Acute Hypoxic Ventilatory Response Research Articles

Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans

Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR. After two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia for 6 hours per day. AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring alpha-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and alpha-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002). Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Hetero or homo, hypoxia has them all

Hetero or homo, hypoxia has them all

Oxidative stress and HIF-1α modulate hypoxic ventilatory responses after hypoxic training on athletes

We investigated the strength of the association between oxidative stress, hypoxia inducible factor 1 (HIF-1 alpha) and acute hypoxic ventilatory response (AHVR) after hypoxic training in elite runners. Six elite runners were submitted to 18-day of "living high-training low" (LHTL) and six performed the same training in normoxia. AHVR was measured during an acute hypoxic test before and after training. Plasma levels of protein oxidation (AOPP), malondialdehydes and (HIF-1 alpha) mRNA in the leukocytes were measured before and after the acute hypoxic test. LHTL increased AHVR and amplified the responses of HIF-1 alpha mRNA and AOPP (Delta(AOPP)) to the acute hypoxic test. Furthermore, between PRE and POST, the changes in Delta(AOPP) were correlated with the changes in AHVR (r=0.69, P=0.01). The ventilatory acclimatization to hypoxia occurring in athletes after LHTL seems to be modulated by oxidative stress. Furthermore, LHTL induced a higher sensitivity of HIF-1 alpha mRNA to acute hypoxia in elite athletes.

Chronic blockade of 5‐HT and NE reuptake alters the timing and patterning of phrenic nerve discharge during eupnea, but not gasping, in arterially‐perfused adult mouse

Previous in vivo and in vitro studies have demonstrated that a long‐term increase in either 5‐HT or NE exerts complex modulatory effects on central respiratory neural control, resulting in a depression of respiratory motor output. The influence of excess endogenous 5‐HT and NE chronically on respiratory motor output, however, requires clarification. Therefore, in an arterially‐perfused adult mouse preparation, we examined phrenic nerve discharge following intraperitoneal (ip) administration for 28‐d of the 5‐HT and NE reuptake inhibitor venlafaxine hydrochloride (VHCL). The results from these experiments were compared with those obtained from a separate group of mice that received ip injections of 0.9% NaCl (vehicle). We found that in mice receiving VHCL, basal phrenic burst frequency was slower by ~45% (P<0.05), with the effects on TI and TE being somewhat variable. Further, post‐inspiratory activity and spurious expiratory bursts were noted. In response to hypoxia/ischemia, we found that both groups exhibited similar acute hypoxic ventilatory responses and ischemia‐induced gasping responses, with gasps exhibiting similar timing and patterning characteristics. These results demonstrate that chronic excess endogenous 5‐HT and NE depress basal respiratory motor output, but exert minimal effects on hypoxic responses. Supported by NS045321

Heme oxygenase is necessary for the excitatory response of cultured neonatal rat rostral ventrolateral medulla neurons to hypoxia by D'Agostino D, Mazza E, and Neubauer JA

the effect of hypoxia to stimulate breathing and the cardiovascular system has been well known for more than a century (for a review, see Ref. [11][1]). In 1938, Heymans was awarded the Nobel Prize for Physiology or Medicine for demonstrating the importance of carotid body chemoreceptors. However,

Effect of Altitude on the Heart and the Lungs

This review focuses on the effects of altitude exposure from 1 to several days or weeks as occurs in tourists, trekkers, and mountaineers who visit high altitude and normally reside near sea level. We briefly review the acute physiological adjustments and early acclimatization that occur in the cardiovascular system and the lungs of healthy individuals. These ensure life-sustaining oxygen delivery to the tissues despite a reduction in the partial pressure of inspired oxygen between 20% and 60% at 2500 and 8000 m, respectively. One of the acute adjustments, hypoxic pulmonary vasoconstriction (HPV), may be disadvantageous in those with a vigorous response and lead to 2 potentially lethal illnesses, high-altitude pulmonary edema (HAPE) and subacute mountain sickness (SAMS), which we present in more detail. Finally, on the basis of knowledge about the acute physiological adjustments and acclimatization and, when available, a review of the literature, we discuss the high-altitude tolerance of patients with coronary artery disease, congestive heart failure, arrhythmias, systemic hypertension, and pulmonary hypertension. ### Circulation The major effects of acute hypoxia on the heart and lung are shown in Figure 1. Hypoxia directly affects the vascular tone of the pulmonary and systemic resistance vessels and increases ventilation and sympathetic activity via stimulation of the peripheral chemoreceptors.1 Interactions occur between the direct effects of hypoxia on blood vessels and the chemoreceptor-mediated responses in the systemic and pulmonary circulation. Figure 1. Effects of hypoxia on systemic and pulmonary circulation. Unraveling the underlying mechanisms of the hypoxic vasodilatation of systemic arterioles is an active area of research. Several mechanisms appear to regulate local oxygen delivery according to the needs of the tissues2,3; for instance, the release of ATP from red blood cells and the generation of NO by various ways appear to regulate local oxygen delivery according to the needs …

Protein kinase C activity in the nucleus tractus solitarii is critically involved in the acute hypoxic ventilatory response, but is not required for intermittent hypoxia‐induced phrenic long‐term facilitation in adult rats

Protein kinase C (PKC) is a broadly expressed and critically important signalling protein with a wide range of functional roles, including central components of respiratory control. For example, systemic and targeted administration of PKC inhibitors within the nucleus of the solitary tract (nTS) markedly attenuates peak hypoxic ventilatory responses (HVR). Protein kinase C activation in phrenic motor nucleus has also been implicated in some forms of acute respiratory plasticity, such as phrenic long-term facilitation (pLTF), a persistent enhancement of phrenic motor output following acute intermittent hypoxia. To further examine the role of PKC within the nTS, the selective PKC antagonist bisindolylmaleimide I (BIM I) was microinjected in the area corresponding to the nTS via bilateral osmotic pumps in normoxic adult male Sprague-Dawley rats; control animals received bisindolylmaleimide V (BIM V, inactive analogue). In one series of experiments, hypoxic challenges (fractional inspired ) were conducted in unrestrained animals (n = 8 per group). No differences in baseline ventilation emerged; however, peak HVR was attenuated following BIM I (P < 0.01), primarily owing to reductions in respiratory frequency increases (P < 0.01). In a second series of experiments, integrated phrenic nerve activity was recorded in anaesthetized, vagotomized, paralysed and ventilated rats exposed to three 5 min hypoxic episodes separated by 5 min hyperoxia . During baseline conditions, no differences emerged in phrenic nerve output; however, phrenic nerve output measured during the initial hypoxic exposure was significantly attenuated in BIM I-treated rats (P < 0.01). In contrast, both groups of animals displayed significant pLTF (BIM I versus BIM V; n.s.). Thus, we conclude that PKC activation within the nTS is critically involved in the central response to acute hypoxia, but does not appear to play a role in either eliciting or maintaining pLTF.

Brain stem NO modulates ventilatory acclimatization to hypoxia in mice

The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.

Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: Effect of acclimation to 3-week hypobaric hypoxia

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.

Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story

since the 1970s, over 200 studies with acetazolamide have shown it safe and 60–80% effective in acute mountain sickness (AMS). Despite much investigation, our understanding of its action in AMS remains incomplete and more complicated than generally taught. This should come as no surprise

Cerebral and muscle tissue oxygenation in acute hypoxic ventilatory response test

Eight men were exposed to progressive isocapnic hypoxia for 10 min to test the hypothesis that (i) cerebral and muscle tissue would follow similar deoxygenation profiles during an acute hypoxic ventilatory response (AHVR) test; and (ii) strong cerebrovascular responsiveness to hypoxia would be related to attenuated cerebral deoxygenation. End-tidal O(2) concentration was reduced from normoxia (approximately 102 mmHg) to approximately 45 mmHg while arterial oxygen saturation (SpO2 %) declined from 98+/-1% to 77+/-7% (P<0.001). Near-infrared spectroscopy (NIRS)-derived local cerebral tissue (frontal lobe) deoxyhemoglobin increased 5.55+/-2.22 microM, while oxyhemoglobin and tissue oxygenation index decreased 2.57+/-1.99 microM and 6.2+/-3.4%, respectively (all P<0.001). In muscle (m. vastus lateralis) the NIRS changes from the initial normoxic level were non-significant. Cerebral blood velocity (V(mean), transcranial Doppler) in the middle cerebral artery increased from 53.4+/-10.4 to 60.6+/-11.6 cms(-1) (P<0.001). In relation to the decline in SpO2 % the mean rate of increase of V(mean) and AHVR were 0.33+/-0.19 cms(-1)%(-1) and 0.52+/-0.20l min(-1)%(-1), respectively. We conclude that cerebral, but not muscle, tissue shows changes reflecting a greater deoxygenation during acute hypoxia. However, the changes in NIRS parameters were not related to cerebrovascular responsiveness or ventilatory chemosensitivity during graded hypoxia.

Anatomical changes in selected cardio-respiratory brainstem nuclei following early post-natal chronic intermittent hypoxia

Early post-natal environmental exposures, including chronic intermittent hypoxia (CIH), may lead to long-term alterations in cardio-respiratory control, such as reductions in baroreflex sensitivity and acute hypoxic ventilatory responses in adult rats. Although the mechanisms underlying CIH-induced functional metaplasticity are unclear, anatomical alterations within selected brainstem nuclei may develop after CIH. To examine this issue, male rats were exposed to CIH (RAIH) or room air (RARA) for the first 30 days of life and were microinjected unilaterally in the right nodose ganglion with the neuronal tracer tetramethylrhodamine-dextran (TMR-D) to label brainstem neurons receiving vagal and glossopharyngeal projections. Substantial reductions in labeled afferents within the nucleus tractus solitarii (nTS) and significant increases in the total number of labeled neurons within the ventrolateral medulla (VLM), principally in the nucleus ambiguus ( N amb; p < 0.01) occurred in RAIH. Furthermore, 5-bromo-2′deoxyuridine labeling revealed enhanced neurogenesis within the N amb in RAIH and could partially account for the increased neuronal population in N amb. Thus, CIH-associated cardio-respiratory metaplasticity is accompanied by substantial structural changes within both the nTS and N amb.

Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man.

The carbonic anhydrase inhibitor acetazolamide may have both inhibitory and stimulatory effects on breathing. In this placebo-controlled double-blind study we measured the effect of an intravenous dose (4 mg kg(-1)) of this agent on the acute isocapnic hypoxic ventilatory response in 16 healthy volunteers (haemoglobin oxygen saturation 83-85%) and examined whether its inhibitory effects on this response could be reversed by antioxidants (1 g ascorbic acid i.v. and 200 mg alpha-tocopherol p.o.). The subjects were randomly divided into an antioxidant (Aox) and placebo group. In the Aox group, acetazolamide reduced the mean normocapnic and hypercapnic hypoxic responses by 37% (P < 0.01) and 55% (P < 0.01), respectively, and abolished the O2-CO2 interaction, i.e. the increase in O2 sensitivity with rising Pco2. Antioxidants completely reversed this inhibiting effect on the normocapnic hypoxic response, while in hypercapnia the reversal was partial. In the placebo group, acetazolamide reduced the normo- and hypercapnic hypoxic responses by 33 and 47%, respectively (P < 0.01 versus control in both cases), and also abolished the O2-CO2 interaction. Placebo failed to reverse these inhibitory effects of acetazolamide in this group. We hypothesize that either an isoform of carbonic anhydrase may be involved in the regulation of the redox state in the carotid bodies or that acetazolamide and antioxidants exert independent effects on oxygen-sensing cells, in which both carbonic anhydrase and potassium channels may be involved. The novel findings of this study may have clinical implications, for example with regard to a combined use of acetazolamide and antioxidants at high altitude.

Does central nitric oxide chronically modulate the acute hypoxic ventilatory response in conscious rats?

Hypoxia initiates an increase in ventilation (VE) through a cascade of events of which central nitric oxide (NO) has been implicated as an important neuromodulator. There have not been any reports describing the consequences of long-term imbalances in the central NO pathways on the modulation of the acute hypoxic ventilatory response (HVR). Chronic hypoxia (CH) can potentially modify the HVR, and so we hypothesized that central NO may be involved. In this study we describe the long-term role of central NO in the modulation of HVR before and after CH. Male Sprague-Dawley rats (BW c. 200-320 g; n = 21) were implanted with an osmotic pump for continuous intracerebroventricular administration of either artificial cerebrospinal fluid (control), Nomega-nitro-L-arginine methyl ester (L-NAME) (150 microg kg(-1) day(-1)) or the NO-donor, 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1) (100 microg kg(-1) day(-1)). The VE response to acute poikilocapnic hypoxia (8% O2 for 20 min) was measured by plethysmography seven days after surgery, in normoxia, and again after 14 days of exposure to CH (CH = 12% O2). The magnitude of the HVR (c. 230% increase in VE) was unaltered by centrally infusing either L-NAME or SIN-1 for 1 week. CH did not modify the HVR, although baseline VE and HVR were shifted downward by L-NAME during CH - because of a reduction in the frequency component. These results suggest that long-term alterations in central NO levels may not alter the HVR under moderate CH, presumably because of the onset/development of compensatory mechanisms. However, NO appears to be an important component of the HVR following CH.

Chronic hypoxia modulates NMDA-mediated regulation of the hypoxic ventilatory response in an amphibian, Bufo marinus

This study examined whether a hypoxia-tolerant amphibian, the Cane toad, undergoes mammalian-like ventilatory acclimatisation to hypoxia (VAH) and whether chronic hypoxia (CH) alters NMDA-mediated regulation of the acute hypoxic ventilatory response (HVR). Toads were exposed to 10 days of CH (10% O2) followed by acute hypoxic breathing trials or an intra-arterial injection of NaCN. Trials were conducted before and after i.p. treatment with an NMDA-receptor channel blocker (MK801). CH blunted the acute HVR but did not alter resting breathing. MK801 did not alter resting ventilation. In control animals, MK801 augmented breathing frequency (fR) during acute hypoxia by increasing the number of breaths per episode. This effect was attenuated following CH although MK801 did enhance the number of episodes per minute during acute hypoxia. MK801 enhanced the fR response to NaCN in both groups. The results indicate that CH did not produce mammalian-like VAH (i.e. increased resting ventilation and an augmented acute HVR) but did alter MK801-sensitive regulation of breathing pattern and the acute HVR.

Effects of chronic hypoxia on MK-801-induced changes in the acute hypoxic ventilatory response

Chronic hypoxia increases the sensitivity of the central nervous system to afferent input from carotid body chemoreceptors. We hypothesized that this process involves N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms and predicted that chronic hypoxia would change the effect of the NMDA receptor blocker dizocilpine (MK-801) on the poikilocapnic hypoxic ventilatory response (HVR). Male Sprague-Dawley rats were studied before and after acclimatization to hypoxia (70 Torr inspiratory Po(2) for 9 days). We measured ventilation (VI) and the HVR before and after systemic MK-801 treatment (3 mg/kg ip). MK-801 resulted in a constant respiratory frequency (approximately 175 min(-1)) during acute exposure to 10% and 30% O(2) before and after acclimatization. MK-801 had no effect on tidal volume (VT) before acclimatization, but it significantly decreased Vt when the animals were breathing 10% O(2) after acclimatization. The net effect of MK-801 was to eliminate the O(2) sensitivity of Vi before (via changes in respiratory frequency) and after (via changes in VT) acclimatization. Hence, chronic hypoxia altered the effect of MK-801 on the acute HVR, primarily because of increased effects on Vt. This indicates that changes in NMDA receptor-mediated neurotransmission may be involved in ventilatory acclimatization to hypoxia. However, further experiments are necessary to determine the precise location of such plasticity in the central nervous system.

Effects of Pain and Audiovisual Stimulation on the Opioid-induced Depression of the Hypoxic Ventilatory Response

Normoxic and hypoxic ventilation are influenced by chemoreceptor and nonchemoreceptor drives. Although inhalational anesthetics blunt hypoxic ventilation, this effect is reversed by audiovisual stimulation but not by pain. Opioids reduce both normoxic and hypoxic ventilation, but their interaction with pain and audiovisual stimulation has not been fully reported. Isocapnic, acute hypoxic ventilatory responses (AHRs) were measured in 11 volunteers. AHR and normoxic ventilation were measured under the following conditions: (1) eyes closed, no audio stimulation (low wakefulness); (2) low wakefulness conditions plus painful thermal stimulation; and (3) playing a computer game (high wakefulness), each with and without remifentanil infusion. The average (+/- sd) remifentanil dose was 0.035 +/- 0.012 microg x kg x min(-1). Both normoxic and hypoxic ventilation were significantly reduced by the remifentanil infusion under all three conditions. The AHR values under low wakefulness conditions were 0.33 +/- 0.19 and 0.89 +/- 0.49 l x min(-1) x sat(-1) with and without remifentanil, respectively (P < 0.05). High wakefulness significantly increased AHR with and without remifentanil, whereas low wakefulness with pain did not. However, high wakefulness with remifentanil did not increase the AHR back to what was observed during low wakefulness without remifentanil. The computer game was a more potent stimulus than pain in countering the depressant effect of remifentanil on AHR. Although the effect of high wakefulness was more attenuated than was previously observed with respect to inhalational anesthetics, the significance of these findings is underlined by the more clinically relevant scenario of what is experienced in the face of opioid administration.

Circadian Influences, Low-dose Isoflurane, and the Ventilatory Response to Hypoxia

Leiden University Medical Center, Leiden, The Netherlands. a.dahan@lumc.nlPandit et al. 1are to be congratulated on their study on the effects pain and audiovisual stimulation on depression of the acute hypoxic ventilatory response by low-dose halothane. Their results are in good correspondence with some of the key studies in this complex field of research.2–6As stated by the authors, there is now ample evidence for the existence of quantitative differences in the ability of low-dose inhalational anesthetics to depress the ventilatory response to acute hypoxia in humans. For example, 0.1% end-tidal halothane depresses the response by 50–60%, whereas the same concentration of isoflurane has much less of an effect (reduction 30–40%).1–6The authors discuss several explanations for the observed differences between halothane and isoflurane, such as differences in pharmacokinetics, differences in the production of reactive oxygen species, and differences in their interaction with sites in the central nervous system involved in behavioral control of breathing. Evenly important are issues related to methodology.7Often, very small differences in protocols may cause large differences in study outcomes. I would like to give an example of the latter. In three subjects, the ventilatory responses to hypoxia at three time points on one single day were measured: 8:00 am, noon, and 4:00 pm. At 9:00 am, one additional response during inhalation of 0.2% end-tidal isoflurane was obtained. The ventilation (Vi) response to five end-tidal Po2levels was analyzed using the following equation: Vi = G exp(−D Peto2) + y0(G is the hypoxic sensitivity, D is a shape parameter, and y0is ventilation at hyperoxia). Control and recovery responses varied considerably by 20–30% for parameter G and 30–40% for parameter y0(fig. 1). Consequently, the depression of the isoflurane response relative to the control and recovery responses was evenly variable and varied from 50 to 70%. The picture that emerges is that the circadian rhythm has important influences on the ventilatory response to hypoxia and consequently on the influences that low-dose anesthetics have on the response. How the behavioral control system interacts with circadian influences remains unknown. Although I realize that the study I present here is of small sample size, it points toward (1) an important and complex role for circadian influences on the interaction between anesthesia and behavioral and chemical control of breathing and (2) the need for identical protocols when comparing agents and studies on the influence of low-dose anesthetic agents on ventilatory control.Leiden University Medical Center, Leiden, The Netherlands. a.dahan@lumc.nl

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats. Thus, we hypothesized that 2-week PNH-treated rats would also exhibit blunted chemoafferent responses to acute hypoxia, but would exhibit ventilatory acclimatization to sustained hypoxia. Rats were born into, and exposed to PNH for 2 weeks, followed by chronic room-air exposure. At 3-4 months of age, two studies were performed to assess: (1) carotid sinus nerve responses to asphyxia and sodium cyanide in anesthetized rats and (2) ventilatory and blood gas responses in awake rats before (d0), during (d1 and d7), and 1 day following (d8) sustained hypoxia. Carotid sinus nerve responses to i.v. NaCN and asphyxia (10 s) were significantly reduced in PNH-treated versus control rats; however, neither the acute hypoxic ventilatory response nor the time course or magnitude of ventilatory acclimatization differed between PNH and control rats despite similar levels of PaO2 . Although carotid body volume was reduced in PNH rats, carotid body volumes increased during sustained hypoxia in both PNH and control rats. We conclude that normal acute and chronic ventilatory responses are related to retained (though impaired) carotid body chemoafferent function combined with central neural mechanisms which may include brainstem hypoxia-sensitive neurons and/or brainstem integrative plasticity relating both central and peripheral inputs.

The acute hypoxic ventilatory response: Testing the adaptive significance in human populations

The acute Hypoxic Ventilatory Response (HVR) is an important component of human hypoxia tolerance, hence presumably physiological adaptation to high altitude. We measured the isocapnic HVR (L min −1 % −1) in two genetically divergent low altitude southern African populations. The HVR does not differ between African Xhosas (X) and Caucasians (C) (X:−0.34±0.36; C:−0.42±0.33; P>0.34), but breathing patterns do. Among all Xhosa subjects, size-independent tidal volume was smaller (X: 0.75±0.20; C: 1.11±0.32 L; P<0.01), breathing frequency higher (X: 22.2±5.7; C: 14.3±4.2 breaths min −1; P<0.01) and hypoxic oxygen saturation lower than among Caucasians (X: 78.4±4.7%; C: 81.7±4.7%; P<0.05). The results remained significant if subjects from Xhosa and Caucasian groups were matched for gender, body mass index and menstrual cycle phase in the case of females. The latter also employed distinct breathing patterns between populations in normoxia. High repeatability (intra-class correlation coefficient) of the HVR in both populations (0.77–0.87) demonstrates that one of the prerequisites for natural selection, consistent between-individual variation, is met. Finally, we explore possible relationships between inter-population genetic distances and HVR differences among Xhosa, European, Aymara Amerindians, Tibetan and Chinese populations. Inter-population differences in the HVR are not attributable to genetic distance (Mantel Z-test, P=0.59). The results of this study add novel support for the hypothesis that differences in the HVR, should they be found between other human populations, may reflect adaptation to hypoxia rather than genetic divergence through time.