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Baseline levels of cardiovascular variables and the effects of intracerebroventricular infusion of sodium nitroprusside (500 g·ml 1 ·h 1 ) in a group of normal () and HF (OE) sheep. n 7/group. *Significant effect of time on CSNA levels P 0.05. Note that the decrease in CSNA is similar in both the normal and the HF groups.
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Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympatho-excitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from down-regulation of neuronal NO synthase (nNOS...
Citations
... It has also been shown that there is greater activation of neurons in the PVN induced by afferent renal nerve stimulation in rats with HF 7,9,51 . It is well known that, just as in various models of hypertension, brain nNOS/NO is decreased in the PVN of various models of HF 6,40,[51][52][53] . Both A-RDN and T-RDN restore nNOS/NO in the PVN with concomitant sympathoinhibition in rats with HF 6,40,51 . ...
Excessive activation of the sympathetic nervous system is one of the pathophysiological hallmarks of hypertension and heart failure. Within the central nervous system, the paraventricular nucleus (PVN) of the hypothalamus and the rostral ventrolateral medulla in the brain stem play critical roles in the regulation of sympathetic outflow to peripheral organs. Information from the peripheral circulation, including serum concentrations of sodium and angiotensin II, is conveyed to the PVN via adjacent structures with a weak blood–brain barrier. In addition, signals from baroreceptors, chemoreceptors and cardiopulmonary receptors as well as afferent input via the renal nerves are all integrated at the level of the PVN. The brain renin-angiotensin system and the balance between nitric oxide and reactive oxygen species in these brain areas also determine the final sympathetic outflow. Additionally, brain inflammatory responses have been shown to modulate these processes. Renal denervation interrupts both the afferent inputs from the kidney to the PVN and the efferent outputs from the PVN to the kidney, resulting in the suppression of sympathetic outflow and eliciting beneficial effects on both hypertension and heart failure.
... Dr. Mitchell has been a mentor of the first author of this review paper. The exercise pressor reflex can be described as follows: Static exercise or isometric skeletal muscle contraction as observed during push-ups, rowing a boat, weight-lifting and exercising with the dumbbells, sends impulses via the group III and IV muscle afferents within the spinal cord to activate neurons in the medulla oblongata, particularly within the RVLM and the CVLM where they are integrated, and the final results are increases in MAP, HR, myocardial contractility, cardiac output, and sympathetic nerve activity [175][176][177][178][179]. This paragraph will discuss how nNOS within the RVLM and the CVLM modulates cardiovascular responses along with alterations in glutamate and GABA neurotransmission during the exercise pressor reflex. ...
This review describes and summarizes the role of neuronal nitric oxide synthase (nNOS) on the central nervous system, particularly on brain regions such as the ventrolateral medulla (VLM) and the periaqueductal gray matter (PAG), and on blood vessels and the heart that are involved in the regulation and control of the cardiovascular system (CVS). Furthermore, we shall also review the functional aspects of nNOS during several physiological, pathophysiological, and clinical conditions such as exercise, pain, cerebral vascular accidents or stroke and hypertension. For example, during stroke, a cascade of molecular, neurochemical, and cellular changes occur that affect the nervous system as elicited by generation of free radicals and nitric oxide (NO) from vulnerable neurons, perioxide formation, superoxides, apoptosis, and the differential activation of three isoforms of nitric oxide synthases (NOSs), and can exert profound effects on the CVS. Neuronal NOS is one of the three isoforms of NOSs, the others being endothelial (eNOS) and inducible (iNOS) enzymes. Neuronal NOS is a critical homeostatic component of the CVS and plays an important role in regulation of different systems and disease process including nociception. The functional and physiological roles of NO and nNOS are described at the beginning of this review. We also elaborate the structure, gene, domain, and regulation of the nNOS protein. Both inhibitory and excitatory role of nNOS on the sympathetic autonomic nervous system (SANS) and parasympathetic autonomic nervous system (PANS) as mediated via different neurotransmitters/signal transduction processes will be explored, particularly its effects on the CVS. Because the VLM plays a crucial function in cardiovascular homeostatic mechanisms, the neuroanatomy and cardiovascular regulation of the VLM will be discussed in conjunction with the actions of nNOS. Thereafter, we shall discuss the up-to-date developments that are related to the interaction between nNOS and cardiovascular diseases such as hypertension and stroke. Finally, we shall focus on the role of nNOS, particularly within the PAG in cardiovascular regulation and neurotransmission during different types of pain stimulus. Overall, this review focuses on our current understanding of the nNOS protein, and provides further insights on how nNOS modulates, regulates, and controls cardiovascular function during both physiological activity such as exercise, and pathophysiological conditions such as stroke and hypertension.
... Аналогічно надекспресія eNOS у ростральній вентролатеральній частині довгастого мозку й ядрах солітарного тракту зменшує артеріальний тиск та активність симпатичного нерва. Нові дані, отримані від прямого виміру симпатичної нервової активності з використанням імплантованих електродів, вказують, що екзогенний NO може зменшити вплив симпатичної нервової системи на серце [27,28]. Є також дані, що зниження біодоступності NO в паравентрикулярному ядрі посилює розрядку ниркового симпатичного нерва. ...
L-аргінін — умовно незамінна амінокислота, яка є клітинним регулятором багатьох життєво важливих функцій організму. Він бере участь у регуляції тонусу гладеньком’язового компонента стінки судин, бронхів, кишечника. L-аргінін є субстратом для синтази оксиду азоту (NOS), яка продукує оксидазоту (NO). NO, що утворюється в ендотелії судин, відповідає за релаксацію гладеньких м’язів і необхідний для зниження артеріального тиску. L-аргінін має високий функціональний пріоритет у продукції NO, а отже, у фізіології серцево-судинної та цереброваскулярної систем. L-аргінін може зменшувати ожиріння, знижувати артеріальний тиск, пригнічувати окислювальні процеси та нормалізувати ендотеліальну дисфункцію, сприяючи ремісії за діабету 2-го типу. L-аргінін також використовується клітинами імунної системи, може знижувати рівень інфікування, надто за порушеня імунної функції. L-аргінін уповільнює старіння, пригнічує агрегацію тромбоцитів, регулює множинні метаболічні шляхи, пов’язані з метаболізмом жирних кислот, глюкози, амінокислот і білків. Тому слід враховувати терапевтичний потенціал L-аргініну та продовжувати вивчення можливостей його використання як перспективного препарату за прогресування судинної дисфункції, пов’язаної зі старінням, діабетом і серцево-судинними захворюваннями.
... A jugular catheter was also inserted for intravenous infusion and drug administration. In six animals, 4 -5 needle electrodes were inserted into the left renal sympathetic nerve as described previously (19,20). Postoperative analgesia (ketofen, 2 mg/kg; Boehringer Ingleheim, Auckland, NZ) was given as needed. ...
... In addition, the ICP and AP catheters were connected to a dual-channel pressure control unit (PCU-2000; Millar, Houston, TX), and the renal sympathetic nerve activity (RSNA) electrodes were connected to a differential amplifier, with the pair of electrodes giving the best signal-to-noise ratio chosen. RSNA was recorded and analyzed as described previously (19,20). The ICP, AP, and RSNA signals were recorded using PowerLab and LabChart (v.8.15; ADInstruments, Sydney, Australia) at a sampling frequency of 1 kHz. ...
Sympathetic overdrive is associated with many diseases, but its origin remains an enigma. An emerging hypothesis in the development of cardiovascular disease is that the brain puts the utmost priority on maintaining its own blood supply; even if this comes at the "cost" of high blood pressure to the rest of the body. A critical step in making a causative link between reduced brain blood flow and cardiovascular disease is how changes in cerebral perfusion affect the sympathetic nervous system. A direct link between decreases in cerebral perfusion pressure and sympathetic tone generation in a conscious large animal has not been shown. We hypothesized that there is a novel control pathway between physiological levels of intracranial pressure (ICP) and blood pressure via the sympathetic nervous system. Intracerebroventricular infusion of saline produced a ramped increase in ICP of up to 20 mmHg over a 30-minute infusion period (baseline 4.0±1.1 mmHg). The ICP increase was matched by an increase mean arterial pressure such that cerebral perfusion pressure remained constant. Direct recordings of renal sympathetic nerve activity indicated that sympathetic drive increased with increasing ICP. Ganglionic blockade, by hexamethonium, preventing sympathetic transmission, abolished the increase in arterial pressure in response to increased ICP and was associated with a significant decrease in cerebral perfusion pressure. This is the first study to show that physiological elevations in intracranial pressure regulate renal sympathetic activity in conscious animals. We have demonstrated a novel physiological mechanism linking ICP levels with sympathetic discharge via a possible novel intracranial baroreflex.
... It has been reported that NO inhibits sympathetic nerve activity by blocking norepinephrine synthesis and release from presynaptic sympathetic nerves. [107][108][109] This in turn blocks norepinephrine-β adrenergic receptor signaling, reduces activation of the reninangiotensin-aldosterone system, and results in cardiac and renal protection (Figure 4). ...
Hydrogen sulfide (H2S)-a potent gaseous signaling molecule-has emerged as a critical regulator of cardiovascular homeostasis. H2S is produced enzymatically by 3 constitutively active endogenous enzymes in all mammalian species. Within the past 2 decades, studies administering H2S-donating agents and the genetic manipulation of H2S-producing enzymes have revealed multiple beneficial effects of H2S, including vasodilation, activation of antiapoptotic and antioxidant pathways, and anti-inflammatory effects. More recently, the heightened enthusiasm in this field has shifted to the development of novel H2S-donating agents that exert favorable pharmacological profiles. This has led to the discovery of novel H2S-mediated signaling pathways. This review will discuss recently developed H2S therapeutics, introduce signaling pathways that are influenced by H2S-dependent sulfhydration, and explore the dual-protective effect of H2S in cardiorenal syndrome.
... NO is generated from the oxidation of L-arginine by NO synthase (NOS) (Calabrese et al. 2007). Tonic CNS production of NO restrains sympathetic outflow (Sakuma et al. 1992, Matsumura et al. 1998, Sander et al. 1999, Ramchandra et al. 2014, possibly due to its sympathoinhibitory action at the PVN, RVLM and NTS (Harada et al. 1993, Zanzinger et al. 1995, Zhang et al. 1997. NO provides inhibitory control to vasopressin-secreting magnocellular neurones (Liu et al. 1997, Srisawat et al. 2000 which appears to be tonically active because central NOS inhibition increases plasma vasopressin in conscious euhydrated rats (Kadekaro et al. 1998). ...
... NO provides inhibitory control to vasopressin-secreting magnocellular neurones (Liu et al. 1997, Srisawat et al. 2000 which appears to be tonically active because central NOS inhibition increases plasma vasopressin in conscious euhydrated rats (Kadekaro et al. 1998). Less clear is the role of central NO in the steady-state regulation of baroreflex function, with conflicting reports that central NO enhances (Jin & D'Alecy 1996, Ramchandra et al. 2014 or alternatively reduces (Matsumura et al. 1998) baroreflex control of heart rate and SNA. Total NO production is decreased in CKD patients (Fig. 1b) (Blum et al. 1998 in part because of reduced NOS activity (Wever et al. 1999, Baylis 2006. ...
Chronic kidney disease (CKD) carries a large cardiovascular burden in part due to hypertension and neurohumoral dysfunction - manifesting as sympathetic overactivity, baroreflex dysfunction and chronically elevated circulating vasopressin. Alterations within the central nervous system (CNS) are necessary for the expression of neurohumoral dysfunction in CKD however the underlying mechanisms are poorly defined. Uraemic toxins are a diverse group of compounds that accumulate as a direct result of renal disease and drive dysfunction in multiple organs, including the brain. Intensive haemodialysis improves both sympathetic overactivity and cardiac baroreflex sensitivity in renal failure patients, indicating that uraemic toxins participate in the maintenance of autonomic dysfunction in CKD. In rodents exposed to uraemia, immediate early gene expression analysis suggests upregulated activity of not only presympathetic but also vasopressin-secretory nuclei. We outline several potential mechanisms by which uraemia might drive neurohumoral dysfunction in CKD. These include superoxide-dependent effects on neural activity, depletion of nitric oxide and induction of low-grade systemic inflammation. Recent evidence has highlighted superoxide production as an intermediate for the depolarising effect of some uraemic toxins on neuronal cells. We provide preliminary data indicating augmented superoxide production within the hypothalamic paraventricular nucleus in the Lewis Polycystic Kidney rat, which might be important for mediating the neurohumoral dysfunction exhibited in this CKD model. We speculate that the uraemic state might serve to sensitise the central actions of other sympathoexcitatory factors, including renal afferent nerve inputs to the CNS and angiotensin II, by way of recruiting convergent superoxide-dependent and pro-inflammatory pathways. This article is protected by copyright. All rights reserved.
... Evidence indicates that stretch induces tissue nitric oxide (NO) production in cardiac muscle (Petroff et al., 2001; Prosser et al., 2014; Umar et al., 2009; van et al., 2006), which may act to regulate force production through altering Ca 2+ release by SR RYR (Jian et al., 2014; Kakizawa et al., 2013; Petroff et al., 2001; Sun et al., 2001; Xu et al., 2012). NO, a cellular second messenger, can mediate numerous biological functions, such as anti-apoptosis activities (Hruby et al., 2008), heart rate, heart development (Liu et al., 2012; Ramchandra et al., 2014) vasodilation and muscle contractility (Denniff et al., 2014; Smiljic et al., 2014). There are three known isoforms of nitric oxide synthase (NOS), with eNOS accounting for most of the NO production in smooth muscle (Grider et al., 2008; Han et al., 2013; Yanai et al., 2008). ...
The stretching of smooth muscle tissue modulates contraction via augmentation of Ca(2+) transients, but the mechanism underlying stretch-induced Ca(2+) transients is still unknown. We found that mechanical stretching and maintenance of mouse urinary bladder smooth muscle strips and single myocytes at the initial length of 30% and 18%, respectively, resulted in Ca(2+) oscillations. Experiments indicated that mechanical stretching remarkably increases the production of nitric oxide (NO) as well as the amplitude and duration of muscle contraction. Stretch-induced Ca(2+) oscillations and contractility increases were completely abolished by NO inhibitor L-NAME or eNOS gene inactivation. Moreover, exposure of eNOS knockout myocytes to exogenous NO donor induced Ca(2+) oscillations. The stretch-induced Ca(2+) oscillations were greatly inhibited by selective IP3R inhibitor xestospongin C and partially inhibited by ryanodine. Moreover, the stretch-induced Ca(2+) oscillations were also suppressed by LY294002, but not by the soluble guanylyl cyclase (sGC) inhibitor ODQ. These results suggest that myocytes stretching and maintenance at a certain length resulted in Ca(2+) oscillations that is NO dependent and sGC/cGMP independent and results from the activation of PI(3)K in smooth muscle.
... 34 More recent data obtained from direct sympathetic nerve activity recordings with the use of chronically implanted electrodes indicate that exogenous NO can reduce sympathetic outflow to the heart in conscious sheep. 35 There is also evidence that reduced NO bioavailability within the paraventricular nucleus augments renal sympathetic nerve discharge. 36,37 A reduction in NO levels may increase sympathetic outflow to the kidney because specific inhibition of eNOS-derived NO within the paraventricular nucleus of the hypothalamus can increase RSNA. ...
Obesity and its complications represent one of the major emerging challenges for the developed world.1,2 Hypertension is a common sequelae of obesity,3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication,4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy.4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension6,7 including that associated with obesity.8
In the current review, we will discuss the role of the l-arginine–NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension.
NO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)–dependent NO formation (Figure 1).9–11 This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant Km of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox.9 The precise factors underlying this paradox remain to be determined, but …
... Truth is that central nitric oxide can reduce blood pressure via attenuation of sympathetic activity in hypertensive rats ( Zhou et al 2014;Ramchandra et al 2014). The question arise which NOS isoform may contribute mostly to this blood pressure reduction. ...
The dysbalance between the sympathetic and parasympathetic vegetative system and increased free radical burden in the central nervous system (CNS) are the important pathophysiological disorders and therapeutic targets in hypertension. Besides the effects on cardiovascular system, the pineal hormone, melatonin (N-acetyl-5-methoxytryptamine) may exert part of its antihypertensive action just through its interaction with the CNS. Melatonin may be protective in CNS on several different levels: it reduces production of reactive oxygen species, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. Increased level of serum melatonin observed in some types of hypertension may represent a counterregulatory adaptive mechanism against the sympathetic overstimulation. All these effects of melatonin may include increased production of nitric oxide in their mechanisms of protection. In different experimental models of hypertension upregulation of nitric oxide synthase (NOS) activity and NOS isoform expression in different parts of brain after melatonin treatment have been documented. Thus, it is supposed that the correction of absolute or relative melatonin deficiency by exogenous melatonin administration in conditions of increased blood pressure, may help to attenuate the excessive catecholamine outflow providing a rational background for therapeutic application of melatonin in hypertension treatment.
... Of note, in the RVLM and NTS, NO can also increase SNA. Recently, it has been reported that endogenous NO in the CNS exerted excitatory effects to increase resting CSNA in healthy subjects, while exogenously administrated NO inhibited CSNA under normal and CHF conditions (71). Thus, the sympathoexcitatory and sympathoinhibitory effects of NO in the CNS may partly depend on the balance of glutamatergic and GABAergic activity, the specific sympathetic activity-regulating nuclei on which it acts and the method of NO administration. ...
Patients with chronic heart failure (CHF) have an insufficient perfusion to the peripheral tissues due to decreased cardiac output. The compensatory mechanisms are triggered even prior to the occurrence of clinical symptoms, which include activation of the sympathetic nervous system (SNS) and other neurohumoral factors. However, the long‑term activation of the SNS contributes to progressive cardiac dysfunction and has toxic effects on the cardiomyocytes. The mechanisms leading to the activation of SNS include changes in peripheral baroreceptor and chemoreceptor reflexes and the abnormal regulation of sympathetic nerve activity (SNA) in the central nervous system (CNS). Recent studies have focused on the role of brain mechanisms in the regulation of SNA and the progression of CHF. The renin‑angiotensin system, nitric oxide and pro‑inflammatory cytokines were shown to be involved in the abnormal regulation of SNA in the CNS. The alteration of these neurohumoral factors during CHF influences the activity of neurons in the autonomic regions and finally increase the sympathetic outflow. The present review summarizes the brain mechanisms contributing to sympathoexcitation in CHF.
