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Myocardial oxygen delivery is primarily regulated through changes in vascular tone to match increased metabolic demands. In males, activation of the muscle metaboreflex during acute isocapnic hypoxia results in paradoxical coronary vasoconstriction. Whether coronary blood velocity is reduced by metaboreflex activation following travel and/or adaptation to high altitude is unknown. This study determined if the response of the coronary vasculature to muscle metaboreflex activation at low altitude differs from acute (1/2 days) and prolonged (8/9 days) high altitude. Healthy males (

Central sleep apnea (CSA) is universal during ascent to high altitude, with intermittent and transient fluctuations in oxygen saturation, but the consequences on mean sleeping blood oxygenation are unclear. We assessed indices of CSA and mean sleeping peripheral oxygen saturation ([Formula: see text]) during ascent to high altitude using two ascent profiles: rapid ascent and residence at 3,800 m and incremental ascent to 5,160 m. The severity of CSA was not correlated with mean sleeping [Formula: see text] with ascent.

The evidence is mounting for a role for abnormal signaling of the stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its canonical receptor PAC1 in the pathogenesis of sudden infant death syndrome. In this study, we investigated whether the PACAP receptors PAC1 or VPAC2 are involved in the neonatal cardiorespiratory response to hypercapnic stress. We used head-out plethysmography and surface ECG electrodes to assess cardiorespiratory responses to an 8% hypercapnic challenge in unanesthetized and spontaneously breathing 4-day-old PAC1 or VPAC2 knockout (KO) and wild-type mouse pups. We demonstrate that compared with WTs, breathing frequency (RR) and minute ventilation ([Formula: see text]) in PAC1 KO pups were significantly blunted in response to hypercapnia. Although heart rate was unaltered in PAC1 KO pups during hypercapnia, heart rate recovery posthypercapnia was impaired. In contrast, cardiorespiratory impairments in VPAC2 KO pups were limited to only an overall higher tidal volume (VT), independent of treatment. These findings suggest that PACAP signaling through the PAC1 receptor plays a more important role than signaling through the VPAC2 receptor in neonatal respiratory responses to hypercapnia. Thus deficits in PACAP signaling primarily via PAC1 may contribute to the inability of infants to mount an appropriate protective response to homeostatic stressors in childhood disorders such as SIDS.

The stress peptide pituitary adenylate cyclase activating polypeptide (PACAP) and its specific receptor PACAP type 1 receptor (PAC1) have been implicated in sudden infant death syndrome (SIDS). PACAP is also critical to the neonatal cardiorespiratory response to homeostatic stressors identified in SIDS, including hypoxia. However, which of PACAP’s three receptors, PAC1, vasoactive intestinal peptide receptor type 1 (VPAC1), and/or vasoactive intestinal peptide receptor type 2 (VPAC2), are involved is unknown. In this study, we hypothesized that PAC1, but not VPAC2, is involved in mediating the cardiorespiratory response to hypoxia during neonatal development. To test this hypothesis, head-out plethysmography and surface ECG electrodes were used to assess the cardiorespiratory variables of unanesthetized postnatal day 4 PAC1 and VPAC2-knockout (KO) and wild-type (WT) mice in response to a 10% hypoxic challenge. Our results demonstrate that compared with WT pups, the early and late hypoxic rate of expired CO2(V̇co2), V̇co2and ventilatory responses were blunted in PAC1-KO neonates, and during the posthypoxic period, minute ventilation (V̇e), V̇co2and heart rate were increased, while the increase in apneas normally associated with the posthypoxic period was reduced. Consistent with impaired cardiorespiratory control in these animals, the V̇e/V̇co2slope was reduced in PAC1-KO pups, suggesting that breathing was inappropriately matched to metabolism. In contrast, VPAC2-KO pups exhibited elevated heart rate variability during hypoxia compared with WT littermates, but the effects of the VPAC2-KO genotype on breathing were minimal. These findings suggest that PAC1 plays the principal role in mediating the cardiorespiratory effects of PACAP in response to hypoxic stress during neonatal development and that defective PACAP signaling via PAC1 may contribute to the pathogenesis of SIDS.

Rapid ascent to high altitude imposes an acute hypoxic and acid-base challenge, with ventilatory and renal acclimatization countering these perturbations. Specifically, ventilatory acclimatization improves oxygenation, but with concomitant hypocapnia and respiratory alkalosis. A compensatory, renally-mediated relative metabolic acidosis follows via bicarbonate elimination, normalizing arterial pH(a). The time-course and magnitude of these integrated acclimatization processes are highly variable between individuals. Using a previously-developed metric of renal reactivity (RR), indexing the change in arterial bicarbonate concentration (∆[HCO3-]a; renal response) over the change in arterial pressure of CO2 (∆PaCO2; renal stimulus), we aimed to characterize changes in RR magnitude following rapid ascent and residence at altitude. Resident lowlanders (n=16) were tested at 1,045 m (Day [D]0) prior to ascent, on D2 within 24-hours of arrival, and D9 during residence at 3,800 m. Radial artery blood draws were obtained to measure acid-base variables: PaCO2, [HCO3-]a and pHa. Compared to D0, PaCO2 and [HCO3-]a were lower on D2 (P0.058) and RR (P=0.056) were not detected. As pHa appeared fully compensated on D2 and RR did not increase significantly from D2 to D9, these data demonstrate renal acid-base compensation within 24-hours at moderate steady-state altitude. Moreover, RR was strongly and inversely correlated with ∆pHa on D2 and D9 (r≤-0.95; P

Maternal cigarette smoke (CS) exposure exhibits a strong epidemiological association with Sudden Infant Death Syndrome, but other environmental stressors, including infection, hyperthermia, and hypoxia, have also been postulated as important risk factors. This study examines whether maternal CS exposure causes maladaptations within homeostatic control networks by influencing the response to lipopolysaccharide, heat stress, and/or hypoxia in neonatal rats. Pregnant dams were exposed to CS or parallel sham treatments daily for the length of gestation. Offspring were studied at postnatal days 6–8 at ambient temperatures (Ta) of 33°C or 38°C. Within each group, rats were allocated to control, saline, or LPS (200 µg/kg) treatments. Cardiorespiratory patterns were examined using head-out plethysmography and ECG surface electrodes during normoxia and hypoxia (10% O2). Serum cytokine concentrations were quantified from samples taken at the end of each experiment. Our results suggest maternal CS exposure does not alter minute ventilation (V̇e) or heart rate (HR) response to infection or high temperature, but independently increases apnea frequency. CS also primes the inflammatory system to elicit a stronger cytokine response to bacterial insult. High Ta independently depresses V̇e but augments the hypoxia-induced increase in V̇e. Moreover, higher Ta increases HR during normoxia and hypoxia, and in the presence of an immune challenge, increases HR during normoxia, and reduces the increase normally associated with hypoxia. Thus, while most environmental risk factors increase the burden on the cardiorespiratory system in early life, hyperthermia and infection blunt the normal HR response to hypoxia, and gestational CS independently destabilizes breathing by increasing apneas.

Abnormal respiratory chemosensitivity is implicated in recurrent apnea syndromes, with the peripheral chemoreceptors, the carotid bodies, playing a particularly important role. Previous work suggests that supraphysiological concentrations of the endocannabinoid endovanilloid and TASK channel blocker anandamide (ANA) excite carotid bodies, but the mechanism(s) and physiological significance are unknown. Given that carotid body output is temperature-sensitive, we hypothesized that ANA stimulates carotid body chemosensory afferents via temperature-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, we used the dual-perfused in situ rat preparation to confirm that independent perfusion of carotid arteries with supraphysiological concentrations of ANA strongly excites carotid sinus nerve afferents and that this activity is sufficient to increase phrenic activity. Next, using ex vivo carotid body preparations, we demonstrate that these effects are mediated by TRPV1 receptors, not CB1 receptors or TASK channels: in CB1-null mouse preparations, ANA increased afferent activity across all levels of Po2, whereas in TRPV1-null mouse preparations, the stimulatory effect of ANA was absent. In rat ex vivo preparations, ANA's stimulatory effects were mimicked by olvanil, a nonpungent TRPV1 agonist, and suppressed by the TRPV1 antagonist AMG-9810. The specific CB1 agonist oleamide had no effect. Physiological levels of ANA had no effect alone but increased sensitivity to mild hyperthermia. AMG-9810 blocked ANA's effect on the temperature response. Immunolabeling and RT-PCR demonstrated that TRPV1 receptors are not expressed in carotid body glomus cells but reside in petrosal sensory afferents. Together, these results suggest that ANA plays a physiological role in augmenting afferent responses to mild hyperthermia by activating TRPV1 receptors on petrosal afferents.

Time-dependent ventilatory responses to hypoxic and hypercapnic challenges, such as posthypoxic frequency decline (PHxFD) and posthypercapnic frequency decline (PHcFD), could profoundly affect breathing stability. However, little is known about the mechanisms that mediate these phenomena. To determine the contribution of specific carotid body chemostimuli to PHxFD and PHcFD, we developed a novel in situ arterially perfused, vagotomized, decerebrate rat preparation in which central and peripheral chemoreceptors are perfused separately (i.e., a nonanesthetized in situ dual perfused preparation). We confirmed that 1) the perfusion of central and peripheral chemoreceptor compartments was independent by applying specific carotid body hypoxia and hypercapnia before and after carotid sinus nerve transection, 2) the Pco2 chemoresponse of the dual perfused preparation was similar to other decerebrate preparations, and 3) the phrenic output was stable enough to allow investigation of time-dependent phenomena. We then applied four 5-min bouts (separated by 5 min) of specific carotid body hypoxia (40 Torr Po2 and 40 Torr Pco2) or hypercapnia (100 Torr Po2 and 60 Torr Pco2) while holding the brain stem Po2 and Pco2 constant. We report the novel finding that specific carotid body chemostimuli were sufficient to elicit several phrenic time-dependent phenomena in the rat. Hypoxic challenges elicited PHxFD that increased with bout, leading to progressive augmentation of the phrenic response. Conversely, hypercapnia elicited short-term depression and PHcFD, neither of which was bout dependent. These results, placed in the context of previous findings, suggest multiple physiological mechanisms are responsible for PHxFD and PHcFD, a redundancy that may illustrate that these phenomena have significant adaptive advantages.

The ventilatory response to several minutes of hypoxia consists of various time-dependent phenomena, some of which occur during hypoxia (e.g., short-term depression), whereas others appear on return to normoxia (e.g., posthypoxic frequency decline). Additional phenomena can be elicited by acute, intermittent hypoxia (e.g., progressive augmentation, long-term facilitation). Current data suggest that these phenomena originate centrally. We tested the hypothesis that carotid body afferent activity undergoes time-dependent modulation, consistent with a direct role in these ventilatory phenomena. Using an in vitro rat carotid body preparation, we found that 1) afferent activity declined during the first 5 min of severe (40 Torr Po2), moderate (60 Torr Po2), or mild (80 Torr Po2) hypoxia; 2) after return to normoxia (100 Torr Po2) and after several minutes of moderate or severe hypoxia, afferent activity was transiently reduced compared with prehypoxic levels; and 3) with successive 5-min bouts of mild, moderate, or severe hypoxia, afferent activity during bouts increased progressively. We call these phenomena sensory hypoxic decline, sensory posthypoxic decline, and sensory progressive augmentation, respectively. These phenomena were stimulus specific: similar phenomena were not seen with 5-min bouts of normoxic hypercapnia (100 Torr Po2 and 50–60 Torr Pco2) or hypoxic hypocapnia (60 Torr Po2 and 30 Torr Pco2). However, bouts of either normoxic hypercapnia or hypocapnic hypoxia resulted in sensory long-term facilitation. We suggest time-dependent carotid body activity acts in parallel with central mechanisms to shape the dynamics of ventilatory responses to respiratory chemostimuli.

Nitric oxide (NO) is a potent central neuromodulator of respiration, yet its scope and site of action are unclear. We used 7-nitroindazole (7-NI), a selective inhibitor of endogenous neuronal NO synthesis, to investigate the neurogenesis of respiration in larval bullfrog ( Rana catesbeiana) isolated brain stems. 7-NI treatment (0.0625–0.75 mM) increased the specific frequency of buccal ventilation (BV) events, indicating influence on BV central rhythm generators (CRGs). The drug reduced occurrence, altered burst shape, and disrupted clustering of lung ventilation (LV) events, without altering their specific frequency. LV burst occurrence and clustering also differed between pH conditions. We conclude that NO has diverse effects on respiratory rhythmogenesis, being necessary for the expression of respiratory rhythms, inhibiting the frequency of BV CRG, and affecting both shape and clustering of LV bursts through conditional modulation of LV CRG. We confirm central chemosensitivity in these preparations and demonstrate chemomodulation of LV burst clustering and occurrence but not specific frequency. Results support distinct oscillators underlying LV and BV CRGs.

The rat working heart-brain stem preparation (WHBP) is an in situ preparation having many of the advantages associated with in vitro preparations while retaining cardiovascular response functionality and an eupnoeic respiratory motor pattern. The preparation is perfused arterially with an aqueous medium having a much lower oxygen-carrying capacity than blood. To evaluate the efficacy of the artificial perfusion in providing adequate gas exchange within the brain stem, we used polarographic Po2and pH microelectrodes to determine the tissue Po2and pH of the medulla oblongata at various depths. When the perfusate was equilibrated with 5% CO2and 95% O2, average tissue Po2was 294 Torr and no hypoxic areas were encountered. Tissue pH was remarkably uniform throughout the tissue, and on average was only 0.04 ± 0.02 pH units more acidic than that of the perfusate. Increasing the Pco2of the perfusate increased tissue Po2and decreased arterial resistance. Decreasing perfusate Pco2(while keeping pH constant) decreased tissue Po2and reduced the respiratory activity. These results suggest that arterial Pco2, independent of arterial pH, is an essential variable in determining both respiratory drive and cerebrovascular perfusion. We conclude that the medulla of the WHBP is oxygenated and within a physiological pH, which accounts for the eupneic pattern of respiratory motor activity it generates. Furthermore, this preparation may be a useful model for exploring mechanisms of central chemoreception as well as the dynamics of the cerebral vasculature responses following changes in blood gases.