Carotid Chemoreceptor Activity Research Articles

Role of the carotid chemoreceptors in insulin-mediated sympathoexcitation in humans.

We examined the contribution of the carotid chemoreceptors to insulin-mediated increases in muscle sympathetic nerve activity (MSNA) in healthy humans. We hypothesized that reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia. Young, healthy adults (9 male/9 female, 28 ± 1 yr, 24 ± 1 kg/m2) completed a 30-min euglycemic baseline followed by a 90-min hyperinsulinemic (1 mU·kg fat-free mass-1·min-1), euglycemic infusion. MSNA (microneurography of the peroneal nerve) was continuously measured. The role of the carotid chemoreceptors was assessed at baseline and during hyperinsulinemia via 1) acute hyperoxia, 2) low-dose dopamine (1-4 µg·kg-1·min-1), and 3) acute hyperoxia + low-dose dopamine. MSNA burst frequency increased from baseline during hyperinsulinemia (P < 0.01). Acute hyperoxia had no effect on MSNA burst frequency at rest (P = 0.74) or during hyperinsulinemia (P = 0.83). The insulin-mediated increase in MSNA burst frequency (P = 0.02) was unaffected by low-dose dopamine (P = 0.60). When combined with low-dose dopamine, acute hyperoxia had no effect on MSNA burst frequency at rest (P = 0.17) or during hyperinsulinemia (P = 0.85). Carotid chemoreceptor desensitization in young, healthy men and women does not attenuate the sympathoexcitatory response to hyperinsulinemia. Our data suggest that the carotid chemoreceptors do not contribute to acute insulin-mediated increases in MSNA in young, healthy adults.

The effect of pulmonary rehabilitation on carotid chemoreceptor activity and sensitivity in chronic obstructive pulmonary disease.

Recent work demonstrates that carotid chemoreceptor (CC) activity/sensitivity is elevated in patients with chronic obstructive pulmonary disease (COPD) compared with healthy controls, and this elevated chemoreception appears to contribute to increased cardiovascular risk. Exercise training has been shown to normalize CC activity/sensitivity in other populations, and therefore, the purpose of this study was to determine whether pulmonary rehabilitation (PR) can reduce CC activity/sensitivity in COPD. Forty-five COPD patients [mean FEV1 (forced expiratory volume in 1 s) = 56.6% predicted] completed PR, while 15 COPD patients (mean FEV1 = 74.6% predicted) served as non-PR controls. CC activity was determined by the reduction in ventilation while breathing transient hyperoxia ([Formula: see text] = 1.0); CC sensitivity was evaluated by the increase in ventilation relative to the drop in arterial saturation while breathing hypoxia. Dyspnea, six-minute walk and autonomic function data were also obtained. PR improved 6-minute walk distance (P < 0.001) and dyspnea (P = 0.04); however, there was no effect on CC activity (P = 0.60), sensitivity (P = 0.69), or autonomic function (P > 0.05 for all). Subgroup analyses indicated that PR reduced CC activity in those with elevated baseline CC activity, independent of changes in autonomic function. No change in dyspnea (P = 0.24), CC activity (P = 0.19), sensitivity (P = 0.80), or autonomic function (P > 0.05 for all) was observed in the control group. Despite improvements in exercise tolerance and dyspnea, PR appears to be generally ineffective at reducing CC sensitivity in stable COPD patients; while PR reduced CC activity in those with elevated basal CC activity, the physiological significance of this is unclear. Further investigations aimed at improving CC function in COPD are needed.NEW & NOTEWORTHY While work in other chronic diseases has shown that exercise training may help normalize carotid chemoreceptor (CC) activity/sensitivity, the current study found that exercise training through pulmonary rehabilitation did not consistently reduce CC activity/sensitivity in patients with chronic obstructive pulmonary disease (COPD). These results suggest that other interventions are needed to normalize CC activity/sensitivity in COPD.

Denervation of carotid chemoreceptors decreases blood pressure in an ovine model of renovascular hypertension

BackgroundHypertension is a major health problem of pandemic proportions that is often inadequately controlled, warranting development of new treatments. There is increasing evidence that hypertension is initiated and maintained by elevated sympathetic nerve activity. There is also strong evidence that aberrant afferent signalling from carotid chemoreceptors promotes sympathoexcitation and hypertension. We hypothesized that hypertension is associated with activation of carotid chemoreceptors and that carotid sinus denervation (CSD) would reduce blood pressure.MethodsAdult ewes either underwent unilateral renal artery clipping or sham surgery. Three weeks later, baroreflex control of heart rate was examined and the contribution of sympathetic mechanisms to hypertension was determined using hexamethonium (125 mg/hr). The mean arterial pressure and renal blood flow response to activation of carotid chemoreceptors was determined in both groups. In a second surgery conducted in hypertensive animals only, the carotid sinus nerve was severed bilaterally (CSD) (n=6) or left intact (sham, n=6) and the effect on blood pressure was examined.ResultsUnilateral renal artery clipping induced hypertension (mean arterial pressure 109 ± 2 vs 91 ± 3 mmHg in shams, p&lt;0.001). The pressor response and the renal vasoconstriction response to chemoreceptor activation was augmented in hypertensive animals compared to the normal group (for e.g. MAP response, 15 ± 1 vs 7 ± 2 mmHg, p&lt;0.05). CSD decreased MAP (−17 ± 1 vs +2 ± 1 mmHg in shams, p&lt;0.0001) and shifted the heart rate baroreflex curve to the left. The contribution of the autonomic nerves to hypertension was elevated in hypertensive animals compared to normal (−19 ± 2 vs −11 ± 2 mmHg, p&lt;0.05) and CSD reduced this contribution.DiscussionIn conclusion, we have shown that hypertension in our large animal model is associated with activation of carotid chemoreceptors and that bilateral CSD lowers arterial pressure. Our data implicates the carotid chemoreceptors in the maintenance of renovascular hypertension.Support or Funding InformationFunded by the University of Auckland Faculty Research Development Fund and the Health Research Council of New Zealand.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension.

Dysfunction of post-exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases. The afferent mechanisms that regulate the post-exercise cardiac autonomic control remain unclear. We found that afferent signals from carotid chemoreceptors restrain the post-exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH). Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults. The results demonstrate that the carotid chemoreceptors contribute to the regulation of post-exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post-exercise cardiac autonomic dysfunction in patients with PAH. Dysfunction of post-exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post-exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post-exercise cardiac autonomic control. Twenty non-hypoxaemic patients with PAH and 13 age- and sex-matched HA pedalled until 90% of peak work rate observed in a symptom-limited ramp-incremental exercise test. Recovery consisted of unloaded pedalling for 5min followed by seated rest for 6min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post-exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300s of recovery, using linear and non-linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post-exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.

Carotid chemoreceptors have a limited role in mediating the hyperthermia-induced hyperventilation in exercising humans.

Hyperthermia causes hyperventilation at rest and during exercise. We previously reported that carotid chemoreceptors partly contribute to the hyperthermia-induced hyperventilation at rest. However, given that a hyperthermia-induced hyperventilation markedly differs between rest and exercise, the results obtained at rest may not be representative of the response in exercise. Therefore, we evaluated whether carotid chemoreceptors contribute to hyperthermia-induced hyperventilation in exercising humans. Eleven healthy young men (23 ± 2 yr) cycled in the heat (37°C) at a fixed submaximal workload equal to ~55% of the individual's predetermined peak oxygen uptake (moderate intensity). To suppress carotid chemoreceptor activity, 30-s hyperoxia breathing (100% O2) was performed at rest (before exercise) and during exercise at increasing levels of hyperthermia as defined by an increase in esophageal temperature of 0.5°C (low), 1.0°C (moderate), 1.5°C (high), and 2.0°C (severe) above resting levels. Ventilation during exercise gradually increased as esophageal temperature increased (all P ≤ 0.05), indicating that hyperthermia-induced hyperventilation occurred. Hyperoxia breathing suppressed ventilation in a greater manner during exercise (-9 to -13 l/min) than at rest (-2 ± 1 l/min); however, the magnitude of reduction during exercise did not differ at low (0.5°C) to severe (2.0°C) increases in esophageal temperature (all P > 0.05). Similarly, hyperoxia-induced changes in ventilation during exercise as assessed by percent change from prehyperoxic levels were not different at all levels of hyperthermia (~15-20%, all P > 0.05). We show that in young men carotid chemoreceptor contribution to hyperthermia-induced hyperventilation is relatively small at low-to-severe increases in body core temperature induced by moderate-intensity exercise in the heat. NEW & NOTEWORTHY Exercise-induced increases in hyperthermia cause a progressive increase in ventilation in humans. However, the mechanisms underpinning this response remain unresolved. We showed that in young men hyperventilation associated with exercise-induced hyperthermia is not predominantly mediated by carotid chemoreceptors. This study provides important new insights into the mechanism(s) underpinning the regulation of hyperthermia-induced hyperventilation in humans and suggests that factor(s) other than carotid chemoreceptors play a more important role in mediating this response.

The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease.

The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk-matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients. Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV1 ) predicted±SD: 83±18%) and 13age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2μgkg-1 min-1 ) while breathing normoxic or hyperoxic air (100% O2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P<0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P<0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD.

The Impact of Nitrate Supplementation on the Peripheral Chemoreceptor Reflex to Hypoxia in Older Adults

Peripheral chemoreceptors located within the carotid bodies activate cardiorespiratory reflexes in response to hypoxia. Carotid body chemoreceptor activity has been shown to be enhanced in conditions such as congestive heart failure, hypertension, and possibly aging. Nitric oxide (NO) has been proposed as an inhibitory modulator of carotid body chemosensitivity in response to hypoxia. Additionally, NO bioavailability is often reduced with cardiovascular risk factors such as aging. In the present study, we tested the hypothesis that increasing NO bioavailability via dietary nitrate (NO3) supplementation would reduce cardiorespiratory responses to hypoxia in older adults. A double‐blind, randomized, placebo‐controlled, cross‐over study design was used to evaluate minute ventilation (VE) and heart rate (HR) responses to acute hypoxia in 7 older adults (66±2 years; 5M/2F) before and after 4 weeks of NO3 supplementation (beetroot powder) and placebo (beetroot powder devoid of NO3). On each study visit, subjects underwent two separate isocapnic hypoxic tests (self‐regulating, partial rebreathing system with 10% O2). Subjects remained on 10% O2 until SpO2 reached ≤80%. The hypoxic exposures were separated by a 15‐minute washout period with the subjects breathing room air. VE, HR, and SpO2 were continuously monitored throughout each hypoxic exposure. Data were grouped together using a 7‐breath average with the slope of the linear regression line for each dependent variable (VE and HR) versus SpO2 serving as a measure of peripheral chemosensitivity. The slopes for the two hypoxia tests on each study visit were averaged and used for statistical comparisons. On study day one (true baseline) acute hypoxia increased both VE and HR (P&lt;0.05 for both). Four weeks of NO3 supplementation reduced the hypoxic ventilatory response (−0.16 ± −0.05 vs. −0.06 ± −0.03 L/minute/%SpO2, P&lt;0.05), whereas no change was observed following the placebo phase of the study (−0.14 ± −0.07 vs. −0.14 ± −0.08 L/minute/%SpO2, P=0.67). Additionally, the heart rate responses to acute hypoxia were also reduced following NO3 supplementation (−0.49 ± −0.08 vs. −0.30 ± −0.05 beats/minute/%SpO2, P&lt;0.05), but not with placebo (−0.54 ± −0.11 vs. −0.45 ± −0.08 beats/minute/%SpO2, P=0.21). Our preliminary findings suggest that supplementation of NO3 to boost NO bioavailability in older adults blunts the cardiorespiratory responses to hypoxia. Future studies should examine the therapeutic potential of NO3 in patient populations exhibiting exaggerated peripheral chemosensitivity.Support or Funding InformationResearch supported by Neogenis Inc.

Reductions in carotid chemoreceptor activity with low-dose dopamine improves baroreflex control of heart rate during hypoxia in humans.

The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of heart rate with exposure to hypoxia. We hypothesized spontaneous cardiac baroreflex sensitivity (scBRS) would be reduced with hypoxia and this effect would be blunted when carotid chemoreceptor activity was reduced with low‐dose dopamine. Fifteen healthy adults (11 M/4 F) completed two visits randomized to intravenous dopamine or placebo (saline). On each visit, subjects were exposed to 5‐min normoxia (~99% SpO2), followed by 5‐min hypoxia (~84% SpO2). Blood pressure (intra‐arterial catheter) and heart rate (ECG) were measured continuously and scBRS was assessed by spectrum and sequence methodologies. scBRS was reduced with hypoxia (P < 0.01). Using the spectrum analysis approach, the fall in scBRS with hypoxia was attenuated with infusion of low‐dose dopamine (P < 0.01). The decrease in baroreflex sensitivity to rising pressures (scBRS “up‐up”) was also attenuated with low‐dose dopamine (P < 0.05). However, dopamine did not attenuate the decrease in baroreflex sensitivity to falling pressures (scBRS “down‐down”; P > 0.05). Present findings are consistent with a reduction in scBRS with systemic hypoxia. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when activity of the chemoreceptors is reduced with low‐dose dopamine. However, the improvement in scBRS with dopamine appears to be specific to rising blood pressures. These results may have important implications for impairments in baroreflex function common in disease states of acute and/or chronic hypoxemia, as well as the experimental use of dopamine to assess such changes.

Chronic Interactions Between Carotid Baroreceptors and Chemoreceptors in Obesity Hypertension.

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%-50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

Obesity, Hypoxemia, and Hypertension: Mechanistic Insights and Therapeutic Implications.

See related article, pp 227–235 Four decades ago, Trzebski et al in Warsaw reported an astonishing discovery, namely that hypersensitivity and augmented tonic activity of arterial chemoreceptors contribute to increased arterial pressure in young hypertensive men.1 This discovery has stood the test of time. In addition to increasing ventilation, activation of carotid chemoreceptors increases sympathetic nerve activity and arterial pressure. Young borderline hypertensive humans have a striking augmentation of the sympathetic nerve responses to chemoreceptor activation by hypoxemia.2 Conversely, suppression of arterial chemoreceptors by breathing 100% oxygen decreases sympathetic nerve activity and arterial pressure in hypertensive but not normotensive humans.3 Studies in spontaneously hypertensive rats and normotensive (Wistar) rats have paralleled and advanced these concepts.4,5 Spontaneously hypertensive rats display augmented increases in carotid sinus afferent activity during hypoxemia. In addition, carotid body denervation reduces the development and maintenance of increased sympathetic activity and arterial pressure in spontaneously hypertensive rats but not normotensive Wistar rats.4 The augmented sympathetic nerve response to hypoxemia is manifest in young prehypertensive spontaneously hypertensive rats and seems to result from a membrane abnormality that underlies the increased chemoreceptor sensitivity and activity.5 This suggests a primary genetic molecular mechanism for increased chemoreceptor sensitivity and tonic activity in spontaneous hypertension. These and other studies in humans and rats have prompted interest in carotid body denervation as treatment for resistant, sympathetically mediated essential hypertension in humans.6 To this story of carotid chemoreceptors in spontaneous hypertension, Tom …

The Effect of Pulmonary Rehabilitation on Carotid Chemoreceptor Activity and Sensitivity in COPD

Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disease characterized by progressive, partially reversible airway obstruction. While considered a disease of the lungs, COPD is associated with increased cardiovascular (CV) mortality; this increased CV risk may result from heightened sympathetic nervous activity secondary to elevated carotid chemoreceptor (CC) activity/sensitivity. Our recent work suggests that COPD patients have an exaggerated resting CC activity/sensitivity which appears to contribute to increased tonic vasoconstriction.Experimental chronic heart failure is characterized by heightened CC activity/sensitivity, and exercise training has been shown to normalize CC activity/sensitivity in this population. COPD patients are commonly referred to pulmonary rehabilitation (PR), an exercise‐based intervention shown to be effective in improving dyspnea, exercise tolerance, and quality of life. However, the physiological mechanisms underlying these improvements are unclear. The purpose of this study was to examine the effects of PR on CC activity/sensitivity in COPD.A case control study design was used; COPD patients either attended PR (experimental) or no PR (control) for 6–8 weeks. CC activity and sensitivity, exercise tolerance, and resting dyspnea were assessed before and after the respective 6–8 week period. Resting CC activity was determined by the reduction in minute ventilation (V̇E) while breathing transient hyperoxia (FIO2=1.0). CC sensitivity was evaluated by the increase in V̇E relative to the drop in arterial saturation while breathing hypoxic gas (ΔV̇E/ΔSpO2). Exercise tolerance was assessed by six minute walk distance (6MWD), and the 0–4 modified Medical Research Council questionnaire (MMRC) was used to determine resting dyspnea.To date, data (mean±SD) have been collected on 45 patients completing PR (FEV1 57±21% predicted; age 67±7 years) and 6 controls (FEV1 68±19% predicted; age 71±6 years). Patients completing PR improved exercise tolerance (pre 6MWD: 441±80 m, post: 478±110 m, p&lt;0.001) and reduced resting dyspnea (pre MMRC: 2.41±0.82, post: 2.15±0.84, p=0.04). Resting CC activity was unchanged following PR (pre: −1.07±1.55 L/min, post: −0.93±1.46 L/min, p=0.60), and similarly no change was observed in the control group (pre: −0.73±0.65 L/min, post: −0.96±1.36 L/min, p=0.53). CC sensitivity also remained unchanged in both the experimental (pre: 0.08±0.07 L/min/%SpO2, post: 0.11±0.15 L/min/%SpO2, p=0.561) and control (pre: 0.26±0.17 L/min/%SpO2, post: 0.31±0.11 L/min/%SpO2, p=0.363) groups.Current data suggest that PR does not influence CC activity/sensitivity in COPD. While previous studies have shown that exercise training normalizes CC activity/sensitivity in other diseases, it is possible that the intensity or length of PR is insufficient to elicit reductions in CC activity/sensitivity. Alternately, despite improving exercise tolerance and resting dyspnea, exercise training may not affect CC activity/sensitivity in COPD.Support or Funding InformationFunding for this work is provided by Alberta Innovates Health Solutions, Canadian Institutes of Health Research, and Heart &amp; Stroke Foundation of Alberta, NWT &amp; Nunavut. (PI: M. Stickland).

Regulation of cardiac output in hypoxia.

This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective.

Role of Chemoreceptor Activation in Hemodynamic Responses to Electrical Stimulation of the Carotid Sinus in Conscious Rats.

Electric carotid baroreflex activation has been used to treat patients with resistant hypertension. It is hypothesized that, in conscious rats, combined activation of carotid baro- and chemoreceptors afferences attenuates the reflex hypotension. Rats were divided into 4 groups: (1) control group, with unilateral denervation of the right carotid chemoreceptors; (2) chemoreceptor denervation group, with bilateral ligation of the carotid body artery; (3) baroreceptor denervation group, with unilateral denervation of the left carotid baroreceptors and right carotid chemoreceptors; and (4) carotid bifurcation denervation group, with denervation of the left carotid baroreceptors and chemoreceptors, plus denervation of the right carotid chemoreceptors. Animals were subjected to 4 rounds of electric stimulation (5 V, 1 ms), with 15, 30, 60, and 90 Hz applied randomly for 20 s. Electric stimulation caused greater hypotensive responses in the chemoreceptor denervation group than in the control group, at 60 Hz (-37 versus -19 mm Hg) and 90 Hz (-33 versus -19 mm Hg). The baroreceptor denervation group showed hypertensive responses at all frequencies of stimulation. In contrast, the carotid sinus denervation group showed no hemodynamic responses. The control group presented no changes in heart rate, whereas the chemoreceptor denervation group and the baroreceptor denervation group showed bradycardic responses. These data demonstrate that carotid chemoreceptor activation attenuates the reflex hypotension caused by combined electric stimulation of the carotid sinus and the carotid sinus nerve in conscious rats. These findings may provide useful insight for clinical studies using baroreflex activation therapy in resistant hypertension and heart failure.

Acute Activation of Carotid Chemoreceptors Increases Ventilatory Instability in Healthy Humans

Patients with sleep apnea exhibit ventilatory instability and increased carotid chemoreceptor activity. Whether ventilatory instability is directly related to altered chemoreceptor activity has not been examined in humans. Therefore we tested the hypothesis that acute activation of the carotid chemoreflex with hypoxia (10% O2) would increase breathing variability (assessed by coefficient of variation of tidal volume {%CV}) and blunting the peripheral chemoreflex with IV dopamine would attenuate the response. To test this hypothesis, nine healthy subjects (3 M/6 F) were studied on two separate study days: 1) saline or 2) low‐dose dopamine infusion. Individualized dopamine dose (1‐4 mg/kg/min), that maximally blunted chemoreflex sensitivity, was identified during a separate screening visit. Respiratory rate (RR), tidal volume (TV), end tidal CO2 (ETCO2)and O2 (ETO2) were measured. Baseline measures were similar between days. Saline infusion did not affect RR, TV, end tidal gases, or %CV. However, dopamine infusion significantly increased %CV (25 ± 5 to 32 ± 6 %; p&lt;0.05) and ETCO2 (0.3 ± 0.1 %; p&lt;0.0001) without affecting RR, or TV. Hypoxia increased %CV during saline infusion (18 ± 3 to 29 ± 3%; p&lt;0.05), and this effect was blunted during dopamine infusion (31 ± 6 to 38 ± 6%; p&gt;0.05). These data indicate hypoxia increases respiratory variability and this effect is mediated by the carotid chemoreceptors. Furthermore, the effect of increased chemoreceptor drive on ventilatory instability, such as that seen in sleep apnea, may be blunted by low‐dose dopamine in humans. These data provide a potential therapeutic target for improving ventilatory instability in human disease.&#x0D; Funding:NIH DK090541

Mechanisms of carotid body chemoreflex dysfunction during heart failure.

What is the topic of this review? Carotid body chemoreceptor activity is tonically elevated in heart failure and contributes to morbidity due to the reflex activation of sympathetic nerve activity and destabilization of breathing. The potential causes for the enhanced chemoreceptor activation in heart failure are discussed. What advances does it highlight? The role of a chronic reduction in blood flow to the carotid body due to cardiac failure and its impact on signalling pathways in the carotid body is discussed. Recent advances have attracted interest in the potential for carotid body (CB) ablation or desensitization as an effective strategy for clinical treatment and management of cardiorespiratory diseases, including hypertension, heart failure, diabetes mellitus, metabolic syndrome and renal failure. These disease states have in common sympathetic overactivity, which plays an important role in the development and progression of the disease and is often associated with breathing dysregulation, which in turn is likely to mediate or aggravate the autonomic imbalance. Evidence from both chronic heart failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic activity and the development of periodic breathing associated with the disease. Although this maladaptive change is likely to derive from altered function at all levels of the reflex arc, a tonic increase in afferent activity from CB glomus cells is likely to be a main driving force. This report focuses on our understanding of mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.

Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea

Arterial chemoreceptors in the carotid body are central to the chemical control of breathing in the chemotransduction of physiological stimuli in the arterial blood for eliciting the chemoreflex, which mediates the respiratory, cardiovascular and autonomic responses to hypoxia, hypercapnia and acidosis. Recent evidence suggests that signaling molecules locally produced in the carotid body, including angiotensin II and pro-inflammatory cytokines play an important role in the modulation of the activity of carotid chemoreceptors, via the angiotensin and cytokine receptors expressed in the chemosensitive cells in an autocrine–paracrine manner. The carotid chemoreceptor activity is augmented in subjects at high altitude and in patients with sleep-disordered breathing. Maladaptive responses of the paracrine signaling to hypoxia in the carotid body have been proposed to play a pathogenic role in sleep apnea. Specifically, recent findings show significant increases in expressions of angiotensin receptors and components of a local angiotensin-generating system in the carotid body in sustained or intermittent hypoxia, which augments the chemoreceptor activity and also mediates the inflammatory response of the carotid body to hypoxia. In addition, inflammation of the carotid body involves an increased local expression of cytokine receptors and pro-inflammatory cytokines in sustained or intermittent hypoxia. This review aims to summarize the evidence supporting that the upregulated expression of the angiotensin receptors and cytokine pathways in the carotid body leads to augmented activities of the carotid chemoreceptor in hypoxic conditions, which could play a role in the pathophysiology of sleep apnea.

The role of local renin-angiotensin system in arterial chemoreceptors in sleep-breathing disorders.

The renin-angiotensin system (RAS) plays pivotal roles in the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Experimental studies have demonstrated a locally expressed RAS in the carotid body, which is functional significant in the effect of angiotensin peptides on the regulation of the activity of peripheral chemoreceptors and the chemoreflex. The physiological and pathophysiological implications of the RAS in the carotid body have been proposed upon recent studies showing a significant upregulation of the RAS expression under hypoxic conditions relevant to altitude acclimation and sleep apnea and also in animal model of heart failure. Specifically, the increased expression of angiotensinogen, angiotensin-converting enzyme and angiotensin AT1 receptors plays significant roles in the augmented carotid chemoreceptor activity and inflammation of the carotid body. This review aims to summarize these results with highlights on the pathophysiological function of the RAS under hypoxic conditions. It is concluded that the maladaptive changes of the RAS in the carotid body plays a pathogenic role in sleep apnea and heart failure, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.

Abstract 032: Carotid Chemoreceptor Activation Blunts The Hypotensive Response Caused By The Electrical Stimulation Of The Carotid Sinus In Conscious Rats

The mechanisms involved in Baroreflex Activation Therapy (BAT) in patients with resistant hypertension require better understanding. It was shown that electrical stimulation of the carotid sinus (ESCS), in conscious carotid body-denervated rats, caused bradycardia and greater hypotensive response when compared with intact control rats. In the current study the activation of the chemoreceptors due to ESCS, in conscious rats, was examined in the absence of the carotid baroreceptors. Wistar rats with unilateral denervation of the right carotid chemoreceptors were divided into three groups: 1) control (CONT, n=7); 2) bilateral carotid chemoreceptor denervation (CD, n=7); 3) unilateral denervation of the left carotid baroreceptors (BD, n=4). Under ketamine/xylazine anesthesia bipolar electrodes were implanted around the left carotid sinus combined with arterial and venous catheters into the femoral vessels. On the next day, after basal hemodynamic recordings, the animals received three ESCS (5V, 1 ms) with 15 Hz, 30 Hz and 60 Hz, applied randomly for 20s. Carotid chemoreceptors denervation was confirmed by the lack of hemodynamic responses after the administration of KCN (40 μg iv). The efficacy of left carotid baroreceptor denervation was confirmed by the absence of hemodynamic responses to changes in the left carotid sinus pressure ranging from 60 mmHg to 180 mmHg. The results showed that ESCS was efficient to cause greater hypotensive responses in the CD as compared with the CONT group at 60 Hz (-37 ± 6 vs -19 ± 3 mmHg) and to cause hypertensive responses in the BD group at 30 Hz and 60 Hz (15 ± 2 and 19 ± 2 mmHg). ESCS caused no alteration of the heart rate in the CONT but caused significant bradycardia in the CD group at 30 Hz and 60 Hz (-31 ± 11 and -35 ± 12 bpm) and in the BD group at 15 Hz, 30 Hz and 60 Hz (-38 ± 6, -37 ± 6 and -34 ± 4 bpm). These data demonstrated that carotid chemoreceptor activation in the absence of the carotid baroreceptors caused hypertension and bradycardia, indicating that when the baroreceptors are intact, the chemoreceptors blunt the hypotensive response caused by ESCS. These findings provide important information for the clinical studies using BAT in patients with resistant hypertension and/or heart failure.

Carotid chemoreceptor afferent projections to leptin receptor containing neurons in nucleus of the solitary tract

Neurons expressing the leptin receptor (Ob-R) exist within the caudal nucleus of the solitary tract (NTS). Additionally, afferent neurons expressing the Ob-R have been identified within the nodose ganglion and NTS. Furthermore, systemic injections or focal injections of leptin directly into NTS potentiate the response of NTS neurons to carotid chemoreceptor activation. However, the distribution of carotid body afferents in relation to Ob-R containing neurons within NTS is not known. In this study, chemoreceptor afferent fibers were labeled following microinjection of the anterograde tract tracer biotinylated dextran amine (BDA) into the carotid body or petrosal/nodose ganglion of Wistar rats. After a survival period of 10–14 days, the NTS was processed for BDA and Ob-R immunoreactivity. Afferent axons originating in the carotid body were found to project to the lateral (Slt), gelantinosa (Sg), and medial (Sm) subnuclei of the NTS complex. A similar, but more robust distribution of BDA labeled fibers was observed in the NTS complex after injections into the petrosal/nodose ganglion. Carotid body BDA labeled fibers were observed in close apposition to Ob-R immunoreactive neurons in the region of Slt, Sg and Sm. In addition, a small number of carotid body afferents were found to contain both BDA and express Ob-R-like immunoreactivity within the regions of Slt, Sg and Sm. Taken together, these data suggest that leptin may modulate carotid chemoreceptor function not only through direct effects on NTS neurons, but also through a direct effect on carotid body primary afferent fibers that innervate NTS neurons.

Pathogenic Roles of the Carotid Body Inflammation in Sleep Apnea

Breathing difficulties in sleep are a hallmark of sleep-disordered breathing commonly observed in patients with sleep disorders. The pathophysiology of sleep apnea is in part due to an augmented activity of the carotid body chemoreflex. Arterial chemoreceptors in the carotid body are sensitive to inflammatory cytokines and immunogenic molecules in the circulation, because cytokine receptors are expressed in the carotid body in experimental animals and human. Intriguingly, proinflammatory cytokines are also locally produced and released in the carotid body. Also, there are significant increases in the expression of proinflammatory cytokines, cytokine receptors, and inflammatory mediators in the carotid body under hypoxic conditions, suggesting an inflammatory response of the carotid body. These upregulated cytokine signaling pathways could enhance the carotid chemoreceptor activity, leading to an overactivity of the chemoreflex adversely effecting breathing instability and autonomic imbalance. This review aims to summarize findings of the literature relevant to inflammation in the carotid body, with highlights on the pathophysiological impact in sleep apnea. It is concluded that local inflammation in the carotid body plays a pathogenic role in sleep apnea, which could potentially be a therapeutic target for the treatment of the pathophysiological consequence of sleep apnea.