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Schematic diagram showing the primary and secondary effects of selective stimulation of peripheral chemoreceptors. + indicates an excitatory effect. Broken arrow indicates direct or local rather than reflex effects. Open arrow to defence areas indicates a higher threshold effect. For further details see text. HR, Heart rate.
Source publication
This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and card...
Contexts in source publication
Context 1
... this basis, it seemed reasonable to propose that in the absence of anaesthesia, mild chemoreceptor stimulation would evoke the primary bradycardia and peripheral va- soconstriction, complicated by the tachycar- dia and/or vasodilator effects of hyperventi- lation in those species in which these sec- ondary influences are evident, but that strong chemoreceptor stimulation would evoke the full cardiovascular pattern of the alerting response (see Figure 1). Correspondingly, behavioural arousal or alerting would be expected to accompany mild chemoreceptor stimulation, while obvious aggressive or de- fensive behaviour might be expected on strong chemoreceptor stimulation ...
Context 2
... the 1930's and 1950's, several studies were published on the cardiovascu- lar changes that could be evoked by selective stimulation of the carotid bodies, either by local injection of substances such as sodium cyanide or saline equilibrated with CO 2 , or by perfusion with hypoxia and hypercapnic blood. The results obtained were somewhat confusing, some studies showing a rise in arterial pressure, others a fall, some showing bradycardia, and others tachycardia (e.g. 1,2). However, already it was beginning to be recognised that the respiratory consequences of chemoreceptor stimulation could have a large impact on the magnitude and direction of the cardiovascular changes (3). The na- ture of these respiratory and cardiovascular interactions was largely established by the carefully controlled work of M. de Burgh Daly and colleagues (see Figure ...
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Citations
... The nucleus tractus solitarii (nTS) of the brainstem receives sensory input from the heart, lungs and other viscera bilaterally via the vagus nerves (Andresen & Kunze, 1994;Zoccal et al., 2014). The nTS then processes and integrates this information, sending projections to other brainstem and forebrain areas to modulate and coordinate the autonomic nervous system, and cardiovascular and respiratory function (Browning & Travagli, 2011;Kline, 2008;Marshall, 1998;Siebenmann et al., 2019;Zoccal et al., 2014). Homeostatic maintenance of these functions in both health and disease states depends to a large extent on the interactions that occur at the first vagal afferent-nTS soma synapse which is enveloped by astrocytes. ...
Viscerosensory information travels to the brain via vagal afferents, where it is first integrated within the brainstem nucleus tractus solitarii (nTS), a critical contributor to cardiorespiratory function and site of neuroplasticity. We have shown that decreasing input to the nTS via unilateral vagus nerve transection (vagotomy) induces morphological changes in nTS glia and reduces sighs during hypoxia. The mechanisms behind post‐vagotomy changes are not well understood. We hypothesized that chronic vagotomy alters cardiorespiratory responses to vagal afferent stimulation via blunted nTS neuronal activity. Male Sprague–Dawley rats (6 weeks old) underwent right cervical vagotomy caudal to the nodose ganglion, or sham surgery. After 1 week, rats were anaesthetized, ventilated and instrumented to measure mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively). Vagal afferent stimulation (2–50 Hz) decreased cardiorespiratory parameters and increased neuronal Ca²⁺ measured by in vivo photometry and in vitro slice imaging of nTS GCaMP8m. Vagotomy attenuated both these reflex and neuronal Ca²⁺ responses compared to shams. Vagotomy also reduced presynaptic Ca²⁺ responses to stimulation (Cal‐520 imaging) in the nTS slice. The decrease in HR, SSNA and PhrNA due to nTS nanoinjection of exogenous glutamate also was tempered following vagotomy. This effect was not restored by blocking excitatory amino acid transporters. However, the blunted responses were mimicked by NMDA, not AMPA, nanoinjection and were associated with reduced NR1 subunits in the nTS. Altogether, these results demonstrate that vagotomy induces multiple changes within the nTS tripartite synapse that influence cardiorespiratory reflex responses to afferent stimulation. image
Key points
Multiple mechanisms within the nucleus tractus solitarii (nTS) contribute to functional changes following vagal nerve transection.
Vagotomy results in reduced cardiorespiratory reflex responses to vagal afferent stimulation and nTS glutamate nanoinjection.
Blunted responses occur via reduced presynaptic Ca²⁺ activation and attenuated NMDA receptor expression and function, leading to a reduction in nTS neuronal activation.
These results provide insight into the control of autonomic and respiratory function, as well as the plasticity that can occur in response to nerve damage and cardiorespiratory disease.
... Peripheral chemoreceptors (mainly the carotid bodies) are in charge for monitoring arterial blood oxygenation (PO 2 ) levels. They initiate a hypoxic ventilatory response (HVR) that increases ventilation and sympathetic activity, for example leading to increased heart rate (Marshall, 1998a). ...
Adequate oxygen supply is essential for the human brain to meet its high energy demands. Therefore, elaborate molecular and systemic mechanism are in place to enable adaptation to low oxygen availability.
Anxiety and depressive disorders are characterized by alterations in brain oxygen metabolism and of its components, such as mitochondria or hypoxia inducible factor (HIF)-pathways. Conversely, sensitivity and tolerance to hypoxia may depend on parameters of mental stress and the severity of anxiety and depressive disorders.
Here we discuss relevant mechanisms of adaptations to hypoxia, as well as their involvement in mental stress and the etiopathogenesis of anxiety and depressive disorders. We suggest that mechanisms of adaptations to hypoxia (including metabolic responses, inflammation, and the activation of chemosensitive brain regions) modulate and are modulated by stress-related pathways and associated psychiatric diseases.
While severe chronic hypoxia or dysfunctional hypoxia adaptations can contribute to the pathogenesis of anxiety and depressive disorders, harnessing controlled responses to hypoxia to increase cellular and psychological resilience emerges as a novel treatment strategy for these diseases.
... The CSN carries sensory information from the carotid bodies (CB), peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia (Gonzalez et al., 1994;Conde et al., 2014). In addition, the CSN also delivers information from carotid sinus baroreceptors, mechanoreceptor sensory neurons directly involved in the control of blood pressure (Marshall, 1998;Chapleau et al., 2001). The CB is implicated in the pathophysiology of several cardiovascular diseases, such as chronic heart failure Schultz et al., 2013) and several forms of hypertension (Prabhakar and Peng, 2004;Abdala et al., 2012;Paton et al., 2013) playing a fundamental role in the genesis and maintenance of these diseases. ...
... The chemoreflex and baroreflex control the cardiovascular system via the profound influences they exert on autonomic outflow (Marshall, 1994). Disclosing the interdependency between these two reflex responses, particularly in the presence of stimuli such as hypoxia or ischemia (Marshall, 1998), is required to address pathophysiological mechanisms and therapeutics in cardiometabolic diseases. Although chemoreceptors are known for their role in the control of ventilation, they also modulate cardiovascular, endocrine, and renal systems. ...
... The same authors observed that unilateral electrical stimulation of the carotid sinus and the CSN activates both the carotid baroreflex and chemoreflex as previously described (Gonzalez et al., 1994;Marshall, 1994Marshall, , 1998, resulting in hypotension in conscious animals (Katayama et al., 2015). ...
Chronic carotid sinus nerve (CSN) electrical modulation through kilohertz frequency alternating current improves metabolic control in rat models of type 2 diabetes, underpinning the potential of bioelectronic modulation of the CSN as a therapeutic modality for metabolic diseases in humans. The CSN carries sensory information from the carotid bodies, peripheral chemoreceptor organs that respond to changes in blood biochemical modifications such as hypoxia, hypercapnia, acidosis, and hyperinsulinemia. In addition, the CSN also delivers information from carotid sinus baroreceptors—mechanoreceptor sensory neurons directly involved in the control of blood pressure—to the central nervous system. The interaction between these powerful reflex systems—chemoreflex and baroreflex—whose sensory receptors are in anatomical proximity, may be regarded as a drawback to the development of selective bioelectronic tools to modulate the CSN. Herein we aimed to disclose CSN influence on cardiovascular regulation, particularly under hypoxic conditions, and we tested the hypothesis that neuromodulation of the CSN, either by electrical stimuli or surgical means, does not significantly impact blood pressure. Experiments were performed in Wistar rats aged 10–12 weeks. No significant effects of acute hypoxia were observed in systolic or diastolic blood pressure or heart rate although there was a significant activation of the cardiac sympathetic nervous system. We conclude that chemoreceptor activation by hypoxia leads to an expected increase in sympathetic activity accompanied by compensatory regional mechanisms that assure blood flow to regional beds and maintenance of hemodynamic homeostasis. Upon surgical denervation or electrical block of the CSN, the increase in cardiac sympathetic nervous system activity in response to hypoxia was lost, and there were no significant changes in blood pressure in comparison to control animals. We conclude that the responses to hypoxia and vasomotor control short-term regulation of blood pressure are dissociated in terms of hypoxic response but integrated to generate an effector response to a given change in arterial pressure.
... Altogether, despite the greater hypoxemia in HH, which could lead to a potential greater decrease in parasympathetic activity, no differences in HRV between NH and HH were found. When taken as a whole, the above results converge toward lowered parasympathetic activity during hypoxic exposures and confirmed previous findings (Marshall, 1998;Wille et al., 2012), again without differences between NH and HH. However, HRV analyses need to be conducted carefully as many other factors than autonomic tone affects HRV. ...
Purpose: This study aimed to investigate the differences between normobaric (NH) and hypobaric hypoxia (HH) on supine heart rate variability (HRV) during a 24-h exposure. We hypothesized a greater decrease in parasympathetic-related parameters in HH than in NH.
Methods: A pooling of original data from forty-one healthy lowland trained men was analyzed. They were exposed to altitude either in NH (FIO2 = 15.7 ± 2.0%; PB = 698 ± 25 mmHg) or HH (FIO2 = 20.9%; PB = 534 ± 42 mmHg) in a randomized order. Pulse oximeter oxygen saturation (SpO2), heart rate (HR), and supine HRV were measured during a 7-min rest period three times: before (in normobaric normoxia, NN), after 12 (H12), and 24 h (H24) of either NH or HH exposure. HRV parameters were analyzed for time- and frequency-domains.
Results: SpO2 was lower in both hypoxic conditions than in NN and was higher in NH than HH at H24. Subjects showed similarly higher HR during both hypoxic conditions than in NN. No difference in HRV parameters was found between NH and HH at any time. The natural logarithm of root mean square of the successive differences (LnRMSSD) and the high frequency spectral power (HF), which reflect parasympathetic activity, decreased similarly in NH and HH when compared to NN.
Conclusion: Despite SpO2 differences, changes in supine HRV parameters during 24-h exposure were similar between NH and HH conditions indicating a similar decrease in parasympathetic activity. Therefore, HRV can be analyzed similarly in NH and HH conditions.
... Collectively, these ventilatory and cardiac responses partially counteract the diminished oxygen supply at high altitude. 21,[51][52][53][54][55] Generally, the rising sensitivity of the peripheral chemoreceptors over days at altitude increases ventilation, but ventilatory acclimatization differs among individuals. 56 Hyperventilation improves oxygenation but lowers P a CO 2 producing alkalemia. ...
Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O2, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.
... Decreased oxygen levels in the blood stimulate chemoreceptors in the cardiopulmonary center in the brain, which causes an increased inspiratory rate to increase oxygen levels in the blood and also initiate the heart to pump faster to deliver oxygen to the body [95]. For this, patients with hypoxemia usually develop tachypnea and tachycardia [96]. However, some patients may be asymptomatic because their immune system keeps it in check or only minor symptoms, such as cough accompanied by shortness of breath and some fever. ...
Introduction
The COVID-19 pandemic has created a public health crisis, infected millions of people, and caused a significant number of deaths. SARS-CoV-2 transmits from person to person through several routes, mainly via respiratory droplets, which makes it difficult to contain its spread into the community. Here, we provide an overview of the epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of COVID-19.
Areas covered
Direct person-to-person respiratory transmission has rapidly amplified the spread of coronavirus. In the absence of any clinically proven treatment options, the current clinical management of COVID-19 includes symptom management, infection prevention and control measures, optimized supportive care, and intensive care support in severe or critical illness. Developing an effective vaccine is now a leading research priority. Some vaccines have already been approved by the regulatory authorities for the prevention of COVID-19.
Expert opinion
General prevention and protection measures regarding the containment and management of the second or third waves are necessary to minimize the risk of infection. Until now, four vaccines reported variable efficacies of between 62–95%, and two of them (Pfizer/BioNTech and Moderna) received FDA emergency use authorization. Equitable access and effective distribution of these vaccines in all countries will save millions of lives.
... However, there are probably multiple pathways controlling cardiovascular response to hypoxia involved. They include peripheral chemoreceptors, arterial baroreceptors, central nervous system hypoxic response, and lung stretch receptors [34]. ...
This study focuses on the determination of the vagal threshold (T va) during exercise with increasing intensity in normoxia and normobaric hypoxia. The experimental protocol was performed by 28 healthy men aged 20 to 30 years. It included three stages of exercise on a bicycle ergometer with a fraction of inspired oxygen (FiO 2) 20.9% (normoxia), 17.3% (simulated altitude~1500 m), and 15.3% (~2500 m) at intensity associated with 20% to 70% of the maximal heart rate reserve (MHRR) set in normoxia. T va level in normoxia was determined at exercise intensity corresponding with (M ± SD) 45.0 ± 5.6% of MHRR. Power output at T va (PO th), representing threshold exercise intensity, decreased with increasing degree of hypoxia (normoxia: 114 ± 29 W; FiO 2 = 17.3%: 110 ± 27 W; FiO 2 = 15.3%: 96 ± 32 W). Significant changes in PO th were observed with FiO 2 = 15.3% compared to normoxia (p = 0.007) and FiO 2 = 17.3% (p = 0.001). Consequentially, normoxic %MHRR adjusted for hypoxia with FiO 2 = 15.3% was reduced to 39.9 ± 5.5%. Considering the convenient altitude for exercise in hypoxia, PO th did not differ excessively between normoxic conditions and the simulated altitude of~1500 m, while more substantial decline of PO th occurred at the simulated altitude of~2500 m compared to the other two conditions.
... Environmental hypoxia is a condition characterized by a decrease in the inspired oxygen pressure (P I O 2 ) (Millet et al., 2012), which per se has a negative influence on autonomic cardiac response (Botek et al., 2015) and induces systemic/integrative metabolic, endocrine and vascular compensation (Marshall, 1998). More precisely, acute hypoxic exposure induces decreases in heart rate variability (HRV) and parasympathetic activity (Wille et al., 2012), whereas sympathetic activity increases (Richalet et al., 1988;Marshall, 1994). ...
Introduction
The present study evaluated the putative effect of hypobaria on resting HRV in normoxia and hypoxia.
Methods
Fifteen young pilot trainees were exposed to five different conditions in a randomized order: normobaric normoxia (NN, PB = 726 ± 5 mmHg, FIO2 = 20.9%), hypobaric normoxia (HN, PB = 380 ± 6 mmHg, FIO2≅40%), normobaric hypoxia (NH, PB = 725 ± 4 mmHg, FIO2≅11%); and hypobaric hypoxia (HH at 3000 and 5500 m, HH3000 and HH5500, PB = 525 ± 6 and 380 ± 8 mmHg, respectively, FIO2 = 20.9%). HRV and pulse arterial oxygen saturation (SpO2) were measured at rest seated during a 6 min period in each condition. HRV parameters were analyzed (Kubios HVR Standard, V 3.0) for time (RMSSD) and frequency (LF, HF, LF/HF ratio, and total power). Gas exchanges were collected at rest for 10 min following HRV recording.
Results
SpO2 decreased in HH3000 (95 ± 3) and HH5500 (81 ± 5), when compared to NN (99 ± 0). SpO2 was higher in NH (86 ± 4) than HH5500 but similar between HN (98 ± 2) and NN. Participants showed lower RMSSD and total power values in NH and HH5500 when compared to NN. In hypoxia, LF/HF ratio was greater in HH5500 than NH, whereas in normoxia, LF/HF ratio was lower in HN than NN. Minute ventilation was higher in HH5500 than in all other conditions.
Discussion
The present study reports a slight hypobaric effect either in normoxia or in hypoxia on some HRV parameters. In hypoxia, with a more prominent sympathetic activation, the hypobaric effect is likely due to the greater ventilation stimulus and larger desaturation. In normoxia, the HRV differences may come from the hyperoxic breathing and slight breathing pattern change due to hypobaria in HN.
... These authors suggested that hypertensive patients would not be at higher risk to develop AMS when acutely exposed to high altitude. Prediction of individual blood pressure response to acute hypoxia is complicated by the complex and temporarily changing interplay between chemoreceptor and baroreceptor activity (Marshall, 1998;Cooper et al., 2005). It is well documented that adrenergic drive (vasoconstriction) at acute high altitude is counterbalanced by peripheral direct effects of hypoxia (vasodilation). ...
This study was aimed at evaluating a potential association between blood pressure variation and acute mountain sickness (AMS) during acute exposure to normobaric hypoxia. A total of 77 healthy subjects (43 males, 34 females) were exposed to a simulated altitude of 4500 m for 12 hours. Peripheral oxygen saturation, heart rate, systemic blood pressure, and Lake Louise AMS scores were recorded before and during (30 minutes, 3, 6, 9, and 12 hours) hypoxic exposure. Blood pressure dips were observed at 3-hour mark. However, systolic blood pressure fell more pronounced from baseline during the initial 30 minutes in normobaric hypoxia (-17.5 vs. -11.0 mmHg, p = 0.01) in subjects suffering from AMS (AMS+; n = 56) than in those remaining unaffected from AMS (AMS-; n = 21); values did not differ between groups over the subsequent time course. Our data may suggest a transient autonomic dysfunction resulting in a more pronounced blood pressure drop during initial hypoxic exposure in AMS+ compared with AMS- subjects.
... Hypoxia which is characterized by a decrease in the inspired oxygen pressure (Millet et al., 2012) is a strong environmental stressor that elicits cardiovascular compensation (Marshall, 1998). The autonomic nervous system (ANS) plays a major role in regulating cardiovascular function (Aubert et al., 2003). ...
... pathways involved: peripheral chemoreceptors, arterial baroreceptors, central nervous system hypoxic response and lung stretch receptors (Marshall, 1998;Ursino & Magosso, 2000a). Assessment of the exact contribution of each control pathway is further complicated by mutual relationships and non-linearities presented in the regulatory mechanisms (Ursino & Magosso, 2000b). ...
... We revealed that DLn RMSSD and DLn SDNN during hypoxia were linearly proportional to DSpO 2 . This result could be explained by the chemoreflex which is responsible for the detection of and response to hypoxia (Marshall, 1998;Freet et al., 2013). However, the role of the chemoreflex is valid during the first 5 min of hypoxia in which SpO 2 did not decrease below 78Á3 AE 7Á1%. ...
Although the heart rate variability (HRV) response to hypoxia has been studied, little is known about the dynamics of HRV after hypoxia exposure. The purpose of this study was to assess the HRV and oxygen saturation (SpO2 ) responses to normobaric hypoxia (FiO2 = 9·6%) comparing 1 min segments to baseline (normoxia). Electrocardiogram and SpO2 were recorded during a 10-min hypoxia exposure in 29 healthy male subjects aged 26·0 ± 4·9 years. Baseline HRV values were obtained from a 5-min recording period prior to hypoxia. The hypoxia period was split into 10 non-overlapping 1-min segments and time domain HRV indexes (RMSSD and SDNN) were calculated for each segment. Differences (Δ) from baseline values were calculated and transformed using natural logarithm (Ln). This study revealed that the decrease in ΔSpO2 became significant (P<0·001) in the first minute of hypoxia, the decrease in ΔLn RMSSD became significant (P = 0·002) in the second minute, and the decrease in ΔLn SDNN became significant (P = 0·001) in the third minute. Between the second and fifth minute of hypoxia, ΔSpO2 correlated with ΔLn RMSSD (r = 0·57, P<0·001) and ΔLn SDNN (r = 0·44, P<0·001). Five min after the onset of hypoxia, ΔSpO2 was significantly (P = 0·002) decreased but changes in ΔLn RMSSD (P = 0·344) and ΔLn SDNN (P = 0·558) were not significant. In conclusion, the decrease in HRV was proportional to desaturation but only during the first 5 min of hypoxia.
