Orexin contributes to eupnea within a critical period of postnatal development

Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1) orexin provides a drive to breathe in infancy; 2) the effect of orexin depends on stage of postnatal development; and 3) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days ( P) 7–8, 12–14, and 17–19. Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia ([Formula: see text] = 0.02, 0.04, 0.06), hypoxia ([Formula: see text] = 0.10), and hyperoxia ([Formula: see text] = 1.0) at P12–14 were also tested. At P12–14, but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased [Formula: see text] to ∼5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12–14. Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ∼2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near term fetal sheep without placental compromise

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterised in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane-anesthesia. Comparable data to baseline was collected 10 (acute hypoxemia) and 60 minutes (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower, and lactate levels higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, while in the carotid artery MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed LVCO or AoI Net Flow-ratio did not correlate with a drop in carotid artery blood pressure.

Cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension at rest and during orthostatic stress: Role of the peripheral chemoreflex

The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in non-hypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity (i.e., V̇O2peak); and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptors inhibition) or 21% O2 (control session), while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEIALL at rest (mean ± SD: PAH = 0.5 ± 0.2 vs HA = 0.7 ± 0.1 a.u., P = 0.02) and lower cBRSALL (PAH = 6.8 ± 7.0 vs HA = 9.7 ± 5.0 ms mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to V̇O2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in non-hypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower V̇O2peak suggesting it could be functionally relevant.

Low ventilatory responsiveness to transient hypoxia or breath-holding predicts fast marathon performance in healthy middle-aged and older men

The aim of this study was to test the utility of haemodynamic and autonomic variables (e.g. peripheral chemoreflex sensitivity [PCheS], blood pressure variability [BPV]) for the prediction of individual performance (marathon time and VO2max) in older men. The post-competition vasodilation and sympathetic vasomotor tone predict the marathon performance in younger men, but their prognostic relevance in older men remains unknown. The peripheral chemoreflex restrains exercise-induced vasodilation via sympathetically-mediated mechanism, what makes it a plausible candidate for the individual performance marker. 23 men aged ≥ 50 year competing in the Wroclaw Marathon underwent an evaluation of: resting haemodynamic parameters, PCheS with two methods: transient hypoxia and breath-holding test (BHT), cardiac barosensitivity, heart rate variability (HRV) and BPV, plasma renin and aldosterone, VO2max in a cardiopulmonary exercise test (CPET). All tests were conducted twice: before and after the race, except for transient hypoxia and CPET which were performed once, before the race. Fast marathon performance and high VO2max were correlated with: low ventilatory responsiveness to hypoxia (r = − 0.53, r = 0.67, respectively) and pre-race BHT (r = − 0.47, r = 0.51, respectively), (1) greater SD of beat-to-beat SBP (all p < 0.05). Fast performance was related with an enhanced pre-race vascular response to BHT (r = − 0.59, p = 0.005). The variables found by other studies to predict the marathon performance in younger men: post-competition vasodilation, sympathetic vasomotor tone (LF-BPV) and HRV were not associated with the individual performance in our population. The results suggest that PCheS (ventilatory response) predicts individual performance (marathon time and VO2max) in men aged ≥ 50 yeat. Although cause-effect relationship including the role of peripheral chemoreceptors in restraining the post-competition vasodilation via the sympathetic vasoconstrictor outflow may be hypothesized to underline these findings, the lack of correlation between individual performance and both, the post-competition vasodilation and the sympathetic vasomotor tone argues against such explanation. Vascular responsiveness to breath-holding appears to be of certain value for predicting individual performance in this population, however.

Measuring Peripheral Chemoreflex Hypersensitivity in Heart Failure

Heart failure with reduced ejection fraction (HFrEF) induces chronic sympathetic activation. This disturbance is a consequence of both compensatory reflex disinhibition in response to lower cardiac output and patient-specific activation of one or more excitatory stimuli. The result is the net adrenergic output that exceeds homeostatic need, which compromises cardiac, renal, and vascular function and foreshortens lifespan. One such sympatho-excitatory mechanism, evident in ~40–45% of those with HFrEF, is the augmentation of carotid (peripheral) chemoreflex ventilatory and sympathetic responsiveness to reductions in arterial oxygen tension and acidosis. Recognition of the contribution of increased chemoreflex gain to the pathophysiology of HFrEF and to patients’ prognosis has focused attention on targeting the carotid body to attenuate sympathetic drive, alleviate heart failure symptoms, and prolong life. The current challenge is to identify those patients most likely to benefit from such interventions. Two assumptions underlying contemporary test protocols are that the ventilatory response to acute hypoxic exposure quantifies accurately peripheral chemoreflex sensitivity and that the unmeasured sympathetic response mirrors the determined ventilatory response. This Perspective questions both assumptions, illustrates the limitations of conventional transient hypoxic tests for assessing peripheral chemoreflex sensitivity and demonstrates how a modified rebreathing test capable of comprehensively quantifying both the ventilatory and sympathoneural efferent responses to peripheral chemoreflex perturbation, including their sensitivities and recruitment thresholds, can better identify individuals most likely to benefit from carotid body intervention.

Cholinergic Chemotransmission and Anesthetic Drug Effects at the Carotid Bodies

General anesthesia is obtained by administration of potent hypnotics, analgesics and muscle relaxants. Apart from their intended effects (loss of consciousness, pain relief and muscle relaxation), these agents profoundly affect the control of breathing, in part by an effect within the peripheral chemoreflex loop that originates at the carotid bodies. This review assesses the role of cholinergic chemotransmission in the peripheral chemoreflex loop and the mechanisms through which muscle relaxants and hypnotics interfere with peripheral chemosensitivity. Additionally, consequences for clinical practice are discussed.

Preeclampsia is not associated with elevated muscle sympathetic reactivity.

Objective: To determine whether increased chemoreflex tonic activity is associated with augmented muscle sympathetic nervous sys activity (MSNA) in women diagnosed with preeclampsia. Methods: Women with preeclampsia (n=19; 32±5 years old, 31±3 weeks gestation) were matched by age and gestational age with pregnant women (controls, n=38, 32±4 years old, 31±4 weeks gestation; 2:1 ratio). MSNA (n=9 preeclampsia) was assessed during baseline, peripheral chemoreflex de-activation (hyperoxia) and a cold pressor test (CPT). Baroreflex gain, diastolic blood pressure at which there is a 50% likelihood of MSNA occurring (T50) and plasma noradrenaline concentrations were measured. Results: Baseline mean arterial pressure (MAP: 106±11 vs. 87±10 mmHg, p<0.0001), noradrenaline concentrations (498±152 pg/mL vs. 326±147, p=0.001) and T50 (79±7 vs. 71±9 mmHg, p=0.02) were greater in women with preeclampsia compared to controls. However, baseline MSNA (burst incidence [BI]: 41±16 vs. 45±13 bursts/100hb, p=0.4) was not different between groups. Responses to hyperoxia (ΔBI -5±7 vs. -1±8 bursts/100hb, p=0.1; ΔMAP -1±3 vs. -2±3 mmHg, p=0.7) and CPT (ΔBI 15±7 vs. 12±11 bursts/100hb, p=0.6; ΔMAP 10±4 vs. 12±11 mmHg, p=0.6) were not different between groups. Conclusion: Our findings question the assumption that increased MSNA contributes to hypertension in women with preeclampsia. The chemoreflex does not appear to contribute to an increase in MSNA in women with preeclampsia.

Acute inorganic nitrate supplementation and the hypoxic ventilatory response in patients with obstructive sleep apnea

Patients with obstructive sleep apnea (OSA) have increased cardiovascular disease risk largely attributable to hypertension. Heightened peripheral chemoreflex sensitivity (i.e., exaggerated responsiveness to hypoxia) facilitates hypertension in these patients. Nitric oxide blunts the peripheral chemoreflex and patients with OSA have reduced nitric oxide bioavailability. We therefore investigated the dose-dependent effects of acute inorganic nitrate supplementation (beetroot juice), an exogenous nitric oxide source, on blood pressure and cardiopulmonary responses to hypoxia in patients with OSA using a randomized, double-blind, placebo-controlled crossover design. Fourteen patients with OSA (53±10years, 29.2±5.8kg/m2, apnea-hypopnea index=17.8±8.1, 43%F) completed three visits. Resting brachial blood pressure, as well as cardiopulmonary responses to inspiratory hypoxia, were measured before, and two hours after, acute inorganic nitrate supplementation (~0.10mmol [placebo], 4.03mmol [low-dose], and 8.06mmol [high-dose]). Placebo did not increase either plasma [nitrate] (30±52 to 52±23μM, P=0.26) or [nitrite] (266±153 to 277±164nM, P=0.21); however, both increased following low-(29±17 to 175±42μM, 220±137 to 514±352nM) and high-doses (26±11 to 292±90μM, 248±155 to 738±427nM, respectively, P<0.01 for all). Following placebo, systolic blood pressure increased (120±9 to128±10mmHg, P<0.05) whereas no changes were observed following low-(121±11 to 123±8mmHg, P=0.19) or high-dose (124±13 to 124±9mmHg, P=0.96). The peak ventilatory response to hypoxia increased following placebo (3.1±1.2 to 4.4±2.6L/min, P<0.01) but not low-(4.4±2.4 to 5.4±3.4L/min, P=0.11) or high-doses (4.3±2.3 to 4.8±2.7L/min, P=0.42). Inorganic nitrate did not change the heart rate responses to hypoxia (beverage-by-time P=0.64). Acute inorganic nitrate supplementation appears to blunt an early-morning rise in systolic blood pressure potentially through suppression of peripheral chemoreflex sensitivity in patients with OSA.