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.

     

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.

     

Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (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 to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases 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 in chemosensitivity to CO2 within the peripheral chemoreflex.     

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.

     

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.

     

Depressed ventilatory response to hypoxia in hypothermic newborn piglets: role of glutamate

To evaluatewhether changes in extracellular glutamate (Glu) levels in the centralnervous system could explain the depressed hypoxic ventilatory responsein hypothermic neonates, 12 anesthetized, paralyzed, and mechanicallyventilated piglets <7 days old were studied. The Glu levels in thenucleus tractus solitarius obtained by microdialysis, minute phrenicoutput (MPO), O₂ consumption, arterial blood pressure, heart rate, and arterial blood gases weremeasured in room air and during 15 min of isocapnic hypoxia (inspiredO₂ fraction = 0.10) at braintemperatures of 39.0 ± 0.5°C [normothermia (NT)]and 35.0 ± 0.5°C [hypothermia (HT)]. During NT, MPO increased significantly during hypoxia and remained above baseline. However, during HT, there was a marked decrease in MPOduring hypoxia (NT vs. HT, P < 0.03). Glu levels increased significantly in hypoxia during NT;however, this increase was eliminated during HT(P < 0.02). A significant linearcorrelation was observed between the changes in MPO and Glu levelsduring hypoxia (r = 0.61, P < 0.0001). Changes in pH, arterialPO₂, O₂ consumption, arterial bloodpressure, and heart rate during hypoxia were not different between theNT and HT groups. These results suggest that the depressed ventilatoryresponse to hypoxia observed during HT is centrally mediated and inpart related to a decrease in Glu concentration in the nucleus tractussolitarius.

     

Effect of prior O2 breathing on ventilatory response to sustained isocapnic hypoxia in adult humans

Honda, Y., H. Tani, A. Masuda, T. Kobayashi, T. Nishino, H. Kimura, S. Masuyama, and T. Kuriyama. Effect of priorO₂ breathing on ventilatoryresponse to sustained isocapnic hypoxia in adult humans.J. Appl. Physiol. 81(4):1627-1632, 1996.Sixteen healthy volunteers breathed 100%O₂ or room air for 10 min in random order, then their ventilatory response to sustained normocapnic hypoxia (80% arterial O₂saturation, as measured with a pulse oximeter) was studied for 20 min.In addition, to detect agents possibly responsible for the respiratorychanges, blood plasma of 10 of the 16 subjects was chemically analyzed.1) Preliminary O₂ breathing uniformly andsubstantially augmented hypoxic ventilatory responses.2) However, the profile ofventilatory response in terms of relative magnitude, i.e., biphasichypoxic ventilatory depression, remained nearly unchanged.3) Augmented ventilatory incrementby prior O₂ breathing wassignificantly correlated with increment in the plasma glutamine level.We conclude that preliminary O₂administration enhances hypoxic ventilatory response without affectingthe biphasic response pattern and speculate that the excitatory aminoacid neurotransmitter glutamate, possibly derived from augmentedglutamine, may, at least in part, play a role in this ventilatoryenhancement.

     

Ventilatory long-term facilitation in unanesthetized rats

Wetested the hypothesis that unanesthetized rats exhibit ventilatorylong-term facilitation (LTF) after intermittent, but not continuous,hypoxia. Minute ventilation (E) and carbon dioxide production (CO₂) were measured inunanesthetized, unrestrained male Sprague-Dawley rats via barometricplethysmography before, during, and after exposure to continuous orintermittent hypoxia. Hypoxia was either isocapnic [inspiredO₂ fraction (FI_O2) = 0.08-0.09 and inspired CO₂ fraction(FI_CO2) = 0.04] or poikilocapnic(FI_O2 = 0.11 andFI_CO2 = 0.00). Sixty minutes afterintermittent hypoxia, E orE/CO₂ wassignificantly greater than baseline in both isocapnic and poikilocapnicconditions. In contrast, 60 min after continuous hypoxia,E andE/CO₂ were notsignificantly different from baseline values. These data demonstrateventilatory LTF after intermittent hypoxia in unanesthetized rats.Ventilatory LTF appeared similar in its magnitude (after accounting forCO₂ feedback), time course, and dependence on intermittenthypoxia to phrenic LTF previously observed in anesthetized,vagotomized, paralyzed rats.

     

Skeletal muscle chemoreflex and pHi in exercise ventilatory control

Oelberg, David A., Allison B. Evans, Mirko I. Hrovat, PaulP. Pappagianopoulos, Samuel Patz, and David M. Systrom. Skeletal muscle chemoreflex and pH_i inexercise ventilatory control. J. Appl.Physiol. 84(2): 676-682, 1998.To determinewhether skeletal muscle hydrogen ion mediates ventilatory drive inhumans during exercise, 12 healthy subjects performed three bouts ofisotonic submaximal quadriceps exercise on each of 2 days in a 1.5-Tmagnet for ³¹P-magnetic resonancespectroscopy(³¹P-MRS). Bilaterallower extremity positive pressure cuffs were inflated to 45 Torr duringexercise (BLPP_ex) or recovery(BLPP_rec) in a randomized orderto accentuate a muscle chemoreflex. Simultaneous measurements were madeof breath-by-breath expired gases and minute ventilation, arterializedvenous blood, and by ³¹P-MRS ofthe vastus medialis, acquired from the average of 12 radio-frequencypulses at a repetition time of 2.5 s. WithBLPP_ex, end-exercise minuteventilation was higher (53.3 ± 3.8 vs. 37.3 ± 2.2 l/min;P < 0.0001), arterializedPCO₂ lower (33 ± 1 vs. 36 ± 1 Torr; P = 0.0009), and quadricepsintracellular pH (pH_i) more acid (6.44 ± 0.07 vs. 6.62 ± 0.07; P = 0.004), compared withBLPP_rec. Bloodlactate was modestly increased withBLPP_ex but without a change inarterialized pH. For each subject, pH_i was linearly relatedto minute ventilation during exercise but not to arterialized pH. Thesedata suggest that skeletal muscle hydrogen ion contributes to theexercise ventilatory response.

     

Alveolar PCO2 and PO2 of high-altitude natives living at sea level

León-Velarde, Fabiola, Manuel Vargas, Carlos Monge-C.,Robert W. Torrance, and Peter A. Robbins. AlveolarPCO₂ andPO₂ of high-altitude natives livingat sea level. J. Appl.Physiol. 81(4): 1605-1609, 1996.Thisstudy was designed to determine whether subjects born at high altitude(HA; 2,000 m or above) who subsequently move to near sea level (SL)develop end-tidal PCO₂(PET_CO2) andPO₂(PET_O2) valuesthat equal those of SL natives living near SL. A total of 108 male HAnatives living near SL were identified by survey of a district in Lima,Peru, and a further 108 male SL natives from the same district wereidentified as control subjects. Of these subjects, satisfactory datafor inclusion in the study were obtained from 93 HA and 82 SL subjects.Mean PET_CO2 and PET_O2 values were 37.7 ± 2.5 (SD) and 104.7 ± 3.2 Torr, respectively, in HA subjects and37.7 ± 2.2 and 104.8 ± 3.0 Torr, respectively, in SL subjects.The average difference between SL natives and HA natives forPET_CO2 was 0.07 Torr(0.64 to 0.78; 95% confidence interval) and forPET_O2 was 0.05 Torr(0.89 to 0.99, 95% confidence interval). The average age andweight of the SL and HA subjects did not differ, but the HA subjectswere shorter and tended to have larger vital capacities, consistentwith their origin at HA. We conclude that thePET_CO2 andPET_O2 near SL of SL nativesand HA natives do not differ.

     

Differences between estimates and measured PaCO2 during rest and exercise in older subjects

Williams, J. S., and T. G. Babb. Differences betweenestimates and measured Pa_CO2 during restand exercise in older subjects. J. Appl.Physiol. 83(1): 312-316, 1997.ArterialPCO₂ (Pa_CO2) has been estimated duringexercise with good accuracy in younger individuals by using the Jonesequation(P_JCO₂)(J. Appl. Physiol. 47: 954-960,1979). The purpose of this project was to determine the utility ofestimating Pa_CO2 from end-tidal PCO₂(PET_CO2) orP_JCO₂at rest, ventilatory threshold (Th), and maximalexercise (Max) in older subjects. PET_CO2 was determined fromrespired gases simultaneously (MGA 1100) with arterial blood gases(radial arterial catheter) in 12 older and 11 younger subjects at restand during exercise. Mean differences were analyzed with pairedt-tests, and relationships between theestimated Pa_CO2 values and the actualvalues of Pa_CO2 were determined withcorrelation coefficients. In the older subjects, PET_CO2 was not significantlydifferent from Pa_CO2 at rest (1.2 ± 4.3 Torr), Th (0.4 ± 2.5), or Max(0.8 ± 2.7), and the two were significantly(P < 0.05) correlated atth (r = 0.84) andMax (r = 0.87) but not atrest (r = 0.47).P_JCO₂was similar to Pa_CO2 at rest (1.0 ± 3.9) and th (1.3 ± 2.3) but significantly lower at Max (3.0 ± 2.6), and the two weresignificantly correlated at th(r = 0.86) and Max(r = 0.80) but not at rest (r = 0.54).PET_CO2 was significantlyhigher than Pa_CO2 during exercise in theyounger subjects but similar to Pa_CO2 at rest.P_JCO₂was similar to Pa_CO2 at rest andth but significantly lower at Max in youngersubjects. In conclusion, our data demonstrate thatPa_CO2 during exercise is betterestimated by PET_CO2 than byP_JCO₂in older subjects, contrary to what is observed in younger subjects.This appears to be related to the finding thatPET_CO2 does not exceedPa_CO2 during exercise in older subjects,as occurs in the younger subjects. However,Pa_CO2 at rest is best estimated byP_JCO₂in both younger and older subjects.

     

Lactate efflux from exercising human skeletal muscle: role of intracellular PO2

It remainscontroversial whether lactate formation during progressive dynamicexercise from submaximal to maximal effort is due to muscle hypoxia. Tostudy this question, we used direct measures of arterial and femoralvenous lactate concentration, a thermodilution blood flow technique,phosphorus magnetic resonance spectroscopy (MRS), and myoglobin (Mb)saturation measured by ¹H nuclearMRS in six trained subjects performing single-leg quadriceps exercise.We calculated net lactate efflux from the muscle and intracellularPO₂ with subjects breathing room airand 12% O₂. Data were obtained at50, 75, 90, and 100% of quadriceps maximalO₂ consumption at each fraction ofinspired O₂. Mb saturation wassignificantly lower in hypoxia than in normoxia [40 ± 3 vs. 49 ± 3% (SE)] throughout incremental exercise to maximalwork rate. With the assumption of aPO₂ at which 50% of Mb-binding sitesare bound with O₂ of 3.2 Torr,Mb-associated PO₂ averaged 3.1 ± 0.3 and 2.3 ± 0.2 Torr in normoxia and hypoxia, respectively. Netblood lactate efflux was unrelated to intracellular PO₂ across the range of incrementalexercise to maximum (r = 0.03 and 0.07 in normoxia and hypoxia, respectively) but linearly related toO₂ consumption(r = 0.97 and 0.99 in normoxia andhypoxia, respectively) with a greater slope in 12%O₂. Net lactate efflux was alsolinearly related to intracellular pH(r = 0.94 and 0.98 in normoxia andhypoxia, respectively). These data suggest that with increasing workrate, at a given fraction of inspiredO₂, lactate efflux is unrelated tomuscle cytoplasmic PO₂, yet theefflux is higher in hypoxia. Catecholamine values from comparablestudies are included and indicate that lactate efflux in hypoxia may bedue to systemic rather than intracellular hypoxia.

     

Physiological and hypoxic O2 tensions rapidly regulate NO production by stimulated macrophages

Nitric oxide (NO) production by inducible NO synthase (iNOS) is dependent on O₂ availability. The duration and degree of hypoxia that limit NO production are poorly defined in cultured cells. To investigate short-term O₂-mediated regulation of NO production, we used a novel forced convection cell culture system to rapidly (response time of 1.6 s) and accurately (±1 Torr) deliver specific O₂ tensions (from <1 to 157 Torr) directly to a monolayer of LPS- and IFN-stimulated RAW 264.7 cells while simultaneously measuring NO production via an electrochemical probe. Decreased O₂ availability rapidly (30 s) and reversibly decreased NO production with an apparent K_mO₂ of 22 (SD 6) Torr (31 µM) and a V_max of 4.9 (SD 0.4) nmol·min^–1·10^–6 cells. To explore potential mechanisms of decreased NO production during hypoxia, we investigated O₂-dependent changes in iNOS protein concentration, iNOS dimerization, and cellular NO consumption. iNOS protein concentration was not affected (P = 0.895). iNOS dimerization appeared to be biphasic [6 Torr (P = 0.008) and 157 Torr (P = 0.258) >36 Torr], but it did not predict NO production. NO consumption was minimal at high O₂ and NO tensions and negligible at low O₂ and NO tensions. These results are consistent with O₂ substrate limitation as a regulatory mechanism during brief hypoxic exposure. The rapid and reversible effects of physiological and pathophysiological O₂ tensions suggest that O₂ tension has the potential to regulate NO production in vivo. inducible nitric oxide synthase; substrate limitation; nitric oxide consumption     

Important role of carotid afferents in control of breathing

The purpose of the present study was todetermine the effect on breathing in the awake state of carotid bodydenervation (CBD) over 1-2 wk after denervation. Studies werecompleted on adult goats repeatedly before and1) for 15 days after bilateral CBD (n = 8),2) for 7 days after unilateral CBD(n = 5), and3) for 15 days after sham CBD(n = 3). Absence of ventilatorystimulation when NaCN was injected directly into a common carotidartery confirmed CBD. There was a significant(P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. Themaximum Pa_CO2 increase (8 Torr forunilateral and 11 Torr for bilateral) occurred ~4 days afterCBD. This maximum was transient because by 7 (unilateral)to 15 (bilateral) days after CBD, Pa_CO2 was only 3-4 Torr above control.CO₂ sensitivity was attenuated from control by 60% on day 4 afterbilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO₂ sensitivity returned tocontrol temporally similar to the return ofPa_CO2 during the breathing of room air.During mild and moderate treadmill exercise 1-8 days afterbilateral CBD, Pa_CO2 was unchanged fromits elevated level at rest, but, 10-15 days after CBD,Pa_CO2 decreased slightly from restduring exercise. These data indicate that1) carotid afferents are animportant determinant of rest and exercise breathing and ventilatoryCO₂ sensitivity, and2) apparent plasticity within theventilatory control system eventually provides compensation for chronicloss of these afferents.

     

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.

     

Ventilatory responses to chemoreceptor stimulation after hypoxic acclimatization in awake goats

Our objective was to test the hypothesis that exposure to prolonged hypoxia results in altered responsiveness to chemoreceptor stimulation. Acclimatization to hypoxia occurs rapidly in the awake goat relative to other species. We tested the sensitivity of the central and peripheral chemoreceptors to chemical stimuli before and after 4 h of either isocapnic or poikilocapnic hypoxia (arterial PO2 40 Torr). We confirmed that arterial PCO2 decreased progressively, reaching a stable value after 4 h of hypoxic exposure (poikilocapnic group). In the isocapnic group, inspired minute ventilation increased over the same time course. Thus, acclimatization occurred in both groups. In goats, isocapnic hypoxia did not result in hyperventilation on return to normoxia, whereas poikilocapnic hypoxia did cause hyperventilation, indicating a different mechanism for acclimatization and the persistent hyperventilation on return to normoxia. Goats exposed to isocapnic hypoxia exhibited an increased slope of the CO2 response curve. Goats exposed to poikilocapnic hypoxia had no increase in slope but did exhibit a parallel leftward shift of the CO2 response curve. Neither group exhibited a significant change in response to bolus NaCN injections or dopamine infusions after prolonged hypoxia. However, both groups demonstrated a similar significant increase in the ventilatory response to subsequent acute exposure to isocapnic hypoxia. The increase in hypoxic ventilatory sensitivity, which was not dependent on the modality of hypoxic exposure (isocapnic vs. poikilocapnic), reinforces the key role of the carotid chemoreceptors in ventilatory acclimatization to hypoxia.     

Ventilatory stability to transient CO2 disturbances in hyperoxia and normoxia in awake humans

Lai, Jie, and Eugene N. Bruce. Ventilatory stability totransient CO₂ disturbances inhyperoxia and normoxia in awake humans. J. Appl.Physiol. 83(2): 466-476, 1997.Modarreszadeh andBruce (J. Appl. Physiol. 76:2765-2775, 1994) proposed that continuous random disturbances inarterial PCO₂ are more likely toelicit ventilatory oscillation patterns that mimic periodic breathingin normoxia than in hyperoxia. To test this hypothesis experimentally,in nine awake humans we applied pseudorandom binary inspiredCO₂ fraction stimulation innormoxia and hyperoxia to derive the closed-loop and open-loopventilatory responses to a briefCO₂ disturbance in terms ofimpulse responses and transfer functions. The closed-loop impulseresponse has a significantly higher peak value [0.143 ± 0.071 vs. 0.079 ± 0.034 (SD)l · min¹ · 0.01 lCO₂¹,P = 0.014] and a significantlyshorter 50% response duration (42.7 ± 13.3 vs. 72.3 ± 27.6 s,P = 0.020) in normoxia than in hyperoxia. Therefore, the ventilatory responses to transientCO₂ disturbances are less damped(but generally not oscillatory) in normoxia than in hyperoxia. For theclosed-loop transfer function, the gain in normoxia increasedsignificantly (P < 0.0005), while phase delay decreased significantly (P < 0.0005). The gain increased by 108.5, 186.0, and 240.6%, whilephase delay decreased by 26.0, 18.1, and 17.3%, at 0.01, 0.03, and0.05 Hz, respectively. Changes in the same direction were found for theopen-loop system. Generally, an oscillatory ventilatory response to asmall transient CO₂ disturbance isunlikely during wakefulness. However, changes in parameters that leadto additional increases in chemoreflex loop gain are more likely toinitiate oscillations in normoxia than in hyperoxia.

     

Methods for detecting local intestinal ischemic anaerobic metabolic acidosis by PCO2

Rozenfeld, Ranna A., Michael K. Dishart, Tor IngeTønnessen, and Robert Schlichtig. Methods for detecting localintestinal ischemic anaerobic metabolic acidosis byPCO₂. J. Appl. Physiol. 81(4): 1834-1842, 1996.Gut ischemia isoften assessed by computing an imaginary tissue interstitial pH fromarterial plasma HCO₃ and thePCO₂ in a saline-filled balloontonometer after equilibration with tissuePCO₂ (Pti_CO2).Pti_CO2 mayalternatively be assumed equal to venous PCO₂(Pv_CO2) in that region of gut. The ideais that as blood flow decreases, gutPti_CO2 andPv_CO2 will increase to the maximumaerobic value, i.e., maximum respiratoryPv_CO2(Pv_CO2 rmax). Above a "critical" anaerobic threshold, lactate(La) generation, bytitration of tissue HCO₃, should raisePti_CO2abovePv_CO2 rmax.During progressive selective whole intestinal flow reduction insix pentobarbital-anesthetized pigs, we usedPCO₂ electrodes to test thehypotheses that criticalPti_CO2is achieved earlier in mucosa than in serosa and thatPv_CO2 rmax,computed using an in vitro model, predicts criticalPti_CO2. Wedefined criticalPti_CO2 as theinflection ofPti_CO2-Pv_CO2vs. O₂ delivery(O₂)plots. CriticalO₂for O₂ uptake was 12.55 ± 2 ml ^· kg^{1 ·} min¹.Critical Pti_CO2 for mucosaand serosa was achieved at similar whole intestineO₂(13.90 ± 5 and 13.36 ± 5 ml ^· kg^{1 ·} min¹,P = NS). CriticalPti_CO2 (129 ± 24 and 96 ± 21 Torr) exceeded Pv_CO2 rmax(62 ± 3 Torr). During ischemia,La excretion into portalvenous blood was matched by K⁺excretion, causing Pv_CO2 to increaseonly slightly, despitePti_CO2 risingto 380 ± 46 (mucosa) and 280 ± 38 (serosa) Torr. These resultssuggest that mucosa and serosa become dysoxic simultaneously, thatischemic dysoxic gut is essentially unperfused, and that in vitropredictedPv_CO2 rmaxunderestimates criticalPti_CO2.

     

Ventilatory and metabolic responses to ambient hypoxia or hypercapnia in rats exposed to CO hypoxia

Gautier, Henry, Cristina Murariu, and Monique Bonora.Ventilatory and metabolic responses to ambient hypoxia orhypercapnia in rats exposed to CO hypoxia. J. Appl. Physiol.83(1): 253-261, 1997.We have investigated at ambienttemperatures (T_am) of 25 and5°C the effects of ambient hypoxia(Hx_am; fractional inspired O₂ = 0.14) and hypercapnia(fractional inspiredCO₂ = 0.04) on ventilation (),O₂ uptake(O₂), andcolonic temperature (T_c) in 12 conscious rats before and after carotid body denervation (CBD). Therats were concomitantly exposed to CO hypoxia (Hx_CO; fractional inspired CO = 0.03-0.05%), which decreases arterial O₂ saturation by ~25-40%.The results demonstrate the following. 1) AtT_am of 5°C, in both intact andCBD rats,/O₂ islarger when Hx_am orCO₂ is associated withHx_CO than with normoxia. At T_am of 25°C, this is also thecase except for CO₂ in CBD rats. 2) AtT_am of 5°C, the changes inO₂ andT_c seem to result from additiveeffects of the separate changes induced byHx_am,CO₂, andHx_CO. It is concluded that, inconscious rats, central hypoxia does not depress respiratory activity.On the contrary, particularly whenO₂ is augmented during acold stress, both/O₂during Hx_CO and the ventilatoryresponses to Hx_am andCO₂ are increased. The mechanismsinvolved in this relative hyperventilation are likely to involvediencephalic integrative structures.

     

Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart

Isolated rat heart perfused with 1.5-7.5µM NO solutions or bradykinin, which activates endothelial NOsynthase, showed a dose-dependent decrease in myocardial O₂uptake from 3.2 ± 0.3 to 1.6 ± 0.1 (7.5 µM NO, n = 18,P < 0.05) and to 1.2 ± 0.1 µM O₂ · min¹ · gtissue¹ (10 µM bradykinin, n = 10,P < 0.05). Perfused NO concentrations correlated with aninduced release of hydrogen peroxide (H₂O₂) inthe effluent (r = 0.99, P < 0.01). NO markedlydecreased the O₂ uptake of isolated rat heart mitochondria(50% inhibition at 0.4 µM NO, r = 0.99,P < 0.001). Cytochrome spectra in NO-treated submitochondrial particles showed a double inhibition of electron transfer at cytochrome oxidase and between cytochrome b andcytochrome c, which accounts for the effects in O₂uptake and H₂O₂ release. Most NO was bound tomyoglobin; this fact is consistent with NO steady-state concentrationsof 0.1-0.3 µM, which affect mitochondria. In the intact heart,finely adjusted NO concentrations regulate mitochondrial O₂uptake and superoxide anion production (reflected byH₂O₂), which in turn contributes to thephysiological clearance of NO through peroxynitrite formation.