractile function) Cardiac electrical and conduction system cells (consisting of “impulse-generating cells” and “specialized conductive cells”) The main cardiac cells are cardiomyocytes with their unique structure having some shared features with both skeletal muscles and smooth muscles, though not completely similar with any of these two muscle types. Cardiac cells have three different but “highly interrelated” physiologic features: Action potential Excitation-contraction coupling (ECC) Contractile mechanisms Each of the three is composed of numerous different physiologic chains to create together, and as a final outcome, a main goal: cardiac contraction leading to cardiac output. There are a number of cardiac controllers which modulate cardiac function based on physiologic demands, which are discussed in this chapter. And finally, a number of physiologic reflexes are involved in cardiac physiology discussed in the final part of the chapter.
Recent studies indicate that erythropoietin (EPO) is present in many areas of the brain and is active in the restoration of impaired neurons. In this study, we examined the presence of EPO and its role in bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Hypoxia is often accompanied by a high blood pressure (BP). We hypothesized that EPO is produced in response to hypoxia in RVLM neurons and then activates them. To investigate whether RVLM neurons are sensitive to EPO, we examined the changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole-cell patch-clamp technique during superfusion with EPO. A brainstem-spinal cord preparation was used for the experiments. EPO depolarized the RVLM neurons, and soluble erythropoietin receptor (SEPOR), an antagonist of EPO, hyperpolarized them. Furthermore, hypoxia-depolarized RVLM neurons were significantly hyperpolarized by SEPOR. In histological examinations, the EPO-depolarized RVLM neurons showed the presence of EPO receptor (EPOR). The RVLM neurons that possessed EPORs showed the presence of EPO and hypoxia inducible factor (HIF)-2α. We also examined the levels of HIF-2α and EPO messenger RNA (mRNA) in the ventral sites of the medullas (containing RVLM areas) in response to hypoxia. The levels of HIF-2α and EPO mRNA in the hypoxia group were significantly greater than those in the control group. These results suggest that EPO is produced in response to hypoxia in RVLM neurons and causes a high BP via the stimulation of those neurons. EPO may be one of the neurotransmitters produced by RVLM neurons during hypoxia.
Microinjections of angiotensin II (Ang II) into the rostral ventrolateral medulla (RVLM) induce a sympathetically-mediated increase in blood pressure (BP), through an interaction with AT1-receptors. Under basal conditions in anaesthetised animals, microinjections of AT 1-receptor antagonists into the RVLM have little, or no effect on BP, suggesting that the angiotensin input to this nucleus is not tonically active. In contrast, microinjections of AT1-receptor antagonists into the RVLM of sodium-deplete rats and TGR(mRen2)27 rats, induce a depressor response through sympatho-inhibition. This indicates that when the renin-angiotensin system is activated, angiotensin can act in the RVLM to support sympathetic nerve discharge and BP. This study examined whether angiotensin inputs to the RVLM are activated in the spontaneously hypertensive rat — a pathophysiological model which displays increases in both brain angiotensin levels and sympathetic nerve activity. Bilateral microinjections of the AT 1-receptor antagonist candesartan cilexetil, (1 nmol in 100 nl), into the RVLM of the spontaneously hypertensive rat induced a significant decrease in lumbar sympathetic nerve discharge (-18±2%) and BP (140±6 to 115±6 mmHg). In contrast, similar microinjections in the Wistar-Kyoto (WKY) rat had no effect on BP or sympathetic nerve discharge. These results are interpreted to suggest that Ang II inputs to the RVLM are activated in the spontaneously hypertensive rat to maintain an elevated level of sympathetic nerve discharge, even in the face of increased BP.
Animals, including humans, react with distinct emotional coping strategies to different sets of environmental demands. Although the hypothalamus has been usually assigned the key role in coordinating emotional responses, it is difficult to reconcile this view with findings that integrated and directed emotional reactions are readily evoked in animals in which the hypothalamus has been either surgically isolated from the rest of the brain or extensively lesioned. An emerging body of evidence suggests that longitudinal columns of midbrain neurons located lateral and ventrolateral to the aqueduct, within the periaqueductal gray region (PAG), play special roles in coordinating distinct emotional strategies for coping with different classes of stress, threat, or pain. This chapter considers functional-anatomical evidence that the lateral and ventrolateral columns of the PAG coordinate fundamentally opposite modes of emotional coping. It is proposed that the PAG offers a useful point of entry for defining neural circuits that mediate different emotional coping strategies. As an example, recent studies of the connections of primate orbital and medial prefrontal cortical (PFC) fields with specific longitudinal neuronal columns within the PAG are discussed. The practices of meditation and yogic breathing, which are suggested alternative methods for the management of pain and stress, likely engage the same neural circuits via which particular emotional coping strategies are expressed.
The location of neurons generating the rhythm of breathing in mammals is unknown. By microsection of the neonatal rat brainstem
in vitro, a limited region of the ventral medulla (the pre-Botzinger Complex) that contains neurons essential for rhythmogenesis
was identified. Rhythm generation was eliminated by removal of only this region. Medullary slices containing the pre-Botzinger
Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons
with voltage-dependent pacemaker-like properties were identified in this region. Thus, the respiratory rhythm in the mammalian
neonatal nervous system may result from a population of conditional bursting pacemaker neurons in the pre-Botzinger Complex.
The effects of caffeine or placebo on blood pressure, heart rate, and baroreflex activation (elicited by phenylephrine) were studied on young normotensive volunteers after a 7-day caffeine-free period. Subjects received oral doses of either 250 mg caffeine (n = 6) or placebo (n = 4), and hemodynamic changes were studied at 0, 30, 60, 120, and 180 minutes after drug administration. Thirty minutes after the caffeine dose, blood pressure had risen from 127 +/- 8/57 +/- 4 mm Hg to 136 +/- 3/68 +/- 5 mm Hg, heart rate was unchanged, and the baroreflex slope had decreased from 31 +/- 7 msec/mm Hg to 11.6 +/- 2 msec/mm Hg. Baroreflex sensitivity remained inhibited for the rest of the single-dose experimental period. In contrast, no significant changes were observed after either long-term caffeine ingestion in the same group or in the placebo group during the single- or multiple-dose study. These findings indicate that single but not multiple caffeine administration inhibits baroreflex activation in normotensive volunteers and this could contribute to the acute hemodynamic effects of caffeine.
Objectives: To explore the rat caudal raphe nuclei for neurons that respond to activation of baroreceptor nerves and that have a spinal axon, and to compare the behavioural properties of barosensitive bulbospinal neurons in the rat caudal raphe with the properties of barosensitive bulbospinal neurons in the rostral ventrolateral medulla. Design: Extracellular unit recordings were obtained from an area extending up to 1.0 mm caudally from the caudal edge of the facial nucleus. Two sites were explored: the rostral ventrolateral medulla and the midline. Materials and methods: Single-unit recordings were made in anaesthetized (75 mg/kg chloral hydrate and 30 mg/kg sodium pentobarbitone then 3-6 mg intravenously as required), immobilized (2 mg pancuronium as required) Sprague-Dawley rats. Central respiratory drive was recorded from phrenic nerve discharge. The barosensitivity of single units was assessed by R-wave triggered histograms and by histograms of their responses to aortic nerve stimulation or to intravenous injection of phenylephrine. Nociceptors were activated by a brief pinch of the tail. Results: Eleven spontaneously active units in the midline that were inhibited by baroreceptor stimulation and had a spinal axon were studied. Respiratory modulation was present and was predominantly inspiratory. Barosensitive neurons in the rostral ventrolateral medulla were activated by nociceptive inputs; midline barosensitive neurons were not. Conclusions: The behavioural characteristics of midline neurons differ from those of the bulbospinal barosensitive neurons in the rostral ventrolateral medulla, indicating that raphe spinal neurons have different sets of afferent inputs and may subserve to a distinct physiological role. The present paper is the first report of bulbospinal neurons in the rat caudal raphe that are inhibited by activation of arterial baroreceptors.
The objective of this study was to characterize the projection pattern and electrophysiological properties of the rostral medullary adrenergic neurons (C-1) that express neuropeptide Y (NPY) mRNA in rat. NPY mRNA was found in a variable fraction of tyrosine hydroxylase immunoreactive (TH-IR) neurons depending on the medullary level. By retrograde labeling (Fast Blue, FluoroGold), NPY mRNA was detected in virtually all C-1 cells (96%) and C-3 cells (100%)) with hypothalamic projections but in only 9% of C-1 cells and 58% of C-3 cells projecting to thoracic segment 3 (T-3) or T-6 of the spinal cord. To identify the electrophysiological properties of the C-1 cells that express NPY mRNA, we recorded from baroinhibited neurons within the C-1 region of the ventrolateral medulla (RVLM) and tested for projections to segment Tsr the hypothalamus, or both. By using the juxtacellular method, we labeled these cells with biotinamide and determined whether the recorded neurons were TI-I-IR and contained NPY mRNA. At rostral levels (Bregma -11.8 mm), barosensitive neurons had a wide range of conduction velocities (0.4-6.0 m/second) and discharge rates (2-28 spikes/ second). Most projected to T-3 only (21 of 31 cells), and 4 projected to both the hypothalamus and the spinal cord. Most of the baroinhibited cells with spinal projections but with no hypothalamic projections had TH-IR but no NPY mRNA(11 of 17 cells). Only 1 cell had both (1 of 17 cells), and 5 cells had neither (5 of 17 cells). Both TH-IR and NPY mRNA were found in neurons with dual projections (2 of 2 cells). At level Bregma - 12.5 mm, baroinhibited neurons had projections to the hypothalamus only (13 of 13 cells! and had unmyelinated axons and a low discharge rate. Four of five neurons contained both TH-IR and NPY mRNA, and 1 neuron contained neither. In short, NPY is expressed mostly by C-1 cells with projection to the hypothalamus. NPY-positive C-1 neurons are barosensitive, have unmyelinated axons, and have a very low rate of discharge. Most bulbospinal C-1 cells with a putative sympathoexcitatory role do not make NPY. (C) 1999 Wiley-Liss, Inc.
Previous studies have shown that pharmacological blockade of ionotropic excitatory amino acid (EAA) receptors in the nucleus tractus solitarii (NTS) with kynurenate (Kyn) abolishes baroreceptor reflexes but fails to affect cardiovascular responses evoked by microinjections of L-glutamate (Glu) into the NTS. These observations have raised doubts as to whether Glu is a neurotransmitter of baroreceptor information in the NTS because the pharmacological actions of exogenously administered Glu are not identical to those of the neurotransmitter released in the NTS coincident with baroreceptor activation. One possible explanation for these results is that exogenously administered Glu might act at receptors that are not blocked by Kyn and are not accessible to synaptically released Glu in the NTS baroreflex pathway. The purpose of this study was to determine if Kyn-insensitive Glu receptors are present in the NTS. One candidate for this Kyn-insensitive receptor is the metabotropic EAA receptor that is selectively activated by trans-DL-1-amino-1,3-cyclopentane-dicarboxylic acid (ACPD). Microinjections of ACPD into the NTS of anesthetized rats produced dose-related depressor responses that were not reduced by Kyn or by pretreatment with the putative ACPD receptor antagonist L-2-amino-3-phosphonopropionate (L-AP-3). Similarly, depressor responses produced by Glu also were not affected by Kyn or by L-AP-3. These data demonstrate the presence of a Kyn-insensitive Glu receptor in the NTS. Moreover, they suggest that the failure of Kyn to reduce cardiovascular responses evoked by Glu injections into the NTS can be explained by an action of Glu at Kyn-insensitive ACPD receptors. Finally, these results suggest that Glu remains a viable candidate neurotransmitter of baroreflex information in the NTS.
Drugs acting within the autonomic nervous system are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease, i.e. hyperkinetic borderline hypertension, a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate. Several classes of drugs acting within the central, as well as the peripheral, autonomic nervous system are very efficient in treating hypertensive disease. One class — the second generation of a group of centrally acting drugs selective for imidazoline receptors — has proved beneficial in this respect, because drugs in this class are well tolerated and have interesting additional effects such as their antiarrhythmic action. Rilmenidine and moxonidine are the lead compounds of this class of drugs. Rilmenidine and moxonidine both proved more selective for cerebral imidazoline receptors than the reference drug, clonidine. It was suggested that this selectivity, attributable to their lower affinity for α2-adrenoceptors, explains the low incidence of adverse effects (including sedation) associated with these drugs. In addition, potentially beneficial actions on cardiac dysrythmias and congestive heart failure enlarge the therapeutic potential of the second generation of imidazoline-related drugs. This review focuses on the main pharmacological and clinical properties of rilmenidine and moxonidine, paying particular attention not only to their efficacy in hypertension but also to other potential cardiovascular indications.
1. Recent studies have shown antagonists at the NK1 subtype of receptor for tachykinins are antiemetics and suggested that this may result from blockade of tachykinin-mediated synaptic transmission at a central site in the emetic reflex. 2. We have used intracellular recording in vitro to study the pharmacology of tachykinins in the nucleus of the solitary tract (NST) and dorsal motor nucleus of the vagus (DMNV). 3. Neurones in the NST were depolarized by substance P (SP), the presumed endogenous ligand for the NK1 receptor and these effects were mimicked by the NK1 agonists, SP-O-methylester (SPOMe), GR73632 and septide; however, SP was nearly an order of magnitude less potent than the latter two agonists. 4. In the DMNV, SP and NK1 receptor agonists evoked similar depolarising responses but SP appeared to be more potent than in the NST and was closer in potency to the other agonists. 5. NK1-receptor antagonists blocked responses to septide and GR73632 in the NST but had little effect on responses to SP and SPOMe. In contrast, in the DMNV the NK1-receptor antagonists blocked responses to septide and GR73632 but also reduced responses to SP and SPOMe. 6. Neurokinin A (NKA) was almost equipotent with septide and GR73632 in depolarizing both NST and DMNV neurones but these effects were not mimicked by a specific NK2-receptor agonist. Responses to NKA were unaffected by an NK2-receptor antagonist; however, the depolarizing effects of NKA were blocked by NK1-receptor antagonists. 7. Neurones in both DMNV and NST were unaffected by the endogenous NK3-receptor ligand, neurokinin B and by a specific agonist for this site, senktide. 8. The results with NK1 receptor agonists and antagonists suggest that the septide-sensitive NK1 site is involved in the excitation of both NST and DMNV neurones. The 'classical' NK1 receptor may play more of a role in the DMNV and a third unknown site may be responsible for the depolarizing response to SP in the NST. The effects of NKA are best interpreted as an action at the septide-sensitive NK1 site. This raises the possibility that anti-emetic action of the NK1 antagonists may be due to blockade of NKA transmission at the septide-sensitive site.
Bulbospinal sympathoexcitatory neurons in the rostral ventrolateral medulla are inhibited by activation of delta opioid receptors. However, it is not known whether this opioidergic effect is pre- or post- synaptic. Here, using retrograde tracing and immunocytochemistry in adult rats, we provide evidence that the delta opioid receptor is located on boutons that are presynaptic to both catecholaminergic and non-catecholaminergic neurons that project to the spinal cord. We suggest that the sympathoinhibitory action of delta opioid receptor activation in the rostral ventrolateral medulla is mediated presynaptically, resulting in a reduction of excitatory neurotransmitter release from boutons that appose sympathoexcitatory bulbospinal neurons. NeuroReport 11:887-891 (C) 2000 Lippincott Williams & Wilkins.
Agonists of the μ-opioid receptor (MOR) produce profound hypotension and sympathoinhibition when microinjected into the rostral ventrolateral medulla (RVL). These effects are likely to be mediated by the inhibition of adrenergic and other presympathetic vasomotor neurons located in the RVL. The present ultrastructural studies were designed to determine whether these vasomotor neurons, or their afferents, contain MORs. RVL bulbospinal barosensitive neurons were recorded in anesthetized rats and filled individually with biotinamide by using a juxtacellular labeling method. Biotinamide was visualized by using a peroxidase method and MOR was identified by using immunogold localization of an antipeptide antibody that recognizes the cloned MOR, MOR1. The subcellular relationship of MOR1 to RVL neurons with fast- or slow-conducting spinal axons was examined by electron microscopy. Fast- and slow-conducting cells were not morphologically distinguishable. Immunogold-labeling for MOR1 was found in all RVL bulbospinal barosensitive neurons examined (9 of 9). MOR1 was present in 52% of the dendrites from both types of cells and in approximately half of these dendrites the MOR1 was at nonsynaptic plasmalemmal sites. A smaller portion of biotinamide-labeled dendrites (16%) from both types of cells were contacted by MOR1-containing axons or axon terminals. Together, these results suggest that MOR agonists can directly influence the activity of all types of RVL sympathoexcitatory neurons and that MOR agonists may also influence the activity of afferent inputs to these cells. The heterogenous distribution of MORs within individual RVL neurons indicates that the receptor is selectively targeted to specific pre- and postsynaptic sites. J. Comp. Neurol. 433:34–47, 2001. © 2001 Wiley-Liss, Inc.
Background and Purpose — In 1998, 8 patients with severe, intractable arterial hypertension and MR tomography-demonstrated neurovascular contact of a looping artery at the root entry zone of cranial nerves IX and X, causing neurovascular compression, underwent neurosurgical decompression. The short-term results showed a normalization of blood pressure with a markedly reduced antihypertensive drug regimen in 7 patients. To determine the longer-term outcome concerning blood pressure and secondary organ damage after neurovascular decompression, we studied these 8 operated patients prospectively for a mean follow-up of 3.5 years after surgical intervention.
Methods — Eight hypertensive patients who had undergone microsurgical decompression were monitored every 6 months after surgery to assess blood pressure (by 24-hour ambulatory pressure readings) and the need for antihypertensive medication. To evaluate secondary organ damage, echocardiographic assessment of left ventricular hypertrophy, fundoscopic assessment of hypertensive lesions, and analysis of renal function and proteinuria were done.
Results — Three of the 8 operated patients remained normotensive in the long-term period with decreased antihypertensive medication. Two patients required gradual increases of antihypertensive medication after the first postoperative year, after which arterial blood pressure levels were 10% to 15% lower than preoperative levels. Three patients suffered serious cardiovascular and renal complications, with the incidence of lethal intracerebral hemorrhage in 1 patient and end-stage renal disease in 2 patients, of whom 1 experienced sudden cardiac death.
Conclusions — The long-term results verify that microsurgical decompression is a successful alternative therapy in a certain subgroup of patients with arterial hypertension due to neurovascular compression. However, the relevance of the looping artery in the other cases, who did not improve, is not clear. Prospective studies to elucidate the pathophysiological role of neurovascular abnormalities and arterial hypertension are needed.
Objective: The rostral ventrolateral medulla is an important center for the regulation of sympathetic and cardiovascular activities. Reportedly, neurovascular compression of the rostral ventrolateral medulla may be causally related to essential hypertension. We aimed to determine the mechanism behind elevated blood pressure in hypertensive patients with compression of the rostral ventrolateral medulla and to investigate whether genetic factors contribute to the etiology of hypertension with compression.
Design and methods: The study included 56 patients with essential hypertension and 25 normotensive individuals. With the use of magnetic resonance imaging, the essential hypertension group was subdivided into hypertension with compression and without compression groups. We compared plasma levels of hormones that raise blood pressure and family histories of hypertension between the two hypertension groups and the normotension group.
Results: Plasma norepinephrine levels, but not plasma renin activity, aldosterone, epinephrine, or vasopressin levels, were significantly higher in the hypertension with compression group (389 ± 53 pg/ml) than in the hypertension without compression group (217 ± 38, P < 0.05) or in the normotension group (225 ± 30, P < 0.05). The percentage of individuals who had two hypertensive parents was significantly higher in the hypertension with compression group (39.4%) than in the hypertension without compression group (13.0%, P < 0.05) or in the normotension group (8.0%, P < 0.01).
Conclusions: These results indicate that neurovascular compression of the rostral ventrolateral medulla might be, at least in part, causally related to essential hypertension by increasing sympathetic nerve activity. They also suggest that genetic factors might contribute to the etiology of hypertension with neurovascular compression.
Calbindin-D28k (calbindin) is a calcium-binding protein that is distributed widely in the rat brain. The localisation of calbindin immunoreactivity in the medulla oblongata and its colocalisation with adrenaline-synthesising neurons [phenylethanolamine-N-methyltransferase-immunoreactive (PNMT-IR)] was examined (Granata and Chang [1994] Brain Res. 645:265–277). However, detailed information about the distribution of calbindin-IR neurons in the reticular formation of the medulla oblongata in particular is lacking. In this report, the authors address this issue with an emphasis on the quantitation of calbindin-IR neurons, catecholamine neurons [tyrosine hydroxylase (TH)-IR, or PNMT-IR], and spinally projecting neurons in the ventral brainstem. Rats received injections of the retrograde tracing agent cholera toxin B (CTB) into the thoracic spinal cord or into the superior cervical ganglion. Immunocytochemistry was used to reveal calbindin, TH, PNMT, and CTB immunoreactivity. Ten calbindin-IR cell groups were identified within the pontomedullary reticular formation. Seven previously undescribed but distinct clusters of calbindin-IR neurons were found. Within the ventral pons, a population of calbindin-IR neurons occurred dorsal but adjacent to the A5 cell group. These calbindin-IR neurons did not contain either TH or PNMT immunoreactivity, and few if any of these neurons projected to the spinal cord. A distinct group of calbindin-IR neurons was present in the ventral medulla. Seventy-five percent of these calbindin-IR neurons contained TH immunoreactivity, 45% contained PNMT immunoreactivity, and 21% were spinally projecting neurons. Spinally projecting, calbindin-IR neurons were a subpopulation of PNMT-IR cells. In the caudal ventral medulla, no TH-IR or PNMT-IR cells were calbindin-IR. In the intermediolateral cell column, close appositions of calbindin-IR terminals on identified sympathetic preganglionic neurons as well as calbindin-IR synapses indicated that these neurons may affect directly the sympathetic outflow. The results demonstrate for the first time the existence of a new subpopulation of spinally projecting, PNMT-IR neurons in the rostral ventrolateral medulla. J. Comp. Neurol. 424:547–562, 2000. © 2000 Wiley-Liss, Inc.
Agonists of the CL-opioid receptor (MOR) have profound effects on blood pressure, heart rate, and respiration that may be mediated by C1 adrenergic neurons in the rostral ventrolateral medulla (RVL). C1 neurons are sympathoexcitatory and are involved in both tonic and reflex regulation of sympathetic outflow. This study was designed to determine whether C1 neurons, or their afferents, contain MOR. C1 neurons were identified by using an antibody against the epinephrine synthesizing enzyme phenylethanolamine-N-methyl transferase (PNMT), whereas MOR was localized by using an antipeptide antibody that recognizes the cloned MOR, MOR1. Combined immunoperoxidase and immunogold methods were used to examine the cellular distribution of MOR1 relative to PNMT-containing neurons in the RVL. MOR1 was found in 22% of PNMT-containing dendrites (n = 392), whereas MOR1-containing axons or axon terminals contacted 14% of PNMT-containing dendrites. This distribution was heterogenous with regard to dendritic size: PNMT-labeled dendrites containing MOR1 were usually large (60% were >1.2 mum), whereas PNMT-containing dendrites that received MOR1-labeled afferents were usually small (79% were <1.2 m). Individual dendrites rarely contained MOR1 at both pre- and postsynaptic sites. Together these results suggest that MOR agonists may directly influence the activity of C1 neurons, as well as the activity of select afferents to these cells. Plasmalemmal membrane labeling for MOR1 was more frequent in smaller PNMT-containing dendrites, suggesting that postsynaptic receptors are more readily available for ligand binding in small dendrites, although the receptor was more frequently detected in larger PNMT dendrites. The selective distribution of MORs to specific pre- and postsynaptic sites suggests the receptor may be selectively trafficked to positions where it may regulate afferent activity that is heterogeneously distributed along the dendritic tree of C1 neurons. (C) 2001 Wiley-Liss, Inc.
Cardiac vagal neurons play a critical role in the control of heart rate and cardiac function. These neurons, which are primarily located in the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DMNX), dominate the neural control of heart rate under normal conditions. Cardiac vagal activity is diminished and unresponsive in many disease states, while restoration of parasympathetic activity to the heart lessens ischemia and arrhythmias and decreases the risk of sudden death. Recent work has demonstrated that cardiac vagal neurons are intrinsically silent and therefore rely on synaptic input to control their firing. To date, three major synaptic inputs to cardiac vagal neurons have been identified. Stimulation of the nucleus tractus solitarius evokes a glutamatergic pathway that activates both NMDA and non-NMDA glutamatergic postsynaptic currents in cardiac vagal neurons. Acetylcholine excites cardiac vagal neurons via three mechanisms, activating a direct ligand-gated postsynaptic nicotinic receptor, enhancing postsynaptic non-NMDA currents, and presynaptically by facilitating transmitter release. This enhancement by nicotine is dependent upon activation of pre- and postsynaptic P-type voltage-gated calcium channels. Additionally, there is a GABAergic innervation of cardiac vagal neurons. The transsynaptic pseudorabies virus that expresses GFP (PRV-GFP) has been used to identify, for subsequent electrophysiologic study, neurons that project to cardiac vagal neurons. Bartha PRV-GFP-labeled neurons retain their normal electrophysiological properties, and the labeled baroreflex pathways that control heart rate are unaltered by the virus.
• This study compared (i) the properties of C1 cells with those of neighbouring non-C1 neurones that project to the hypothalamus and (ii) the properties of C1 cells that project to the hypothalamus with those of their medullospinal counterparts. • Extracellular recordings were made at three rostrocaudal levels of the ventrolateral medulla (VLM) in α-chloralose-anaesthetized, artificially ventilated, paralysed rats. Recorded cells were filled with biotinamide. • Level I (0-300 mbehind facial nucleus) contained spontaneously active neurones that were silenced by baro- and cardiopulmonary receptor activation and virtually unaffected by nociceptive stimulation (firing rate altered by • Level II (600-800 mbehind facial nucleus) contained (i) type I neurones ( n= 3 ) (ii) type II neurones ( n= 11) , (iii) neurones that projected to the hypothalamus and were silenced by baro- and cardiopulmonary receptor activation but activated by strong nociceptive stimulation (type III, n= 2) , (iv) non-barosensitive cells activated by weak nociceptive stimulation which projected only to the hypothalamus (type IV, n= 9) , (v) cells that projected to the hypothalamus and responded to none of the applied stimuli (type V, n= 7 ) and (vi) neurones activated by elevating blood pressure which projected neither to the cord nor to the hypothalamus (type VI, n= 4 ). • Level III (1400-1600 mbehind facial motor nucleus) contained all the cell types found at level II except type I. • Most of type I and II (17/26) and half of type III cells (4/8) were C1 neurones. Type IV-V were rarely adrenergic (2/12) and type VI were never adrenergic (0/3). • All VLM baroinhibited cells project either to the cord or the hypothalamus and virtually all (21/23) C1 cells receive inhibitory inputs from arterial and cardiopulmonary receptors.
It has been reported that neurovascular compression of the rostral ventrolateral medulla might be causally related to essential hypertension. Recently, we found that pulsatile compression of the rostral ventrolateral medulla increases sympathetic nerve activity and elevates arterial pressure via activation of glutamate receptors in rats. We also found that increases in sympathetic and cardiovascular activities by microinjection of L-glutamate into the rostral ventrolateral medulla are mediated by c-fos expression-related substance(s) following activation of the nitric oxide-cyclic GMP pathway.
Herein, we investigated whether responses to pulsatile compression are mediated by local activation of the nitric oxide-cyclic GMP pathway and/or c-fos expression-related substance(s) in rats.
Increases in arterial pressure (15±1 mmHg), heart rate (9±1 b.p.m.), and sympathetic nerve activity (% change: 8.5±1.1%) induced by pulsatile compression were partially but significantly inhibited after local microinjection of a nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (8±2 mmHg, 1±1 b.p.m., 4.0±1.3%; P<0.05 vs compression without pretreatment) or 7-nitroindazole (7±2 mmHg, 2±1 b.p.m., 4.0±1.5%; P<0.05), or a soluble guanylate cyclase inhibitor, methylene blue (9±1 mmHg, 4±1 b.p.m., 4.1±1.4%; P<0.05). In addition, increases in arterial pressure, heart rate, and sympathetic nerve activity by pulsatile compression were significantly reduced 6 h after microinjection of antisense oligodeoxynucleotide to c-fos mRNA (2±2 mmHg, 2±1 b.p.m., 1.0±1.0%; P<0.05 vs sense oligodeoxynucleotide).
These results suggest that increases in sympathetic and cardiovascular activities induced by pulsatile compression of the rostral ventrolateral medulla are mediated, at least in part, by local activation of the nitric oxide-cyclic GMP pathway and c-fos expression-related substance(s) in rats.
British Journal of Pharmacology (2000) 129, 859–864; doi:10.1038/sj.bjp.0703121
Amino acid neurotransmitters in the nucleus tractus solitarius (NTS) are thought to play a key role in the mediation of visceral reflexes and glutamate has been proposed as the neurotransmitter of visceral afferent nerves projecting to this region. The present studies sought to characterize the use of in vivo microdialysis to examine extracellular fluid levels of amino acids in the NTS of anesthetized rats. Using a microdialysis probe that was 450 μm in length and a sensitive HPLC assay for amino acids, amino acids could be measured in dialysate samples collected from the NTS. Perfusion of the microdialysis probe with 60 mM K±, to elicit depolarization of nerve terminals in the vicinity of the probe, resulted in increased dialysate fluid levels of aspartate, glutamate, glycine, taurine, and GABA. In contrast, glutamine and tyrosine were decreased and other amino acids were not significantly affected. Prior removal of the ipsilateral nodose ganglion did not alter the K±-evoked changes in dialysate levels of any of these amino acids. Electrical stimulation of the vagus nerves, using a variety of stimulus parameters, did not significantly alter dialysate levels of glutamate or any of the other amino acids that were measured. Blockade of glutamate uptake with dihydrokainate increased dialysate levels of glutamate, aspartate, and GABA, but in the presence of dihydrokainate vagal stimulation did not alter dialysate levels of these amino acids. The results show that in vivo microdialysis can be used to examine amino acid efflux in the rat NTS and provide further evidence for amino acidergic neural transmission in the NTS. However, these studies fail to support the hypothesis that vagal afferents release glutamate or aspartate.
The central neural circuit mediating baroreceptor control of sympathetic vasomotor outflow involves an excitatory projection from arterial baroreceptors to nucleus tractus solitarius, an excitatory projection from nucleus tractus solitarius to the caudal ventrolateral medulla, an inhibitory projection from the caudal ventrolateral medulla to the rostral ventrolateral medulla (RVLM), and an excitatory projection from the RVLM to sympathetic preganglionic neurons in the spinal cord. For this circuit to be operational, the relevant neurons in the RVLM must be tonically active. Indeed, numerous studies have demonstrated that RVLM vasomotor neurons are tonically active; however, little is known regarding the nature of the tonic excitatory drive to these neurons. We present a model in which RVLM vasomotor neurons are tonically excited by inputs to the RVLM that can be blocked by the excitatory amino acid receptor antagonist, kynurenic acid, as well as an input from the caudal ventrolateral medulla that is not sensitive to kynurenic acid.
Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key component in the control of arterial blood pressure. Classically, C1 cells have been identified by their immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and/or phenylethanolamine N-methyltransferase (PNMT). However, no studies have simultaneously demonstrated the expression of aromatic L-amino acid decarboxylase (AADC) and dopamine β-hydroxylase (DBH) in these neurons. We examined the expression and colocalization of all four enzymes in the rat ventrolateral medulla using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Retrograde tracer injected into thoracic spinal segments T2–T4 was used to identify bulbospinal neurons. Using fluorescence and confocal microscopy, most cells of the C1 group were shown to be double or triple labeled with TH, DBH, and PNMT, whereas only 65–78% were immunoreactive for AADC. Cells that lacked detectable immunoreactivity for AADC were located in the rostral C1 region, and approximately 50% were spinally projecting. Some cells in this area lacked DBH immunoreactivity (6.5–8.3%) but were positive for TH and/or PNMT. Small numbers of cells were immunoreactive for only one of the four enzymes. Numerous fibres that were immunoreactive for DBH but not for TH or PNMT were noted in the rostral C1 region. Single-cell RT-PCR analysis conducted on spinally projecting C1 neurons indicated that only 76.5% of cells that contained mRNA for TH, DBH, and PNMT contained detectable message for AADC. These experiments suggest that a proportion of C1 cells may not express all of the enzymes necessary for adrenaline synthesis. J. Comp. Neurol. 432:20–34, 2001. © 2001 Wiley-Liss, Inc.
The caudal ventrolateral medulla (CVLM) plays a critical role in cardiovascular regulation. Convincing data now support the hypothesis that inhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM) by CVLM neurons constitutes the necessary inhibitory link in baroreceptor reflex mediated control of sympathetic vasomotor outflow. Inhibition or destruction of the CVLM produces severe acute hypertension, consistent with blockade of baroreceptor reflexes and withdrawal of inhibition of RVLM sympathoexcitatory neurons. However, other data indicate that the CVLM also tonically inhibits RVLM sympathoexcitatory neurons in a manner not driven by baroreceptor input. In some studies, inhibition of the CVLM results in an increase in arterial pressure (AP) without inhibiting baroreceptor reflexes, possibly reflecting baroreceptor-independent and baroreceptor-dependent sub-regions of the CVLM. Furthermore, in baroreceptor-denervated rats, inhibition of the CVLM still leads to large increases in AP. In addition, in spontaneously hypertensive rats (SHR) central processing of baroreceptor reflexes appears normal but CVLM-mediated inhibition of the RVLM seems to be attenuated, suggesting that it is specifically a baroreceptor-independent mechanism of cardiovascular regulation in SHR that is altered. Taken together, these findings support an important, tonic, baroreceptor-independent inhibition of RVLM sympathoexcitatory neurons exerted by the CVLM.
Brainstem projections of the aortic nerve in the rat were studied using the transganglionic transport of horseradish peroxidase. Labeled axons were found to project predominantly to the ipsilateral interstitial nucleus and to the ipsilateral dorsolateral aspect of the nucleus of the solitary tract near the level of the obex. Lighter bilateral projections were also found to the medial, ventrolateral and dorsolateral aspects of the solitary complex, and to the commissural nucleus. These data provide evidence of direct aortic baroreceptor afferent projections to restricted regions of the solitary complex and indicate that these specific areas function in the intergration of the baroreceptor reflex.
Antibodies raised to phosphorylated forms of tyrosine hydroxylase, the first and rate-limiting enzyme in the catecholamine biosynthesis, were applied in immunohistochemical studies on rat brain slices incubated in vitro with a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, IBMX) and forskolin on formalin-perfused rat brains. Four antisera/antibodies were used: polyclonal rabbit antisera to (i) tyrosine hydroxylase phosphorylated at serine 40 (THS40p antiserum), (ii) tyrosine hydroxylase phosphorylated at serine 19 (THS19p antiserum), (iii) to the native enzyme (pan-tyrosine hydroxylase antiserum), and mouse monoclonal antibody to (iv) native tyrosine hydroxylase. In the in vitro studies THS40p-like immunoreactivity was not observed unless slices were treated with IBMX–forskolin after which a dense fibre network was found in the striatum, and immunoreactive cell bodies were found in the ventral mesencephalon, especially in the ventral tegmental area. Although these cells were pan-tyrosine hydroxylase-positive, several of them were not stained with the tyrosine hydroxylase-monoclonal antibody. Moreover, there was a marked reduction of tyrosine hydroxylase-monoclonal antibody-immunoreactive fibres in drug-treated slices, suggesting that this tyrosine hydroxylase-monoclonal antibody does not recognize the Serine 40-phosphorylated form of tyrosine hydroxylase. Treated slices did not show any THS40p-immunoreactive cell bodies in the dopaminergic A11 cell group and only a few, weakly fluorescent neurons were observed in locus coeruleus. However, a sparse fibre lexus was observed in locus coeruleus, possibly reflecting epinephrine fibres. In the perfused brains THS40p-like immunoreactivity could be visualized in some dopamine neurons in the ventral mesencephalon, especially the A10 area, and in noradrenergic locus coeruleus neurons, whereas THS19p-like immunoreactivity was found in all catecholamine groups studied, similar to the results obtained with the pan-tyrosine hydroxylase antiserum and the tyrosine hydroxylase-monoclonal antibody. In forebrain areas known to be innervated by mesencephalic dopamine neurons, no THS40p-positive fibres were observed, whereas THS19p-immunoreactive fibres were found in subregions of the striatum, olfactory tubercle and nucleus accumbens, essentially overlapping with dopamine fibres previously shown to contain cholecystokinin-like immunoreactivity.The present results suggest that antibodies directed against phosphorylated forms of tyrosine hydroxylase can be used to evaluate the state of tyrosine hydroxylase phosphorylation in individual neuronal cell bodies and processes both in vitro and in vivo.
The present in vitro study was performed to characterize neurons within dorsal regions of the nucleus tractus solitarii (NTS), principally at the level of area postrema, and known to recieve inputs predominantly from cardiovascular and respiratory afferents (i.e. cardiorespiratory NTS). This report describes 4 classes of neurons (S1–S4) that were silent at their resting membrane potential and received relatively short (<3.6 ms). and consistent latency synaptic inputs (±0.4 ms) comprising either an EPSP or EPSP/IPSP sequence following low intensity electrical stimulation of the solitary tract (ts). Intracellular recording with sharp electrodes were used to characterize neuron types based on their different firing response patterns to injection of depolarizing current. S1 cells showed a single action potential; s2 fired repetitively; S3 produced a 2–5 spike burst coincident with the start of the current pulse and S4 neurons showed delayed exicitation. Accommodation of firing frequency was seen in S2, S3 and some S4 cells. The voltage dependency of the different discharge patterns of the 4 cell groups was tested by current pulse stimulation at different holding potentials. However, in the majority of cells in any one cell class the firing pattern was qualitatively similar. Based on these findings it is suggested that the different firing characteristics in intrinsic membrane properties between neuron classes. Representative examples from each of the defined cell classes were further studied in current and voltage clamp using the whole cell patch technique to define the presence and role of certain ionic currents in the firing response patterns of the cell groups. In the current clamp configuration the firing behavior of S1 neurons (single spiking) was unaltered during exposure to 4-aminopyridine (4-AP; 2 mM), cobalt of this neuron is due (Co; 5 mM), norepinephrine (NE; 20 μM) and muscarine chloride (50 μM). It is suggested that the relatively low excitability of this neuron is due a persistent outward current which occurred at −40 mV during depolarizing voltage steps in the voltage clamp configuration. A common characteristic of S2 neurons (repetitively firing) was that they showed accommodation during current injection which was greatly attenuated in the presence of Co or NE. In addition, 4-AP slowed the firing frequency, reduced the afterhyperpolarization and broadened the spike width of S2 cells. Interestingly, the amount of accommodation observed in S2 cells was variable for cells of this class and was proportional to the magnitude of a Co-sensitive inward current present during depolarizing voltage steps between −45 to −5 mV. Exposure of S3 cells to NE resulted in repetitive firing with reduced accommodation during current pulse injection. The frequency of discharge during a current pulse was further increased by subsequent administration of 4-AP. Finally, the magnitude of the delayed excitation of S4 neurons was dependent on the voltage and was abolished by 4-AP. This was consistent with voltage clamp data showing a voltage-dependent and 4-AP sensitive outward current, first evident at −40 mV. The present study demonstrates the presence of 4 different cell types within the dorsal or cardiorespiratory region of the NTS. The distinction between the 4 cell groups are based on firing response pattern to injected current and these differences correlate with qualitative differences in the magnitude, time course and voltage dependency of : (1) a 4-AP sensitive current, (2) a Ca, and (3) Ca-dependent currents sensitive to NE and apamin. It is suggested that the intrinsic membrane properties of neurons within the cardiorespiratory NTS may play a role in the integration of afferent inputs. In order to explore these possibilities the following paper describes computational model neurons based on the present data and a previous study on rhythmically active neurons (Paton et al., J. Neurophysiol., 66 (1991) 824–838).
Recent anatomical and physiological studies showed that chemoreceptor afferent fibers are present in the rat aortic depressor nerve (ADN), which has been considered to contain exclusively baroreceptor afferent fibers. However, it remains to be proven whether the chemoreceptor afferents of the ADN are practically involved in chemoreflexes. The present study was performed in chloralose/urethane-anesthetized rats of either Sprague–Dawley (SD) or Wistar strain to examine whether the ADN carries sufficient information regarding arterial hypoxia and hypercapnia, and whether the ADN indeed participates in chemoreflexes, the circulatory and respiratory components. It was found in either strain that afferent discharges of the ADN were not affected at all by hypoxia or hypercapnia, whereas those of the carotid sinus nerve (CSN) markedly increased due to these stimuli. Hypoxia produced hypertension, transient bradycardia followed by tachycardia, and respiratory facilitation, which characterize the chemoreflexes. Any of these responses was not affected at all by the ADN section, but all were abolished by the CSN section. Intraaortic injection of cyanide also induced transient bradycardia and respiratory facilitation, but any of them was not affected by the ADN section while all were abolished by the CSN section. Furthermore, electrical stimulation of the ADN produced solely baroreflex responses, i.e. hypotension and respiratory suppression, whereas that of the CSN provoked chemoreflex responses, i.e. early, transient hypertension and respiratory facilitation. In conclusion, the rat ADN does not contain a functionally significant number of chemoreceptor afferent fibers, if at all, and does not appreciably contribute to generation of chemoreflexes.
It is now clear that ATP acts as a neurotransmitter in both the peripheral and central nervous systems. In the periphery, purinergic transmission has been best studied at certain sympathetic neuroeffector junctions where ATP, co-localized with noradrenaline, is used to elicit the primary post-junctional response . More recently, several groups have raised the possibility that central catecholaminergic neurons might use ATP in a similar fashion . Accordingly, we now present findings from immediate early gene expression and electrophysiological studies which indicate that ATP, acting through P2 purinoreceptors, is used as a transmitter by caudal brainstem noradrenergic neurons, the A1 group, in their interaction with vasopressinergic neurosecretory cells. Supraoptic nucleus vasopressin cell responses to moderate haemorrhage, known to be generated by the Al projection, were suppressed by hypothalamic application of the P2 receptor antagonist suramin. However, suramin did not alter vasopressin cell responses to osmotic challenge or severely hypotensive haemorrhage, two stimuli known to excite vasopressin cells independently of the A1 projection. These data are consistent with an identity of action between the Al input to vasopressin cells and the activation of ATP receptors on vasopressin cells. The use of ATP as a transmitter by other catecholamine neurons in the brain awaits further confirmation, but the present findings suggest that in certain instances the therapeutic manipulation of central catecholamine neuron output might best be achieved with pharmacological agents which target purinergic rather than adrenergic transmission.
We investigated the role of potassium conductances in the nucleus of the solitary tract (NTS) in determining the efficacy of the baroreceptor and cardiopulmonary reflexes in anesthetized rats. The baroreceptor reflex was elicited with an intravenous injection of phenylephrine to evoke a reflex bradycardia, and the cardiopulmonary reflex was evoked with a right atrial injection of phenylbiguanide. Microinjection of two Ca-dependent potassium channel antagonists (apamin and charybdotoxin) into the NTS potentiated the baroreceptor reflex bradycardia. This may reflect the increased neuronal excitability observed previously in vitro with these blockers. In contrast, the Ca-dependent potassium channel antagonists attenuated the cardiopulmonary reflex, whereas voltage-dependent potassium channel antagonists (4-aminopyridine and dendrotoxin) attenuated both the baro- and cardiopulmonary reflexes when microinjected into the NTS. The possibility that the reflex attenuation observed indicates a predominant distribution of certain potassium channels on gamma-aminobutyric acid interneurons is discussed.
The distribution of carotid sinus nerve (CSN) afferent fibers to the solitary tract and its various nuclei has been determined using transganglionic transport of horseradish peroxidase (HRP). The ipsilateral solitary tract was labeled and, in addition, the heaviest labeling was seen dorsomedial within the medial solitary nucleus, as well as just lateral to the tractus solitarius in the lateral solitary nucleus. Bilateral labeling was present caudal to the obex in both the medial and commissural nuclei. The paucity of reaction product within the ventrolateral solitary nucleus supports previous neurophysiological studies suggesting carotid chemoreceptors do not make monosynaptic contacts with respiratory neurons within that nucleus.
Bilateral electrolytic lesions of the nucleus tractus solitarii (NTS) were made at the level of the obex in seven cats. Within 1 hour the mean arterial pressure (MAP) rose to a maximum of 144 mm Hg (141% of control), and by 7 hours heart rate reached a peak of 236 beats/min (148% of control). The baroreceptor reflexes were abolished. After 24 hours the arterial pressure became extremely labile, with variations of 80-100 mm Hg observed. The lability occurred spontaneously and during behaviors that were self-initiated or elicited by environmental stimuli. The MAP in the lesion group was 144 mm Hg (180% of control) during the day, and 96 mm Hg (120% of control) at night. The lability, measured by the standard deviation, during the day in the lesion group was 4 times greater than in the control group and at night there were no differences. The heart rate of the lesion group was always higher than that of the control group but the lability of both groups was the same. We conclude that lesions of the NTS produced labile hypertension, probably by disinhibition of sympathetic activity through central interruption of the baroreceptor reflexes. The higher, more labile arterial pressures during the day may be caused by uninhibited increases in sympathetic activity elicited by environmental stimuli that are present during the day and absent at night. The daily variation of pressure may also be caused by somatomotor activity or by a daily rhythm of sympathetic activity which is unmasked by the lesions.
Carotid and aortic chemoreceptor function was studied in normal Wistar rats. Sodium cyanide, lobeline HCl, and doxapram HCl in the doses of 2-400 mug/kg injected into the external carotid artery stimulated respiration significantly. Injections of the drugs into the ascending aorta produced less effects which were abolished after section of the carotid sinus nerves. The drugs produced a significant increase in the carotid sinus nerve activity but failed to do so in the aortic depressor or recurrent laryngeal nerves. These results indicate that the carotid chemoreceptor function in Wistar rats in normal while functional aortic chemoreceptors are absent in them.
Central catecholaminergic nerves have an integral place in the central connections of the autonomic nervous system, and they play an important role in the regulation of arterial blood pressure. Some evidence suggests that central serotonergic nerves also participate in the control of blood pressure. Studies in various models of experimental hypertension have demonstrated changes in the metabolism and the activity of these central monoaminergic nerves. In addition, selective ablation of central catecholaminergic or serotonergic nerves with a variety of chemical compounds profoundly modifies the development of high blood pressure in a number of experimental models. It seems clear that central monoaminergic systems participate in the regulation of normal blood pressure and that their function is altered in experimental hypertension. However, the exact significance of these changes in experimental hypertension has not been established. Moreover, it is not yet clear which changes are of primary causal importance and which are secondary in nature. There are definite qualitative and quantitative differences in the activity of central monoaminergic nerves in these models of experimental hypertension and in normal animals. These differences are manifest in the markedly different patterns of central monoamine metabolism and the different central effects of selective antagonists on arterial blood pressure in the various preparations. It is clearly not tenable to regard all of these central circulatory effects as nonspecific sequelae of interference with central aminergic tracts participating normally in the normal control of arterial blood pressure. Central catecholaminergic nerves play an important role in the regulation of arterial blood pressure. Although they appear to have little importance in the maintenance of resting arterial blood pressure in normal unstressed animals, they play a major role in the reflex control of blood pressure through the arterial baroreceptor reflexes. The activity of bulbospinal noradrenergic nerves appears to facilitate the increase in arterial blood pressure in neurogenic hypertension and possibly in deoxycorticosterone (DOCA) salt hypertension. The activity of brain stem catecholaminergic nerves appears to inhibit the activity of bulbospinal noradrenergic and serotonergic nerves and hence to have a depressor effect on arterial blood pressure. Disinhibition of bulbospinal noradrenergic and serotonergic fibers by deafferentation of arterial baroreceptors (neurogenic hypertension) or by decreased activity of inhibitory catecholaminergic nerves in the brain stem (DOCA salt and renal hypertension) could play a significant role in the pathogenesis of experimental hypertension. The participation of central catecholaminergic nerves in genetic hypertension (the spontaneously hypertensive rat) has not yet been established. Central serotonergic nerves also appear to play a significant role in the regulation of arterial blood pressure in normal animals and in some models of experimental hypertension. The activity of bulbo spinal serotonergic nerves seems to facilitate the maintenance of arterial blood pressure in normal animals and the increase in blood pressure in experimental neurogenic hypertension, although this matter is still controversial. Central serotonergic nerves do not appear to contribute to experimental renal hypertension, but they may play a role in elevating the pressure in the spontaneously hypertensive rat. The central connections of the autonomic nervous system utilize a variety of neurotransmitters in much the same way as do the peripheral components. It should be expected that each of these central neurotransmitters can be facilitatory or inhibitory in different pathways and that each can synapse with a variety of functionally distinct receptors. These facts, with the presence of short excitatory or inhibitory interneurons, increase the complexity of experimental data on the functional role of central monoaminergic pathways.
Previous studies have indicated that tonic stimulation of GABAB receptors in the nucleus tractus solitarius (NTS) contributes to the regulation of arterial blood pressure (AP). The present studies examined the hypotheses that (1) tonic stimulation of GABAB receptors in the NTS provides a tonic attenuation of the baroreceptor reflex and (2) enhanced stimulation of these GABAB receptors markedly attenuates the baroreceptor reflex resulting in an increase in AP. In chloralose-anesthetized rats electrical stimulation of the aortic depressor nerve elicited frequency-dependent decreases in AP and heart rate (HR). These responses were markedly attenuated, but not eliminated, by injection of the GABAB receptor agonist baclofen into the ipsilateral NTS. In contrast, the GABAA receptor agonist muscimol completely inhibited aortic depressor nerve-evoked responses. Blockade of GABAB receptors in the NTS by local injection of CGP-35348 elicited a dose-dependent decrease in AP, and a dose-dependent blockade of the pressor response elicited by injection of baclofen into the NTS. These results support the hypothesis that GABA acts tonically on GABAB receptors in the NTS to attenuate the baroreceptor reflex, thereby contributing to the regulation of AP.
Bilateral injection into the nucleus tractus solitarius (NTS) of the alpha 2-adrenergic receptor antagonist yohimbine produced a dose-related (10-500 pmol) increase in arterial pressure, with a maximal response of approximately 60 mm Hg. Idazoxan, also an alpha 2-adrenergic receptor antagonist, produced a similar response although idazoxan was less potent than yohimbine. The pressor response elicited by these drugs was attenuated by stimulation of adrenergic receptors in the NTS by local administration of either clonidine or tyramine. Doses of yohimbine (200 pmol) or idazoxan (5 nmol) that maximally increased arterial pressure also completely inhibited the depressor and bradycardic responses to electrical stimulation of the aortic depressor nerve. These results indicate that tonic stimulation of alpha 2-adrenergic receptors in the NTS is required for baroreceptor reflex function.
Unilateral microinjection of L-glutamate into the nucleus tractus solitarii of conscious rats increased arterial pressure and caused bradycardia while microinjection of S-nitrosocysteine into the same site of these animals caused hypotension and bradycardia. The responses to S-nitrosocysteine were blocked by prior microinjection of methylene blue into the nucleus tractus solitarii. The bradycardia and fall in arterial pressure induced by S-nitrosocysteine resemble more the cardiovascular changes in response to activation of baroreceptor afferents than the bradycardia and increase in arterial pressure induced by microinjection of L-glutamate into the nucleus tractus solitarii of conscious rats.
Previous studies have shown that pharmacological blockade of ionotropic excitatory amino acid (EAA) receptors in the nucleus tractus solitarii (NTS) with kynurenate (Kyn) abolishes baroreceptor reflexes but fails to affect cardiovascular responses evoked by microinjections of L-glutamate (Glu) into the NTS. These observations have raised doubts as to whether Glu is a neurotransmitter of baroreceptor information in the NTS because the pharmacological actions of exogenously administered Glu are not identical to those of the neurotransmitter released in the NTS coincident with baroreceptor activation. One possible explanation for these results is that exogenously administered Glu might act at receptors that are not blocked by Kyn and are not accessible to synaptically released Glu in the NTS baroreflex pathway. The purpose of this study was to determine if Kyn-insensitive Glu receptors are present in the NTS. One candidate for this Kyn-insensitive receptor is the metabotropic EAA receptor that is selectively activated by trans-DL-1-amino-1,3-cyclopentane-dicarboxylic acid (ACPD). Microinjections of ACPD into the NTS of anesthetized rats produced dose-related depressor responses that were not reduced by Kyn or by pretreatment with the putative ACPD receptor antagonist L-2-amino-3-phosphonopropionate (L-AP-3). Similarly, depressor responses produced by Glu also were not affected by Kyn or by L-AP-3. These data demonstrate the presence of a Kyn-insensitive Glu receptor in the NTS. Moreover, they suggest that the failure of Kyn to reduce cardiovascular responses evoked by Glu injections into the NTS can be explained by an action of Glu at Kyn-insensitive ACPD receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
The rostral ventrolateral medulla (RVLM) contains sympathoexcitatory neurons that exert a powerful control over the sympathetic outflow to the cardiovascular system. In the cat there is a concentration of such neurons (but not neurons subserving other functions) within a narrow longitudinal column in the RVLM termed the subretrofacial (SRF) nucleus. Furthermore, it has been suggested that there are subgroups of cells, located at different rostrocaudal levels of the SRF nucleus, that preferentially or exclusively control different vascular beds (e.g. in the kidney and hindlimb). The aim of this study was to map quantitatively the rostrocaudal distribution within the nucleus of different cell types, defined according to morphological and/or chemical criteria, and to correlate this with the regional vasomotor effects (in hindlimb and kidney) evoked by stimulation of SRF cells at the corresponding rostrocaudal levels. SRF cells were highly heterogeneous with respect to both their morphology and chemical properties. They varied greatly in size (equivalent diameter ranging from 10-40 microns) as well as in shape and orientation. An immunohistochemical examination using the avidin-biotin procedure revealed that many SRF cells (estimated 57% of all SRF cells) were immunoreactive for tyrosine hydroxylase (TH, a marker of catecholamine cells). In addition, there were SRF cells immunoreactive for neuropeptide Y (NPY, 11% of total), enkephalin (ENK, 16% of total), and serotonin (5HT, 10% of total), but not for substance P, galanin or somatostatin. Different cell types, defined according to their morphology and/or chemical properties, were unevenly distributed throughout the nucleus. In the most caudal part of the SRF nucleus, virtually all cells were TH-positive, and the large majority (estimated 80%) were NPY-positive, suggesting that many cells at this level contained both TH and NPY. In contrast, in the most rostral part of the SRF nucleus, only 30% of cells were TH-positive, and no NPY-positive cells were observed. Both 5HT- and ENK-positive cells were found throughout the rostrocaudal extent of the nucleus, but predominantly within its rostral part. Furthermore, TH-positive cells in the rostral SRF nucleus were on average significantly larger (mean equivalent diameter 18-43% greater) than TH/NPY-positive cells in the caudal part of the nucleus, but smaller than 5HT- or ENK-positive cells at the same level. Overall, rostral cells (regardless of their chemical type) were larger than caudal cells within the SRF nucleus (mean equivalent diameter 13-28% greater).(ABSTRACT TRUNCATED AT 400 WORDS)
The caudal ventrolateral medulla (CVLM) contains vasodepressor neurons which, when activated, decrease vasomotor tone. To investigate whether excitatory amino acid receptors in the CVLM of the rat are involved in mediation of the aortic baroreceptor reflex, we microinjected amino acid antagonists unilaterally into the CVLM and examined their effects on the depressor response to electrical stimulation of the aortic nerve which contains mainly baroreceptor afferent fibers in rats. Male Wistar rats were anaesthetized with urethane, paralyzed and artificially ventilated. To block reflex vagal effects, methylatropine (1 mg/kg) was given intravenously. Kynurenate (227 ng), an excitatory amino acid antagonist, injected ipsilaterally but not contralaterally into the CVLM markedly inhibited the depressor response to aortic nerve stimulation, while both injections produced a similar small increase in basal blood pressure. Muscimol (1 ng), a GABA receptor agonist, injected ipsilaterally into the CVLM partly inhibited the baroreflex response, while it produced a moderate increase in basal blood pressure. 2-Amino-5-phosphonovalerate (APV) (10 ng), a N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801 (30 ng), a NMDA receptor channel blocker, partly inhibited the baroreflex response. MK-801 (30 ng) injected into the CVLM reduced the depressor response to the NMDA receptor agonist NMDA (0.3 ng) but not to the quisqualate receptor agonist quisqualate (0.1 ng) and the kainate receptor agonist kainate (0.1 ng), while kynurenate (227 ng) inhibited the depressor response to all three excitatory amino acid receptor agonists. These findings provide further evidence for the presence of excitatory amino acid receptors involved in mediating the aortic baroreceptor reflex in the rat CVLM.(ABSTRACT TRUNCATED AT 250 WORDS)
We made extracellular recordings from 104 spinally projecting neurons in the rostral ventrolateral medulla of urethan-anesthetized rabbits to test whether inhibitory vasomotor neurons in the caudal ventrolateral medulla act by inhibiting rostral sympathoexcitatory neurons. The median conduction velocity was 8.3 m/s, and the median discharge rate was 2.9 spikes/s. Raising arterial pressure with intravenous phenylephrine inhibited 88% of 77 neurons tested. The remaining units were excited. Lowering arterial pressure with nitroprusside excited 90% of 30 neurons tested. Remaining units were unaffected. Ninety-one percent of 58 rostral neurons inhibited by phenylephrine were also inhibited by injection of L-glutamate into the caudal ventrolateral medulla and 81% of 43 tested were excited by caudal injection of gamma-aminobutyric acid. These results confirm our suggestion [Brain Res. 253: 161-171, 1982; Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H686-H692, 1988] and the findings of S. K. Agarwal, A. J. Gelsema, and F. R. Calaresu [Am. J. Physiol. 257 (Regulatory Integrative Comp. Physiol. 26): R265-R270, 1989]. The depressor neurons in the caudal medulla act substantially by inhibition of spinally projecting sympathoexcitatory neurons in the rostral medulla. All rostral units excited by phenylephrine were also excited by injections of L-glutamate into the caudal ventrolateral medulla, suggesting that some sympathoinhibition of baroreceptor and caudal medullary origin may take place in the spinal cord and be mediated by a subpopulation of rostral sympathoinhibitory neurons.
Phosphate activated glutaminase (PAG), an enzyme of glutamate synthesis, was localized by immunohistochemistry in all PNMT-immunoreactive and all serotonin-immunoreactive neurons in the rostral ventral medulla of the rat. Between 71 and 83% of bulbospinal neurons localised in the rostral ventral medulla projecting to the intermediolateral cell column in the upper thoracic spinal cord contained PAG immunoreactivity. Of these bulbospinal PAG-immunoreactive neurons 17-27% contained PNMT immunoreactivity and 9-16% contained serotonin immunoreactivity. Other bulbospinal PAG-immunoreactive neurons (60-70%) contained neither PNMT- nor serotonin immunoreactivity. The results provide anatomical evidence suggestive of a glutamatergic input to the sympathetic preganglionic neurons of the spinal cord arising from different populations of neurons located in the rostral ventral medulla.
As microinjection of either substance P (SP) or acetylcholine (ACh) into the right intermediolateral cell nucleus (IML) at the T2 level elicits increases in heart rate (HR) in the anesthetized rat, we investigated the possibility of a synergistic effect on HR and arterial pressure (AP) of ACh and SP microinjected in this nucleus. Moreover, we studied the effect on HR and AP of microinjection of either ACh or SP into the IML combined with activation of cardiovascular neurons in the ipsilateral rostral ventrolateral medulla (RVLM) by microinjection of glutamate (Glu). Male Wistar rats (n = 16) were anesthetized with urethane (1.4 g/kg i.p.), artificially ventilated, and the dorsal medulla and spinal cord (T1-T3) were exposed. Micropipettes containing SP and ACh were positioned in the right IML at the T2 level. Microinjection of threshold amounts of ACh (5 x 10(-2) M, 2-10 nl) and SP (3 x 10(-6) M, 2-10 nl) that caused small or no changes in HR or AP (less than 10 bpm or mmHg) elicited statistically significant synergistic increases in HR (22.9 +/- 3.3 bpm) but no changes in AP. Threshold microinjections of Glu (0.18 M, 2-10 nl) into the right RVLM combined with microinjections of threshold amounts of SP or ACh into the ipsilateral IML elicited significant synergistic increases in HR of 13.1 +/- 1.9 bpm and 10.6 +/- 1.9 bpm and in AP of 9.7 +/- 1.9 mmHg and 10.8 +/- 1.7 mmHg, respectively. These results indicate that SP and ACh interact to influence cardioacceleratory spinal preganglionic neurons (SPN) and interact with the transmitter released in the IML by RVLM stimulation to elicit increases in HR.(ABSTRACT TRUNCATED AT 250 WORDS)
The caudal ventrolateral medulla (CVLM) plays a significant role in the regulation of sympathetic nerve activity (SNA) and arterial pressure; however, the use of lesions to examine its role in mediating baroreceptor reflex control of SNA has yielded discrepant results. We hypothesize that this may have arisen from anatomic segregation of neurons within the CVLM that subserve different functions in sympathetic control. Thus we used microinjections of the excitotoxic agent kainic acid (200 pmol in 20 nl) to determine the effects of inactivation of neuronal cell bodies in a rostral and a caudal subregion of the CVLM on SNA, arterial pressure, and baroreceptor reflex function in urethan-anesthetized rats. Interruption of neuronal activity in the rostral CVLM (sites from 0.6 mm caudal to 0.5 mm rostral to the rostral border of the lateral reticular nucleus) elevated SNA (post-kainic acid 214% of control) and arterial pressure (+34 mmHg) and eliminated the inhibition of splanchnic SNA evoked by either aortic nerve stimulation or the pressor response to intravenous norepinephrine. In addition, the cardiac-related component of spontaneous SNA was abolished as judged from post-R wave averages and from power spectral analysis. In contrast, although a similar disruption of neuronal activity in the caudal CVLM (sites 0.0-0.6 mm rostral to the caudal border of the lateral reticular nucleus) produced a comparable increase in spontaneous SNA (post-kainic acid 196% of control) and arterial pressure (+20 mmHg), it was without effect on the ability of the baroreceptor reflex to inhibit SNA, and it enhanced the synchronization of the spontaneous bursts in SNA to the cardiac cycle. Our results suggest an organization of the CVLM in which neurons in its rostral portion are required for an effective baroreceptor reflex, whereas those in the caudal CVLM serve to limit SNA and blood pressure independent of the baroreceptor reflex.
Experiments were done to test the hypothesis that caudal ventrolateral medulla (CVLM) neurons excited by activation of arterial baroreceptors and by stimulation of depressor sites in the nucleus tractus solitarii (NTS) project monosynaptically to the rostral ventrolateral medulla (RVLM). In urethan anaesthetized and artificially ventilated rats we recorded extracellular activity from 46 spontaneously firing units in the CVLM. Twenty of these units were excited by baroreceptor activation (1-3 micrograms phenylephrine i.v.) and of these 6 were excited (mean latency of 9.8 +/- 2.3 ms) by single pulses (0.1 ms, 30 +/- 8.3 microA) delivered once per second to a depressor site in the ipsilateral NTS. These 6 units were also antidromically activated with a latency of 4.1 +/- 0.12 ms by stimulation of a pressor region in the ipsilateral RVLM. These results provide evidence for the existence of an excitatory projection from the NTS to the CVLM which, in turn, projects monosynaptically to sympathoexcitatory neurons in the RVLM.
Indirect evidence suggests that excitatory amino acids (EAA) are involved in synaptic transmission of visceral afferents at their synapses within the nucleus tractus solitarius (NTS). Little is known about the identity of the postsynaptic receptors or response mechanisms. Here we report results from a longitudinal brain slice of the rat medulla. Intracellular recordings were made from neurons in delimited portions of the dorsal medial NTS (mNTS) known to receive baroreceptor inputs. Stimulation of the solitary tract 1-3 mm from the mNTS recording site evoked short (2 ms) latency excitatory postsynaptic potentials (EPSPs), which had durations of 40-50 ms. Addition of the non-N-methyl-D-aspartate (non-NMDA) selective antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) to the slice surface near the recording electrode resulted in a rapid (within 30-45 s) suppression of the EPSP. Complete EPSP blockade was only slowly reversed by drug-free saline. Concentration-response relations (n = 14) showed 50% depression of EPSPs by surface concentrations of 1-10 microM CNQX. EPSP amplitude was resistant to the selective NMDA antagonist 2-amino-5-phosphonovalerate (AP 5) and, on average, was reduced less than 20% at 100 microM AP 5, an effect that was not statistically significant (n = 10; P greater than 0.05). In conclusion, this study offers the first direct evidence that EAAs mediate the primary events of afferent synaptic transmission in NTS. The experiments suggest that excitatory sensory afferent synaptic transmission to mNTS neurons is mediated by an EAA transmitter acting at non-NMDA receptors, but NMDA receptors may have a modulatory role.
Neuropeptide Y (NPY), neurotensin, arginine vasopressin (AVP), angiotensin II (ANG II), atrial natriuretic peptide (ANP) and calcitonin gene-related peptide (CGRP) have been suggested as putative neurotransmitters in the nucleus tractus solitarii (NTS) where baro- and chemoreceptor afferents terminate. To investigate modulation of the aortic baroreceptor reflex by neuropeptides, we microinjected these neuropeptides into the medial area of the rat NTS and examined their effects on the depressor and bradycardic responses to electrical stimulation of the aortic nerve which contains mainly baroreceptor afferent fibers in rats. Male Wistar rats were anesthetized with urethane, paralyzed and artificially ventilated. NPY (3 ng) and neurotensin (0.3 ng) injected into the NTS caused a decrease in blood pressure and/or heart rate, and facilitated the depressor and bradycardic responses to aortic nerve stimulation. AVP (3 ng) produced an increase in blood pressure and heart rate, and inhibited the responses to aortic nerve stimulation, whereas d(CH2)5Tyr(Me)AVP(100 ng), a V1 vasopressin receptor antagonist, did not affect the basal cardiovascular parameters and the baroreflex responses. ANG II (0.3 and 3 ng) caused a decrease in blood pressure and heart rate whereas at 0.3 ng it did not affect the baroreflex responses. ANP (3 ng) and CGRP (3 ng) did not affect the basal blood pressure and heart rate, and the responses to aortic nerve stimulation. These findings indicate that NPY, neurotensin and AVP microinjected into the rats NTS can modify the aortic baroreceptor reflex. Some of these neuropeptides may play a role in modulation of the aortic baroreceptor reflex within the NTS.
Neurons of the subretrofacial nucleus in the rostral ventrolateral medulla have been studied by in vivo intracellular recording in the chloralose-anaesthetized cat. Impalements of sufficient quality to demonstrate inhibition by carotid baroreceptor stimulation (blind sac inflation) were obtained for 9 cells. In 8 of these, a clear hyperpolarization followed approximately 100-200 ms after the baroreceptor stimulus, reaching a maximum of 2-9 mV, 200-500 ms later. These findings confirm by more direct methods the inhibition of subretrofacial neurons by arterial baroreceptors.