Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia

Dwinell, M. R., P. L. Janssen, J. Pizarro, and G. E. Bisgard. Effects of carotid body hypocapnia during ventilatory acclimatization to hypoxia. J. Appl.Physiol. 82(1): 118-124, 1997.Hypoxicventilatory sensitivity is increased during ventilatory acclimatizationto hypoxia (VAH) in awake goats, resulting in a time-dependent increasein expired ventilation (E). Theobjectives of this study were to determine whether the increasedcarotid body (CB) hypoxic sensitivity is dependent on the level of CB CO₂ and whether the CBCO₂ gain is changed during VAH.Studies were carried out in adult goats with CB blood gases controlled by an extracorporeal circuit while systemic (central nervous system) blood gases were regulated independently by the level of inhaled gases. Acute E responsesto CB hypoxia (CB PO₂ 40 Torr) and CBhypercapnia (CB PCO₂ 50 and 60 Torr)were measured while systemic normoxia and isocapnia were maintained. CBPO₂ was then lowered to 40 Torr for 4 h while the systemic blood gases were kept normoxic and normocapnic.During the 4-h CB hypoxia, E increasedin a time-dependent manner. Thirty minutes after return to normoxia,the ventilatory response to CB hypoxia was significantly increasedcompared with the initial response. The slope of the CBCO₂ response was also elevatedafter VAH. An additional group of goats(n = 7) was studied with asimilar protocol, except that CB PCO₂was lowered throughout the 4-h hypoxic exposure to prevent reflexhyperventilation. CB PCO₂ wasprogressively lowered throughout the 4-h CB hypoxic period to maintainE at the control level. After the 4-hCB hypoxic exposure, the ventilatory response to hypoxia was alsosignificantly elevated. However, the slope of the CBCO₂ response was not elevatedafter the 4-h hypoxic exposure. These results suggest that CBsensitivity to both O₂ andCO₂ is increased after 4 h of CBhypoxia with systemic isocapnia. The increase in CB hypoxic sensitivityis not dependent on the level of CBCO₂ maintained during the 4-hhypoxic period.

     

Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans

The ventilatorysensitivity to CO₂, in hyperoxia, is increased after an 8-hexposure to hypoxia. The purpose of the present study was to determinewhether this increase arises through an increase in peripheral orcentral chemosensitivity. Ten healthy volunteers each underwent 8-hexposures to 1) isocapnic hypoxia, with end-tidalPO₂ (PET_O2) = 55 Torr and end-tidal PCO₂(PET_CO2) = eucapnia; 2)poikilocapnic hypoxia, with PET_O2 = 55 Torr and PET_CO2 = uncontrolled;and 3) air-breathing control. The ventilatory response toCO₂ was measured before and after each exposure with theuse of a multifrequency binary sequence with two levels of PET_CO2: 1.5 and 10 Torr above the normalresting value. PET_O2 was held at 250 Torr.The peripheral (Gp) and the central (Gc) sensitivities were calculatedby fitting the ventilatory data to a two-compartment model. There wereincreases in combined Gp + Gc (26%, P < 0.05),Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase inchemosensitivity to CO₂ within the peripheral chemoreflex.

     

Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI)

Gelfand, R., C. J. Lambertsen, J. M. Clark, and E. Hopkin.Hypoxic ventilatory sensitivity in men is not reduced by prolongedhyperoxia (Predictive Studies V and VI). J. Appl.Physiol. 84(1): 292-302, 1998.Potential adverseeffects on the O₂-sensing functionof the carotid body when its cells are exposed to toxic O₂ pressures were assessed duringinvestigations of human organ tolerance to prolonged continuous andintermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxicventilatory responses (HVR) were determined at 1.0 ATA before and aftersevere hyperoxic exposures: 1)continuous O₂ breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and2) intermittentO₂ breathing at 2.0 ATA (30 minO₂-30 min normoxia) for 14.3 O₂ h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared withpreexposure controls. The hyperbolas were temporarily elevated tohigher ventilations than controls due to increments in respiratory frequency that were proportional toO₂ exposure time, notO₂ pressure. In humans, prolongedhyperoxia does not attenuate the hypoxia-sensing function of theperipheral chemoreceptors, even after exposures that approach limits ofhuman pulmonary and central nervous system O₂ tolerance. Current applicationsof hyperoxia in hyperbaric O₂therapy and in subsea- and aerospace-related operations are guided byand are well within these exposure limits.

     

Cardiorespiratory responses to systemic administration of a protein kinase C inhibitor in conscious rats

Gozal, David, Gavin R. Graff, José E. Torres, SanjayG. Khicha, Gautam S. Nayak, Narong Simakajornboon, and Evelyne Gozal. Cardiorespiratory responses to systemic administration of aprotein kinase C inhibitor in conscious rats. J. Appl.Physiol. 84(2): 641-648, 1998.Although proteinkinase C (PKC) is an essential component of multiple neurally mediatedevents, its role in respiratory control remains undefined. Theventilatory effects of a systemically active PKC inhibitor (Ro-32-0432;100 mg/kg ip) were assessed by whole body plethysmography duringnormoxia, hypoxia (10% O₂), andhyperoxia (100% O₂) inunrestrained Sprague-Dawley rats. A sustained expiratory time increaseoccurred within 8-10 min of injection in room air[mean 44.8 ± 5.2 (SE) % ], was similarto expiratory time prolongations after Ro-32-0432 administration during100% O₂ (45.5 ± 8.1%; not significant), and was associated with mildminute ventilation (E) decreases.Hypercapnic ventilatory responses (5%CO₂) remained unchanged afterRo-32-0432. During 10% O₂,E increased from 122.6 ± 15.6 to 195.7 ± 10.1 ml/min in vehicle-treated rats(P < 0.001). In contrast, markedattenuation of E hypoxic responsesoccurred after Ro-32-0432 [86.2 ± 6.2 ml/min inroom air to 104.1 ± 7.1 ml/min in 10%O₂; pre- vs. post-Ro32-0432, P < 0.001 (analysis ofvariance)]. Overall, PKC activity was reduced and increases withhypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating thatthis compound readily crosses the blood-brain barrier. We conclude thatsystemic PKC inhibition elicits significant centrally mediatedexpiratory prolongations and ventilatory reductions as well as bluntedventilatory responses to hypoxia but not to hypercapnia. Wepostulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.

     

Ventilatory effects of specific carotid body hypocapnia and hypoxia in awake dogs

Smith, Curtis A., Craig A. Harms, Kathleen S. Henderson, andJerome A. Dempsey. Ventilatory effects of specific carotid bodyhypocapnia and hypoxia in awake dogs. J. Appl.Physiol. 82(3): 791-798, 1997.Specific carotidbody (CB) hypocapnia in the 10-Torr (less than eupneic) rangereduced ventilation in the awake and sleeping dog to the same degree asdid CB hyperoxia [CB PO₂ (PCB_O2);>500 Torr; C. A. Smith, K. W. Saupe, K. S. Henderson, and J. A. Dempsey. J. Appl. Physiol. 79:689-699, 1995], suggesting a powerful inhibitory effect ofhypocapnia at the carotid chemosensor over a range ofPCO₂ encountered commonly inphysiological hyperpneas. The primary purpose of this study was toassess the ventilatory effect of CB hypocapnia on the ventilatoryresponse to concomitant CB hypoxia. The secondary purpose was to assess the relative gains of the CB and central chemoreceptors to hypocapnia. In eight awake female dogs the vascularly isolated CB was perfused withhypoxic blood (mild,PCB_O2 50 Torr or severe, PCB_O2 36 Torr) in a background of normocapnia or hypocapnia (10 Torr lessthan eupneic arterial PCO₂) in theperfusate. The systemic (and brain) circulation was normoxicthroughout, and arterial PCO₂ was notcontrolled (poikilocapnia). With CB hypocapnia, the peak ventilation(range 19-27 s) in response to hypoxic CB perfusion increased 48%(mild) and 77% (severe) due to increased tidal volume. When CBhypocapnia was present, these increases in ventilation were reduced to21 and 27%, respectively. With systemic hypocapnia, with the isolatedCB maintained normocapnic and hypoxic for >70 s, the steady-statepoikilocapnic ventilatory response (i.e., to systemic hypocapnia alone)decreased 15% (mild CB hypoxia) and 27% (severe CB hypoxia) from thepeak response, respectively. We conclude that carotid body hypocapniacan be a major source of inhibitory feedback to respiratory motoroutput during the hyperventilatory response to hypoxic carotid bodystimulation.

     

Human ventilatory response to acute hyperoxia during and after 8h of both isocapnic and poikilocapnic hypoxia

Tansley, J. G., C. Clar, M. E. F. Pedersen, and P. A. Robbins. Human ventilatory response to acute hyperoxia during andafter 8 h of both isocapnic and poikilocapnic hypoxia.J. Appl. Physiol. 82(2): 513-519, 1997.During 8 h of either isocapnic or poikilocapnic hypoxia,there may be a rise in ventilation(E) thatcannot be rapidly reversed with a return to higherPO₂ (L. S. G. E. Howard and P. A. Robbins. J. Appl. Physiol. 78:1098-1107, 1995). To investigate this further, threeprotocols were compared: 1) 8-hisocapnic hypoxia [end-tidalPCO₂(PET_CO2 ) held atprestudy value, end-tidal PO₂(PET_O2) = 55 Torr],followed by 8-h isocapnic euoxia(PET_O2 = 100 Torr);2) 8-h poikilocapnic hypoxia followed by 8-h poikilocapnic euoxia; and3) 16-h air-breathing control.Before and at intervals throughout each protocol, theE response to eucapnichyperoxia (PET_CO2 held1-2 Torr above prestudy value,PET_O2 = 300 Torr) wasdetermined. There was a significant rise in hyperoxic E over 8 hduring both forms of hypoxia (P < 0.05, analysis of variance) that persisted during the subsequent 8-heuoxic period (P < 0.05, analysis ofvariance). These results support the notion that an 8-h period ofhypoxia increases subsequenthyperoxic E, even if acid-base changes have been minimized through maintenance ofisocapnia during the hypoxic period.

     

Effect of chronic resistive loading on hypoxic ventilatory responsiveness

Greenberg, Harly E., Rammohan S. Rao, Anthony L. Sica, andSteven M. Scharf. Effect of chronic resistive loading on hypoxicventilatory responsiveness. J. Appl.Physiol. 82(2): 500-507, 1997.Depression ofventilation mediated by endogenous opioids has been observed acutelyafter resistive airway loading. We evaluated the effects of chronicallyincreased airway resistance on hypoxic ventilatory responsivenessshortly after load imposition and 6 wk later. A circumferentialtracheal band was placed in 200-g rats, tripling tracheal resistance.Sham surgery was performed in controls. Ventilation and the ventilatoryresponse to hypoxia were measured by using barometric plethysmographyat 2 days and 6 wk postsurgery in unanesthetized rats during exposureto room air and to 12% O₂-5%CO₂-balanceN₂. Trials were performed with andwithout naloxone (1 mg/kg ip). Room air arterial blood gases demonstrated hypercapnia with normoxia in obstructed rats at 2 days and6 wk postsurgery. During hypoxia, a 30-Torr fall inPO₂ occurred with no change inPCO₂. Hypoxic ventilatory responsiveness was suppressed in obstructed rats at 2 days postloading. Naloxone partially reversed this suppression. However, hypoxic responsiveness at 6 wk was not different from control levels. Naloxonehad a small effect on ventilatory pattern at this time with no overalleffect on hypoxic responsiveness. This was in contrast to previouslydemonstrated long-term suppression ofCO₂ sensitivity in this model,which was partially reversible by naloxone only during the immediateperiod after load imposition. Endogenous opioids apparently modulateventilatory control acutely after load imposition. Their effect waneswith time despite persistence of depressedCO₂ sensitivity.

     

Effect of different levels of hyperoxia on breathing in healthy subjects

Becker, Heinrich F., Olli Polo, Stephen G. McNamara, MichaelBerthon-Jones, and Colin E. Sullivan. Effect of different levelsof hyperoxia on breathing in healthy subjects. J. Appl. Physiol. 81(4): 1683-1690, 1996.Wehave recently shown that breathing 50%O₂ markedly stimulates ventilationin healthy subjects if end-tidal PCO₂(PET_CO2) ismaintained. The aim of this study was to investigate apossible dose-dependent stimulation of ventilation byO₂ and to examine possiblemechanisms of hyperoxic hyperventilation. In eight normalsubjects ventilation was measured while they were breathing 30 and 75%O₂ for 30 min, withPET_CO2 being held constant.Acute hypercapnic ventilatory responses were also tested in thesesubjects. The 75% O₂ experimentwas repeated without controllingPET_CO2 in 14 subjects, andin 6 subjects arterial blood gases were taken at baseline and at theend of the hyperoxia period. Minute ventilation(I) increased by 21 and 115% with 30 and 75% isocapnic hyperoxia, respectively. The 75%O₂ without any control onPET_CO2 led toa 16% increase inI, butPET_CO2 decreased by3.6 Torr (9%). There was a linear correlation(r = 0.83) between the hypercapnic and the hyperoxic ventilatory response. In conclusion, isocapnic hyperoxia stimulates ventilation in a dose-dependent way, withI more than doubling after 30 min of75% O₂. If isocapnia is notmaintained, hyperventilation is attenuated by a decrease in arterialPCO₂. There is a correlation betweenhyperoxic and hypercapnic ventilatory responses. On the basis of datafrom the literature, we concluded that the Haldane effect seems to bethe major cause of hyperventilation duringboth isocapnic and poikilocapnichyperoxia.

     

Mild sustained and intermittent hypoxia induce apoptosis in PC-12 cells via different mechanisms

Episodic hypoxia, a characteristic feature of obstructive sleep apnea, induces cellular changes and apoptosis in brain regions associated with neurocognitive function. To investigate whether mild, intermittent hypoxia would induce more extensive neuronal damage than would a similar degree of sustained hypoxia, rat pheochromocytoma PC-12 neuronal cells were subjected to either sustained (5% O₂) or intermittent (alternating 5% O₂ 35 min, 21% O₂ 25 min) hypoxia for 2 or 4 days. Quantitative assessment of apoptosis showed that while mild sustained hypoxia did not significantly increase cell apoptosis at 2 days (1.31 ± 0.29-fold, n = 8; P = NS), a significant increase in apoptosis occurred after 4 days (2.25 ± 0.4-fold, n = 8; P < 0.002), without increased caspase activation. Furthermore, caspase inhibition with the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) did not modify sustained hypoxia-induced apoptosis. In contrast, mild, intermittent hypoxia induced significant increases in apoptosis at 2 days (3.72 ± 1.43-fold, n = 8; P < 0.03) and at 4 days (4.57 ± 0.82-fold, n = 8; P < 0.001) that was associated with enhanced caspase activity and attenuated by Z-VAD-FMK pretreatment. We conclude that intermittent hypoxia induces an earlier and more extensive apoptotic response than sustained hypoxia and that this response is at least partially dependent on caspase-mediated pathways. In contrast, caspases do not seem to play a role in sustained hypoxia-induced apoptosis. These findings suggest that different signaling pathways are involved in sustained and intermittent hypoxia-induced cell injury and may contribute to the understanding of differential brain susceptibility to sustained and intermittent hypoxia. episodic hypoxia; neuronal cell death; caspase; hypoxic adaptation     

Changes in respiratory control during and after 48h of isocapnic and poikilocapnic hypoxia in humans

Ventilatory acclimatization tohypoxia is associated with an increase in ventilation under conditionsof acute hyperoxia(E_hyperoxia) and an increase in acute hypoxic ventilatory response (AHVR). Thisstudy compares 48-h exposures to isocapnic hypoxia( protocol I) with 48-hexposures to poikilocapnic hypoxia ( protocolP) in 10 subjects to assess the importance ofhypocapnic alkalosis in generating the changes observed in ventilatoryacclimatization to hypoxia. During both hypoxic exposures,end-tidal PO₂ was maintained at60 Torr, with end-tidal PCO₂ held at the subject's prehypoxic level( protocol I) or uncontrolled( protocol P).E_hyperoxiaand AHVR were assessed regularly throughout the exposures.E_hyperoxia(P < 0.001, ANOVA) and AHVR(P < 0.001) increased during thehypoxic exposures, with no significant differences betweenprotocols I andP. The increase inE_hyperoxiawas associated with an increase in slope of theventilation-end-tidal PCO₂ response(P < 0.001) with no significantchange in intercept. These results suggest that changes in respiratorycontrol early in ventilatory acclimatization to hypoxiaresult from the effects of hypoxia per se and not the alkalosisnormally accompanying hypoxia.

     

Curtailed respiration by repeated vs. isolated hypoxia in maturing piglets is unrelated to NTS ME or SP levels

Waters, Karen A., André Laferrière, JuliePaquette, Cynthia Goodyer, and Immanuela R. Moss. Curtailedrespiration by repeated vs. isolated hypoxia in maturing piglets isunrelated to NTS ME or SP levels. J. Appl.Physiol. 83(2): 522-529, 1997.In earlydevelopment, respiratory disorders can produce recurring hypoxicepisodes during sleep. To examine possible effects of daily repeatedvs. isolated hypoxic hypoxia, cardiorespiratory functions and central,respiratory-related neuromodulator levels in 21- to 32-day-old,chronically instrumented, unsedated piglets were compared between afifth sequential daily hypoxia and an isolated hypoxia (10%O₂-90%N₂ for 30 min). Diaphragmaticelectromyographic activity, heart rate and arterial pressure, and pHand gas tensions were measured. In vivo microdialysis, via chronicallyimplanted guides, served to sample interstitial substance P (SP) andmethionine-enkephalin (ME) at the level of the respiratory-relatednucleus tractus solitarii (NTS). Compared with an isolated hypoxia,repeated hypoxia resulted in 1)lower respiratory frequency (f), ventilation equivalent, and arterialpH, higher arterial PO₂during hypoxia, and lower f in recovery from hypoxia; and2) increased SP concentrations butno change in ME concentrations. We conclude that, in these maturingswine, repeated vs. isolated hypoxic exposure curtails respiratoryresponses to hypoxia by a mechanism(s) unrelated to SP or ME levels atthe NTS.

     

Acute alveolar hypoxia increases blood-to-tissue albumin transport: role of atrial natriuretic peptide

Albert, T. S. E., V. L. Tucker, and E. M. Renkin. Acutealveolar hypoxia increases blood-to-tissue albumin transport: role ofatrial natriuretic peptide. J. Appl.Physiol. 82(1): 111-117, 1997.Plasmaimmunoreactive atrial natriuretic peptide (irANP) and blood-to-tissueclearance of ¹³¹I-labeled ratserum albumin (C_RSA) wereexamined in anesthetized rats during hypoxic ventilation(n = 5-7/group). Hypoxia (10 min) increased irANP from 211 ± 29 (room air) to 229 ± 28 (15%O₂, not significant), 911 ± 205 (10% O₂), and 4,374 ± 961 pg/ml (8% O₂),respectively. Graded increases inC_RSA were significant at 8%O₂ in fat (3.6-fold), ileum(2.2-fold), abdominal muscles (2.0-fold), kidney (1.8-fold), andjejunum (1.4-fold). C_RSA wasdecreased in back skin and testes; heart, brain, and lungs wereunaffected. The increases in C_RSAwere related to irANP and not to arterial PO₂. Circulating plasma volume wasnegatively correlated with whole bodyC_RSA. Graded increases inextravascular water content (EVW) were found in the kidney, left heart,and cerebrum and were positively related toC_RSA in the kidney. EVW decreased in gastrointestinal tissues; the magnitude was inversely related toC_RSA. We conclude that ANP-inducedprotein extravasation contributes to plasma volume contraction duringacute hypoxia.

     

Human ventilatory response to CO2 after 8h of isocapnic or poikilocapnic hypoxia

Duringventilatory acclimatization to hypoxia (VAH), the relationship betweenventilation (E) and end-tidalPCO₂ (PET_CO2) changes.This study was designed to determine 1) whether these changes can be seenearly in VAH and 2) if these changesare present, whether the responses differ between isocapnic andpoikilocapnic exposures. Ten healthy volunteers were studied by usingthree 8-h exposures: 1) isocapnichypoxia (IH), end-tidal PO₂(PET_O2) = 55 Torr andPET_CO2 held at thesubject's normal prehypoxic value;2) poikilocapnic hypoxia (PH),PET_O2 = 55 Torr; and3) control (C), air breathing. TheE-PET_CO2relationship was determined in hyperoxia (PET_O2 = 200 Torr) beforeand after the exposures. We found a significant increase in theslopes ofE-PET_CO2 relationship after both hypoxic exposures compared with control (IH vs.C, P < 0.01; PH vs. C,P < 0.001; analysis of covariance with pairwise comparisons). This increase was not significantly different between protocols IH andPH. No significant changes in theintercept were detected. We conclude that 8 h of hypoxia, whetherisocapnic or poikilocapnic, increases the sensitivity of the hyperoxicchemoreflex response to CO₂.

     

Ventilatory response to exercise in subjects breathing CO2 or HeO2

Babb, T. G. Ventilatory response to exercise insubjects breathing CO₂ orHeO₂.J. Appl. Physiol. 82(3): 746-754, 1997.To investigate the effects of mechanical ventilatory limitationon the ventilatory response to exercise, eight older subjects with normal lung function were studied. Each subject performed graded cycleergometry to exhaustion once while breathing room air; once whilebreathing 3% CO₂-21%O₂-balanceN₂; and once while breathing HeO₂ (79% He and 21%O₂). Minute ventilation(E) and respiratory mechanics weremeasured continuously during each 1-min increment in work rate (10 or20 W). Data were analyzed at rest, at ventilatory threshold (VTh),and at maximal exercise. When the subjects were breathing 3%CO₂, there was an increase(P < 0.001) inE at rest and at VTh but not duringmaximal exercise. When the subjects were breathingHeO₂,E was increased(P < 0.05) only during maximalexercise (24 ± 11%). The ventilatory response to exercise belowVTh was greater only when the subjects were breathing 3% CO₂(P < 0.05). Above VTh, theventilatory response when the subjects were breathingHeO₂ was greater than whenbreathing 3% CO₂(P < 0.01). Flow limitation, aspercent of tidal volume, during maximal exercise was greater(P < 0.01) when the subjects werebreathing CO₂ (22 ± 12%) thanwhen breathing room air (12 ± 9%) or when breathingHeO₂ (10 ± 7%)(n = 7). End-expiratory lung volumeduring maximal exercise was lower when the subjects were breathingHeO₂ than when breathing room airor when breathing CO₂(P < 0.01). These data indicate thatolder subjects have little reserve for accommodating an increase inventilatory demand and suggest that mechanical ventilatory constraintsinfluence both the magnitude of Eduring maximal exercise and the regulation ofE and respiratory mechanics duringheavy-to-maximal exercise.

     

Atrial natriuretic peptide levels and plasma volume contraction in acute alveolar hypoxia

Albert, T. S. E., V. L. Tucker, and E. M. Renkin.Atrial natriuretic peptide levels and plasma volume contraction in acute alveolar hypoxia. J. Appl.Physiol. 82(1): 102-110, 1997.Arterial oxygentensions (Pa_O2), atrial natriureticpeptide (ANP) concentrations, and circulating plasma volumes (PV) weremeasured in anesthetized rats ventilated with room air or 15, 10, or8% O₂(n = 5-7). After 10 min ofventilation, Pa_O2 values were 80 ± 3, 46 ± 1, 32 ± 1, and 35 ± 1 Torrand plasma immunoreactive ANP (irANP) levels were 211 ± 29, 229 ± 28, 911 ± 205, and 4,374 ± 961 pg/ml, respectively. AtPa_O2 40 Torr, irANP responses weremore closely related to inspiredO₂(P = 0.014) than toPa_O2 (P = 0.168). PV was 36.3 ± 0.5 µl/g in controls but 8.5 and9.9% lower (P  0.05) for10 and 8% O₂, respectively.Proportional increases in hematocrit were observed in animals withreduced PV; however, plasma protein concentrations were not differentfrom control. Between 10 and 50 min of hypoxia, small increases (+40%)in irANP occurred in 15% O₂;however, there was no further change in PV, hematocrit, plasma protein,or irANP levels in the lower O₂groups. Urine output tended to fall during hypoxia but was notsignificantly different among groups. These findings are compatiblewith a role for ANP in mediating PV contraction during acute alveolarhypoxia.

     

Potentiation of hypoxic ventilatory response by hyperoxia in the conscious rat: putative role of nitric oxide

In humans, the hypoxic ventilatory response(HVR) is augmented when preceded by a short hyperoxic exposure (Y. Honda, H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. J. Appl.Physiol. 81: 1627-1632, 1996). To examine whetherneuronal nitric oxide synthase (nNOS) is involved in such hyperoxia-induced HVR potentiation, 17 male Sprague-Dawley adult ratsunderwent hypoxic challenges (10%O₂-5%CO₂-balanceN₂) preceded either by 10 min ofroom air (O₂) or of 100%O₂(+O₂). At least 48 h later,similar challenges were performed after the animals received theselective nNOS inhibitor 7-nitroindazole (25 mg/kg ip). InO₂ runs, minute ventilation(E)increased from 121.3 ± 20.5 (SD) ml/min in room air to 191.7 ± 23.8 ml/min in hypoxia (P < 0.01). After +O₂,E increasedfrom 114.1 ± 19.8 ml/min in room air to 218.4 ± 47.0 ml/min inhypoxia (+O₂ vs.O₂:P < 0.005, ANOVA). After7-nitroindazole administration, HVR was not affected in theO₂ treatment group withE increasingfrom 113.7 ± 17.8 ml/min in room air to 185.8 ± 35.0 ml/min inhypoxia (P < 0.01).However, HVR potentiation in+O₂-exposed animals was abolished(111.8 ± 18.0 ml/min in room air to 184.1 ± 35.6 ml/min inhypoxia; +O₂ vs.O₂:P not significant). We conclude that in the conscious rat nNOS activation mediates essential components ofthe HVR potentiation elicited by a previous short hyperoxic exposure.

     

Ventilatory response to helium-oxygen breathing during exercise: effect of airway anesthesia

Krishnan, Bharath S., Ron E. Clemens, Trevor A. Zintel,Martin J. Stockwell, and Charles G. Gallagher. Ventilatory response to helium-oxygen breathing during exercise: effect of airwayanesthesia. J. Appl. Physiol. 83(1):82-88, 1997.The substitution of a normoxic helium mixture(HeO₂) for room air (Air) during exercise results in a sustained hyperventilation, which is present evenin the first breath. We hypothesized that this response is dependent onintact airway afferents; if so, airway anesthesia (Anesthesia) shouldaffect this response. Anesthesia was administered to the upper airwaysby topical application and to lower central airways by aerosolinhalation and was confirmed to be effective for over 15 min. Subjectsperformed constant work-rate exercise (CWE) at 69 ± 2 (SE) % maximal work rate on a cycle ergometer on three separate days: twiceafter saline inhalation (days 1 and3) and once after Anesthesia(day 2). CWE commenced after a briefwarm-up, with subjects breathing Air for the first 5 min (Air-1),HeO₂ for the next 3 min, and Airagain until the end of CWE (Air-2). The resistance of the breathingcircuit was matched for Air andHeO₂. BreathingHeO₂ resulted in a small butsignificant increase in minute ventilation(I) anddecrease in alveolar PCO₂ in both theSaline (average of 2 saline tests; not significant) and Anesthesiatests. Although Anesthesia had no effect on the sustainedhyperventilatory response to HeO₂breathing, theI transientswithin the first six breaths ofHeO₂ were significantly attenuatedwith Anesthesia. We conclude that theI response to HeO₂ is not simply due to areduction in external tubing resistance and that, in humans, airwayafferents mediate the transient but not the sustained hyperventilatoryresponse to HeO₂ breathing duringexercise.

     

Effect of 2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats

Saiki, Chikako, and Jacopo P. Mortola. Effect of2,4-dinitrophenol on the hypometabolic response to hypoxia of conscious adult rats. J. Appl. Physiol. 83(2):537-542, 1997.During acute hypoxia, a hypometabolic response iscommonly observed in many newborn and adult mammalian species. Wehypothesized that, if hypoxic hypometabolism were entirely a regulatedresponse with no limitation in O₂availability, pharmacological uncoupling of the oxidativephosphorylation should raise O₂consumption(O₂) bysimilar amounts in hypoxia and normoxia. Metabolic, ventilatory, andcardiovascular measurements were collected from conscious rats in airand in hypoxia, both before and after intravenous injection of themitochondrial uncoupler 2,4-dinitrophenol (DNP). In hypoxia (10%O₂ breathing, 60% arterialO₂ saturation),O₂, as measured by anopen-flow technique, was less than in normoxia (~80%). SuccessiveDNP injections (6 mg/kg, 4 times) progressively increasedO₂ in both normoxia andhypoxia by similar amounts. Body temperature slightly increased innormoxia, whereas it did not change in hypoxia. The DNP-stimulatedO₂ during hypoxia couldeven exceed the control normoxic value. A single DNP injection (17 mg/kg iv) had a similar metabolic effect; it also resulted inhypotension and a drop in systemic vascular resistance. We concludethat pharmacological stimulation ofO₂ counteracts theO₂ drop determined byhypoxia and stimulates O₂not dissimilarly from normoxia. Hypoxic hypometabolism is likely toreflect a regulated process of depression of thermogenesis, with nolimitation in cellular O₂availability.

     

Ventilation and hypoxic ventilatory responsiveness in Chinese-Tibetan residents at 3,658m

Curran, Linda S., Jianguo Zhuang, Shin Fu Sun, and Lorna G. Moore. Ventilation and hypoxic ventilatory responsiveness inChinese-Tibetan residents at 3,658 m. J. Appl.Physiol. 83(6): 2098-2104, 1997.When breathingambient air at rest at 3,658 m altitude, Tibetan lifelong residents of3,658 m ventilate as much as newcomers acclimatized to high altitude;they also ventilate more and have greater hypoxic ventilatory responses(HVRs) than do Han ("Chinese") long-term residents at 3,658 m.This suggests that Tibetan ancestry is advantageous in protectingresting ventilation levels during years of hypoxic exposure and is ofinterest in light of the permissive role of hypoventilation in thedevelopment of chronic mountain sickness, which is nearly absent amongTibetans. The existence of individuals with mixed Tibetan-Chineseancestry (Han-Tibetans) residing at 3,658 m affords an opportunity totest this hypothesis. Eighteen men born in Lhasa, Tibet, China (3,658 m) to Tibetan mothers and Han fathers were compared with 27 Tibetan menand 30 Han men residing at 3,658 m who were previously studied. We usedthe same study procedures (minute ventilation was measured with adry-gas flowmeter during room air breathing and hyperoxia and with a13-liter spirometer-rebreathing system during the hypoxic andhypercapnic tests). During room air breathing at 3,658 m (inspired O₂ pressure = 93 Torr),Han-Tibetans resembled Tibetans in ventilation (12.1 ± 0.6 vs.11.5± 0.5 l/min BTPS,respectively) but had HVR that were blunted (63 ± 16 vs. 121 ± 13, respectively, for HVR shape parameterA) and declined with increasingduration of high-altitude residence. During administered hyperoxia(inspired O₂ pressure = 310 Torr)at 3,658 m, the paradoxical hyperventilation previously seen in Tibetanbut not Han residents at 3,658 m (11.8 ± 0.5 vs. 10.1 ± 0.5 l/min BTPS) was absent in theseHan-Tibetans (9.8 ± 0.6 l/minBTPS). Thus, although longerduration of high-altitude residence appears to progressively blunt HVRamong Han-Tibetans born and residing at 3,658 m, their Tibetan ancestryappears protective in their maintenance of high resting ventilationlevels despite diminished chemosensitivity.

     

Acceleration of VO2 kinetics in heavy submaximal exercise by hyperoxia and prior high-intensity exercise

MacDonald, Maureen, Preben K. Pedersen, and Richard L. Hughson. Acceleration ofO₂ kinetics in heavysubmaximal exercise by hyperoxia and prior high-intensity exercise.J. Appl. Physiol. 83(4):1318-1325, 1997.We examined the hypothesis thatO₂ uptake (O₂) wouldchange more rapidly at the onset of step work rate transitions inexercise with hyperoxic gas breathing and after prior high-intensityexercise. The kinetics ofO₂ were determined from themean response time (MRT; time to 63% of total change inO₂) andcalculations of O₂ deficit andslow component during normoxic and hyperoxic gas breathing in one groupof seven subjects during exercise below and above ventilatory threshold(VT) and in another group of seven subjects during exercise above VTwith and without prior high-intensity exercise. In exercise transitions below VT, hyperoxic gas breathing did not affect the kinetic response of O₂ at theonset or end of exercise. At work rates above VT, hyperoxic gasbreathing accelerated both the on- and off-transient MRT, reduced theO₂ deficit, and decreased theO₂ slow component fromminute 3 to minute6 of exercise, compared with normoxia. Prior exerciseabove VT accelerated the on-transient MRT and reduced theO₂ slow component fromminute 3 to minute6 of exercise in a second bout of exercise with bothnormoxic and hyperoxic gas breathing. However, the summatedO₂ deficit in the second normoxicand hyperoxic steps was not different from that of the first steps inthe same gas condition. Faster on-transient responses in exerciseabove, but not below, VT with hyperoxia and, to a lesser degree, afterprior high-intensity exercise above VT support the theory of anO₂ transport limitation at theonset of exercise for workloads >VT.