Chemoreflex Function Research Articles

Paul Ivan Korner

Paul Korner died on October 3, 2012 after a short illness on the day he was to receive a Lifetime Achievement Award from the International Society of Hypertension in recognition of his contribution to our understanding of cardiovascular disease, particularly hypertension. His legacies include his own original contributions in the field of circulatory control, the work of many esteemed scientists and academics he trained, and his recent monograph: Essential Hypertension and Its Causes. In >330 publications spanning from the 1950s to the present day, he made important contributions in the field of central nervous control of the circulation, particularly baroreflex and chemo reflex function. He studied how structural adaptations are responsible for many characteristics of the hypertension phenotype, developing the concept of the cardiac and vascular amplifier having been influenced by his friend Bjorn Folkow. In many of these fields, he not only introduced new concepts but also methodologies that were taken up by others. Techniques for studying the baroreflex and autonomic versus nonautonomic contributions to peripheral vascular resistance are examples. He was also among the first to understand that reduction of overall risk was the objective in the prevention of coronary heart disease …

Hypobaric Intermittent Hypoxia Attenuates Hypoxia-induced Depressor Response

BackgroundHypobaric intermittent hypoxia (HIH) produces many favorable effects in the cardiovascular system such as anti-hypertensive effect. In this study, we showed that HIH significantly attenuated a depressor response induced by acute hypoxia.Methodology/Principal FindingsSprague-Dawley rats received HIH in a hypobaric chamber simulating an altitude of 5000 m. The artery blood pressure (ABP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded in anesthetized control rats and rats received HIH. The baseline ABP, HR and RSNA were not different between HIH and control rats. Acute hypoxia-induced decrease in ABP was significantly attenuated in HIH rat compared with control rats. However, acute hypoxia-induced increases in HR and RSNA were greater in HIH rat than in control rats. After removal of bilateral ascending depressor nerves, acute hypoxia-induced depressor and sympathoexcitatory responses were comparable in control and HIH rats. Furthermore, acute hypoxia-induced depressor and sympathoexcitatory responses did not differ between control and HIH groups after blocking ATP-dependent K+ channels by glibenclamide. The baroreflex function evaluated by intravenous injection of phenylephrine and sodium nitroprusside was markedly augmented in HIH rats compared with control rats. The pressor and sympathoexcitatory responses evoked by intravenous injection of cyanide potassium were also significantly greater in HIH rats than in control rats.Conclusions/SignificanceOur findings suggest that HIH suppresses acute hypoxia-induced depressor response through enhancement of baroreflex and chemoreflex function, which involves activation of ATP-dependent K+ channels. This study provides new information and underlying mechanism on the beneficiary effect of HIH on maintaining cardiovascular homeostasis.

Role of blood flow in carotid body chemoreflex function in heart failure

Peripheral chemoreflex sensitivity is potentiated in clinical and experimental chronic heart failure (CHF). Blood supply to tissues is inevitably reduced in CHF. However, it remains poorly understood whether the reduced blood flow is the cause of increased peripheral chemoreflex sensitivity in CHF. This work highlights the effect of chronically reduced blood flow to the carotid body (CB) on peripheral chemoreflex function in rabbits. In pacing-induced CHF rabbits, blood flow in the carotid artery was reduced by 36.4 ± 5.2% after 3 weeks of pacing. For comparison, a similar level of blood flow reduction was induced by carotid artery occlusion (CAO) over a similar 3 week time course without pacing. CB blood supply was reduced by similar levels in both CHF and CAO rabbits as measured with fluorescent microspheres. Compared with sham rabbits, CAO enhanced peripheral chemoreflex sensitivity in vivo, increased CB chemoreceptor activity in an isolated CB preparation and decreased outward potassium current (Ik) in CB glomus cells to levels similar to those that were observed in CHF rabbits. In CAO CB compared to sham, neural nitric oxide (NO) synthase (nNOS) expression and NO levels were suppressed, and angiotensin II (Ang II) type 1 receptor (AT1-R) protein expression and Ang II concentration were elevated; these changes were similar to those seen in the CB from CHF rabbits. A NO donor and AT1-R antagonist reversed CAO-enhanced chemoreflex sensitivity. These results suggest that a reduction of blood flow to the CB is involved in the augmentation of peripheral chemoreflex sensitivity in CHF.

HIGHLIGHTS FROM THE LITERATURE

HIGHLIGHTS FROM THE LITERATURE

Chronic intermittent hypoxia affects integration of sensory input by neurons in the nucleus tractus solitarii

The autonomic nervous and respiratory systems, as well as their coupling, adapt over a wide range of conditions. Chronic intermittent hypoxia (CIH) is a model for recurrent apneas and induces alterations in breathing and increases in sympathetic nerve activity which may ultimately result in hypertension if left untreated. These alterations are believed to be due to increases in the carotid body chemoreflex pathway. Here we present evidence that the nucleus tractus solitarii (nTS), the central brainstem termination site of chemoreceptor afferents, expresses a form of synaptic plasticity that increases overall nTS activity following intermittent hypoxia. Following CIH, an increase in presynaptic spontaneous neurotransmitter release occurs under baseline conditions. Furthermore, during and following afferent stimulation there is an augmentation of spontaneous transmitter release that occurs out of synchrony with sensory stimulation. On the other hand, afferent evoked synchronous transmitter release is attenuated. Overall, this shift from synchronous to asynchronous transmitter release enhances nTS cellular discharge. The role of the neurotransmitter dopamine in CIH-induced plasticity is also discussed. Dopamine attenuates synaptic transmission in nTS cells by blockade of N-type calcium channels, and this mechanism occurs tonically following normoxia and CIH. This dopaminergic pathway, however, is not altered in CIH. Taken together, alterations in nTS synaptic activity may play a role in the changes of chemoreflex function and cardiorespiratory activity in the CIH apnea model.

Enhanced peripheral chemoreflex function in conscious rats with ligation‐induced heart failure

Our previous studies showed peripheral chemoreflex sensitivity is enhanced in conscious rabbits with pacing‐induced chronic heart failure (CHF), which is mediated by an elevated Angiotensin II (Ang II) effect on the carotid body (CB). Here we investigated whether CB chemoreflex function and CB Ang II are similarly altered in a rat model of 8 week ligation‐induced CHF. Minute ventilation (VE) and renal sympathetic nerve activity (RSNA) in response to stimulation of peripheral chemoreceptor by isocapnic/hypoxic gases were measured in conscious state. The degree of CHF was assessed by echocardiography. It was found that the baselines VE and RSNA at normoxia and graded hypoxia were elevated in CHF rats (> 30% reduction of FS) than those in sham rats. In addition, the concentration of tissue Ang II measured by radioimmunoassay was higher in CHF CBs compared to sham CBs (51.44 ± 0.16 vs. 36.20 ± 1.29 pg/mg protein, p<0.05). Furthermore, protein expression of Ang II type 1 receptor and angiotensin converting enzyme 1 in CHF CBs were increased compared to those in sham CBs. These results suggest that, similar to the pacing model in rabbits, increased Ang II in the CBs may contribute to the enhanced peripheral chemoreflex function in the coronary ligation model of CHF in rats. Supported by NIH grant PO‐1 HL 62222.

Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits

Peripheral chemoreflex sensitivity is enhanced in both clinical and experimental chronic heart failure (CHF). Here we investigated the role of manganese superoxide dismutase (MnSOD), the SOD isoform specially targeted to mitochondria, and mitochondrial superoxide levels in the enhanced chemoreceptor activity and function of the carotid body (CB) in CHF rabbits. CHF suppressed MnSOD protein expression and elevated mitochondrial superoxide levels in CB compared with that in sham CB. Adenovirus (Ad) MnSOD (1 x 10(8) plaque-forming units/ml) gene transfer selectively to the CBs normalized mitochondrial superoxide levels in glomus cells from CHF CB. In addition, Ad MnSOD reduced the elevation of superoxide level in CB tissue from CHF rabbits. Ad MnSOD significantly increased MnSOD expression in CHF CBs and normalized the baseline renal sympathetic nerve activity and the response of renal sympathetic nerve activity to hypoxia in CHF rabbits. Ad MnSOD decreased baseline single-fiber discharge from CB chemoreceptors compared with Ad Empty (6.3 + or - 1.5 vs. 12.7 + or - 1.4 imp/s at approximately 100-Torr Po(2), P < 0.05) and in response to hypoxia (20.5 + or - 1.8 vs. 32.6 + or - 1.4 imp/s at approximately 40-Torr Po(2), P < 0.05) in CHF rabbits. Compared with Ad Empty, Ad MnSOD reversed the blunted K(+) currents in CB glomus cells from CHF rabbits (385 + or - 11 vs. 551 + or - 20 pA/pF at +70 mV, P < 0.05). The results suggest that decreased MnSOD in the CB and elevated mitochondrial superoxide levels contribute to the enhanced CB chemoreceptor activity and peripheral chemoreflex function in CHF rabbits.

Peripheral chemoreflex regulation of sympathetic vasomotor tone in apnea divers

Involuntary apnea episodes in obstructive sleep apnea patients result in selective potentiation of peripheral chemoreceptor regulation of sympathetic vasomotor tone. Breath-hold diving is associated with repeated "voluntary" apnea episodes and massive arterial oxygen desaturation, which could also perturb chemoreflex function. We measured ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 11 breath-hold divers and eleven matched control subjects. The study was carried out at least 1 month after intense apnea training. Baseline MSNA frequency was 30 +/- 4 bursts/min in control subjects and 31 +/- 7 bursts/min in divers (ns). During hypoxia MSNA frequency and total activity increased similarly in both groups (30 and 66% in controls and 27 and 60% in divers, respectively). MSNA remained increased after termination of hypoxia and approached baseline measurements after 20 min. Hypoxia-induced stimulation of minute ventilation was similar in both groups, although in divers it was maintained by higher tidal volumes and lower breathing frequency compared with control subjects. In both groups, hypoxia-induced tachycardia drove an increase in cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged. We conclude that after the end of intensive training/competition periods, apnea divers show normal peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone. Although voluntary apnea may not lead to sustained changes in sympathetic nervous system regulation, we cannot exclude the possibility that repeated sympathetic activation elicited by voluntary apnea imposes a burden on the cardiovascular system.

Decreased ventilatory response to exercise by dopamine-induced inhibition of peripheral chemosensitivity

The contribution of the peripheral chemoreflex to the ventilatory response to exercise and aerobic exercise capacity remains incompletely understood. Low-dose dopamine has been reported to specifically inhibit the peripheral chemoreceptors. We therefore investigated the effects of intravenous dopamine (3 microg kg(-1)min(-1)) on cardiopulmonary exercise test (CPET) variables in 13 healthy young male subjects. The study was prospective, placebo-controlled, and randomized with more than 24h between placebo and dopamine administrations. During the CPET, dopamine decreased the .V(E)/.V(CO2) output slope (24.61+/-1.84 vs. 23.09+/-1.81, placebo vs. Dopamine respectively, p=0.025), without affecting maximum workload, .V(E) and O(2) uptake. In conclusion, our study reveals that inhibition of peripheral chemoreflex function with dopamine decreases the .V(E)/.V(CO2) slope during dynamic exercise, with no change in aerobic exercise capacity.

Adenovirus‐mediated gene transfer of Mn superoxide dismutase to carotid body normalizes enhanced chemoreceptor function in heart failure rabbits

Peripheral chemoreflex sensitivity is enhanced in both clinical and experimental chronic heart failure (CHF). We have found CuZn superoxide dismutase (SOD) gene transfer to the carotid body (CB) and tempol (an SOD mimetic) reverse the enhanced chemoreceptor function in heart failure rabbits. Here we investigated the role of MnSOD in the enhanced chemoreceptor activity and function of the CB in CHF rabbits. MnSOD protein expression was lower in CHF CB compared with that in sham CBs. Ad MnSOD (1x108 pfu/ml) gene transfer to the CBs significantly increased MnSOD expression in CHF CBs and reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits. Ad MnSOD decreased the baseline single‐fiber discharge from CB chemoreceptors (6.4± 1.3 vs.10.5±0.9 imp/s at ~100 mm Hg PO2) and the response to hypoxia (18.4±2.1 vs. 36.7±2.2 imp/s at ~40 mm Hg PO2, p&lt;0.05) in CHF rabbits. In addition, Ad MnSOD normalized the blunted IK in CB glomus cells from CHF rabbits (362±41 vs. 520±65 pA/pF at +70 mV, p&lt;0.05). Ad MnSOD also normalized the blunted IK induced by angiotensin II in CB glomus cells from sham rabbits. These results suggest that decreased MnSOD in the CB may contribute to the enhanced CB chemoreceptors activity and peripheral chemoreflex function in CHF rabbits.Supported by NIH grant PO‐1 HL 62222

Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits

Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase-derived superoxide mediates angiotensin II (Ang II)-enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II- and CHF-enhanced superoxide anion effect. Here we investigated the role of cytoplasmic SOD [CuZn superoxide dismutase (CuZnSOD)] in the CB on chemoreceptor activity and function in CHF rabbits. CuZnSOD protein expression was decreased in CBs from CHF rabbits vs. sham (P < 0.05). Adenoviral CuZnSOD (Ad CuZnSOD) gene transfer to the CBs increased CuZnSOD protein expression and significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits (P < 0.05). Single-fibre discharge from CB chemoafferents during normoxia (baseline, at approximately 100 mmHg PO2) and in response to hypoxia were enhanced in CHF vs. sham rabbits (P < 0.05). Ad CuZnSOD decreased the baseline discharge (7.6 +/- 1.3 vs. 12.6 +/- 1.7 imp/s at approximately 100 mmHg PO2) and the response to hypoxia (22.4 +/- 1.6 vs. 32.3 +/- 1.2 imp/s at approximately 40 mmHg PO2, P < 0.05) in CHF rabbits. Ad CuZnSOD also normalized the blunted outward K+ current (IK) in CB glomus cells from CHF rabbits (369 +/- 14 vs. 565 +/- 31 pA/pF at +70 mV, P < 0.05). In addition, Ad CuZnSOD reduced the elevation of superoxide level in CBs from CHF rabbits. Downregulation of CuZnSOD in the CB contributes to the enhanced activity of CB chemoreceptors and chemoreflex function in CHF rabbits.

Effects of acute acidemia on the fetal cardiovascular defense to acute hypoxemia

In complicated pregnancy, fetal hypoxemia rarely occurs in isolation but is often accompanied by fetal acidemia. There is growing clinical concern about the combined effects of fetal hypoxemia and fetal acidemia on neonatal outcome. However, the effects on the fetal defense responses to acute hypoxemia during fetal acidemia are not well understood. This study tested the hypothesis that fetal acidemia affects the fetal defense responses to acute hypoxemia. The hypothesis was tested by investigating, in the late-gestation sheep fetus surgically prepared for long-term recording, the in vivo effects of acute fetal acidemia on 1) the fetal cardiovascular responses to acute hypoxemia and 2) the neural and endocrine mechanisms mediating these responses. Under general anesthesia, five sheep fetuses at 0.8 gestation were instrumented with catheters and Transonic flow probes around the femoral and umbilical arteries. After 5 days, animals were subjected to an acute hypoxemia protocol during intravenous infusion of saline or treatment with acidified saline. Treatment with acidified saline reduced fetal basal pH from 7.35 +/- 0.01 to 7.29 +/- 0.01 but did not alter basal cardiovascular variables, blood glucose, or plasma concentrations of catecholamines, ACTH, and cortisol. During hypoxemia, treatment with acidified saline increased the magnitude of the fetal bradycardia and femoral vasoconstriction and concomitantly increased chemoreflex function and enhanced the increments in plasma concentrations of catecholamines, ACTH, and cortisol. Acidemia also reversed the increase in umbilical vascular conductance during hypoxemia to vasoconstriction. In conclusion, the data support our hypothesis and show that acute acidemia markedly alters fetal hemodynamic, metabolic, and endocrine responses to acute hypoxemia.

Exercise training improves peripheral chemoreflex function in heart failure rabbits

An enhancement of peripheral chemoreflex sensitivity contributes to sympathetic hyperactivity in chronic heart failure (CHF) rabbits. The enhanced chemoreflex function in CHF involves augmented carotid body (CB) chemoreceptor activity via upregulation of the angiotensin II (ANG II) type 1 (AT(1))-receptor pathway and downregulation of the neuronal nitric oxide synthase (nNOS)-nitric oxide (NO) pathway in the CB. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanisms mediating this effect. EXT partially, but not fully, normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline CB nerve single-fiber discharge (4.9 +/- 0.4 vs. 7.7 +/- 0.4 imp/s at Po(2) = 103 +/- 2.3 Torr) and the response to hypoxia (20.6 +/- 1.1 vs. 36.3 +/- 1.3 imp/s at Po(2) = 41 +/- 2.2 Torr) from CB chemoreceptors in CHF rabbits, which could be reversed by treatment of the CB with ANG II or a nNOS inhibitor. Our results also showed that NO concentration and protein expression of nNOS were increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, elevated ANG II concentration and AT(1)-receptor overexpression of the CBs in CHF state were blunted by EXT. These results indicate that EXT normalizes the CB chemoreflex in CHF by preventing an increase in afferent CB chemoreceptor activity. EXT reverses the alterations in the nNOS-NO and ANG II-AT(1)-receptor pathways in the CB responsible for chemoreceptor sensitization in CHF.

Interaction between cardiac sympathetic afferent reflex and chemoreflex is mediated by the NTS AT1 receptors in heart failure

Several sympathoexcitatory reflexes, such as the cardiac sympathetic afferent reflex (CSAR) and arterial chemoreflex, are significantly augmented and contribute to elevated sympathetic outflow in chronic heart failure (CHF). This study was undertaken to investigate the interaction between the CSAR and the chemoreflex in CHF and to further identify the involvement of angiotensin II type 1 receptors (AT1Rs) in the nucleus of the tractus solitarius (NTS) in this interaction. CHF was induced in rats by coronary ligation. Acute experiments were performed in anesthetized rats. The chemoreflex-induced increase in cardiovascular responses was significantly greater in CHF than in sham-operated rats after either chemical or electrical activation of the CSAR. The inhibition of the CSAR by epicardial lidocaine reduced the chemoreflex-induced effects in CHF rats but not in sham-operated rats. Bilateral NTS injection of the AT1R antagonist losartan (10 and 100 pmol) dose-dependently decreased basal sympathetic nerve activity in CHF but not in sham-operated rats. This procedure also abolished the CSAR-induced enhancement of the chemoreflex. The discharge and chemosensitivity of NTS chemosensitive neurons were significantly increased following the stimulation of the CSAR in sham-operated and CHF rats, whereas CSAR inhibition by epicardial lidocaine significantly attenuated chemosensitivity of NTS neurons in CHF but not in sham-operated rats. Finally, the protein expression of AT1R in the NTS was significantly higher in CHF than in sham-operated rats. These results demonstrate that the enhanced cardiac sympathetic afferent input contributes to an excitatory effect of chemoreflex function in CHF, which is mediated by an NTS-AT1R-dependent mechanism.

NO and CO have got to GO for enhanced chemoreceptor sympathoexcitation in heart failure

arterial chemoreceptors located in the carotid body are an important defense mechanism against systemic hypoxemia. Activation of arterial chemoreceptors increases alveolar ventilation and sympathetic outflow to most vascular beds. During acute exposures to hypoxia, the sympathoexcitatory responses

Gene transfer of Cu‐Zn superoxide dismutase to the carotid body reverses enhanced chemoreceptor function in heart failure rabbits

Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase‐derived superoxide anion mediates angiotensin II‐enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II‐ and CHF‐enhanced superoxide anion effect (Cardiovasc Res. 2007, 75:546–54). Here we investigated the effect of adenoviral Cu‐Zn SOD gene transfer in the CB on chemoreceptor activity and function in CHF rabbits. Ad Cu‐Zn SOD (1×108 pfu/ml) gene transfer to the CBs significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits. Baseline single‐fiber discharge from CB chemoreceptors during normoxia and the response to hypoxia were enhanced in CHF vs. sham rabbits. Ad Cu‐Zn SOD decreased the baseline discharge (2.9 ± 1.1 vs. 8.1 ± 0.8 imp/s at 104 ± 2.4 mm Hg PO2) and the response to hypoxia (16.4 ± 2.3 vs. 38.7 ± 2.3 imp/s at 41 ± 2.6 mm Hg PO2, p&lt;0.05) in CHF rabbits. In addition, Ad Cu‐Zn SOD normalized the blunted IK in CB glomus cells from CHF rabbits (1020 ± 142 vs. 2156 ± 230 pA at +70 mV, p&lt;0.05). Ad SOD did not affect CB afferent discharge and IK of CB glomus cells in sham rabbits. These results suggest that Cu‐Zn SOD activity in the CB may be involved in the enhanced activity of the CB chemoreceptors and peripheral chemoreflex function in CHF rabbits.

Exercise training normalizes enhanced peripheral chemoreflex function in chronic heart failure rabbits

Our previous studies have shown that the enhanced sensitivity of the peripheral chemoreflex contributes to the sympathetic hyperactivity in chronic heart failure (CHF) rabbits and an augmented carotid body (CB) chemoreceptor activity is involved in the enhancement of peripheral chemoreflex function. Furthermore, we have also found that upregulation of angiotensin (Ang) II‐AT1 receptor pathway and downregulation of NOS‐NO pathway in the CB contribute to the enhanced CB chemoreceptor sensitivity in the CHF state. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanism mediating this effect. EXT partially but not fully normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline carotid body nerve single‐fiber discharge (4.9 ± 0.4 vs 7.7 ± 0.4 imp/s at PO2 =103 ± 2.3 mm Hg) and the response to hypoxia (20.6 ± 1.1 vs 36.3 ± 1.3 imp/s at PO2 =41 ± 2.2 mm Hg) from CB chemoreceptors in CHF rabbits. Western and immunofluorescence data showed that protein expression of nNOS was increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, the AT1 receptor overexpression of the CB in CHF state was also blunted by EXT. These results indicate that EXT improves the enhanced chemoreflex in CHF, which is due to EXT‐induced upregulation of nNOS‐NO pathway and downexpression of Ang II‐AT1 receptor pathway in the CBs.

Effects of enoximone on peripheral and central chemoreflex responses in humans

cAMP plays an important role in peripheral chemoreflex function in animals. We tested the hypothesis that the phosphodiesterase inhibitor and inotropic medication enoximone increases peripheral chemoreflex function in humans. In a single-blind, randomized, placebo-controlled crossover study of 15 men, we measured ventilatory, muscle sympathetic nerve activity, and hemodynamic responses to 5 min of isocapnic hypoxia, 5 min of hyperoxic hypercapnia, and 3 min of isometric handgrip exercise, separated by 1 wk, with enoximone and placebo administration. Enoximone increased cardiac output by 120 +/- 3.7% from baseline (P < 0.001); it also increased the ventilatory response to acute hypoxia [13.6 +/- 1 vs. 11.2 +/- 0.7 l/min at 5 min of hypoxia, P = 0.03 vs. placebo (by ANOVA)]. Despite a larger minute ventilation and a smaller decrease in O(2) desaturation (83 +/- 1 vs. 79 +/- 2%, P = 0.003), the muscle sympathetic nerve response to hypoxia was similar between enoximone and placebo (123 +/- 6 and 117 +/- 6%, respectively, P = 0.28). In multivariate regression analyses, enoximone enhanced the ventilatory (P < 0.001) and sympathetic responses to isocapnic hypoxia. Hyperoxic hypercapnia and isometric handgrip responses were not different between enoximone and placebo (P = 0.13). Enoximone increases modestly the chemoreflex responses to isocapnic hypoxia. Moreover, this effect is specific for the peripheral chemoreflex, inasmuch as central chemoreflex and isometric handgrip responses were not altered by enoximone.

Arterial Chemoreceptors and Sympathetic Nerve Activity

Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Sympathetic Chemoreflex Responses in Obstructive Sleep Apnea and Effects of Continuous Positive Airway Pressure Therapy

Sympathetic nerve activity is increased in awake and regularly breathing patients with obstructive sleep apnea (OSA). Over time, repetitive hypoxic stress could alter sympathetic chemoreflex function in OSA. We determined the responses to acute hypoxia (fraction of inspired oxygen of 0.1, for 5 min), static handgrip exercise, and the cold pressor test (CPT) in 24 patients with OSA (age, 50 +/- 3 years [mean +/- SEM]; apnea-hypopnea index, 47 +/- 6 events per hour) and in 14 age- and weight-matched nonapneic control subjects. Muscle sympathetic nerve activity (MSNA) [peroneal microneurography], BP, and ventilation were monitored. Basal MSNA was higher in OSA patients compared to control subjects (45 +/- 4 bursts per minute vs 33 +/- 4 bursts per minute, respectively; p < 0.05). Furthermore, compared to control subjects, the MSNA responses to hypoxia were markedly enhanced in OSA (p < 0.001). Whereas the ventilatory responses to hypoxia tended to be increased in OSA (p = 0.06), the BP responses did not differ between the groups (p = 0.45). The neurocirculatory reflex responses to handgrip exercise and to the CPT were similar in the two groups (p = not significant). In OSA patients who were retested after 1 to 24 months of continuous positive airway pressure (CPAP) therapy (n = 11), basal MSNA (p < 0.01) and the responses of MSNA to hypoxia (p < 0.01) decreased significantly, whereas the ventilatory responses remained unchanged (p = 0.82). These data suggest that the sympathetic responses to hypoxic chemoreflex stimulation are enhanced in OSA and may normalize in part following CPAP therapy.