Cerebral vasomotor reactivity at high altitude in humans

The purpose of this study was twofold:1) to determine whether at highaltitude cerebral blood flow (CBF) as assessed during CO₂ inhalation and duringhyperventilation in subjects with acute mountain sickness (AMS) wasdifferent from that in subjects without AMS and2) to compare the CBF as assessedunder similar conditions in Sherpas at high altitude and in subjects atsea level. Resting control values of blood flow velocity in themiddle cerebral artery (V_MCA), pulseoxygen saturation (Sa_O2), andtranscutaneous PCO₂ were measured at4,243 m in 43 subjects without AMS, 17 subjects with AMS, 20 Sherpas,and 13 subjects at sea level. Responses ofCO₂ inhalation andhyperventilation onV_MCA,Sa_O2, and transcutaneous PCO₂ were measured, and the cerebralvasomotor reactivity (VMR = V_MCA/PCO₂)was calculated as the fractional change ofV_MCA per Torrchange of PCO₂, yielding ahypercapnic VMR and a hypocapnic VMR. AMS subjects showeda significantly higher resting controlV_MCA than didno-AMS subjects (74 ± 22 and 56 ± 14 cm/s, respectively;P < 0.001), andSa_O2 was significantly lower (80 ± 8 and 88 ± 3%, respectively; P < 0.001). Resting control V_MCA values inthe sea-level group (60 ± 15 cm/s), in the no-AMS group, and inSherpas (59 ± 13 cm/s) were not different. Hypercapnic VMR valuesin AMS subjects were 4.0 ± 4.4, in no-AMS subjects were 5.5 ± 4.3, in Sherpas were 5.6 ± 4.1, and in sea-level subjects were 5.6 ± 2.5 (not significant). Hypocapnic VMR values were significantly higher in AMS subjects (5.9 ± 1.5) compared with no-AMS subjects (4.8 ± 1.4; P < 0.005) but werenot significantly different between Sherpas (3.8 ± 1.1) and thesea-level group (2.8 ± 0.7). We conclude that AMS subjects havegreater cerebral hemodynamic responses to hyperventilation, higherV_MCAresting control values, and lower Sa_O2 compared with no-AMSsubjects. Sherpas showed a cerebral hemodynamic patternsimilar to that of normal subjects at sea level.     

Physical exercise and normobaric hypoxia: independent modulators of peripheral cholecystokinin metabolism in man

The purpose ofthe present investigation was to determine the independent effects ofhypoxia and physical exercise on peripheral cholecystokinin (CCK)metabolism in humans. Thirty-two physically active men wererandomly assigned in a double-blind manner to either a normoxic (N;n = 14) or hypoxic (H; n = 18) group.During the acute study, subjects in the H group only participated in two tests, separated by 48 h, which involved a cycling test to exhaustion in normobaric normoxia and normobaric hypoxia (inspired O₂ fraction = 0.21 and 0.16, respectively). In theintermittent study, N and H groups cycle-trained for 4 wk at the samerelative exercise intensity in both normoxia and hypoxia. Acutenormoxic exercise consistently raised plasma CCK during both studies by 290-723%, which correlated with increases in the plasma ratio offree tryptophan to branched chain amino acids (r = 0.58-0.71, P < 0.05). In contrast, acute hypoxicexercise decreased CCK by 7.0 ± 5.5 pmol/l, which correlated withthe decrease in arterial oxygen saturation (r = 0.56, P < 0.05). In the intermittent study, plasma CCKresponse at rest and after normoxic exercise was not altered afterphysical training, despite a slight decrease in adiposity. We concludethat peripheral CCK metabolism 1) is more sensitive to acutechanges than chronic changes in energy expenditure and 2) ispotentially associated with acute changes in tissue PO₂ and metabolic precursors of cerebralserotoninergic activity.

     

Increasing maximal heart rate increases maximal O2 uptake in rats acclimatized to simulated altitude

Gonzalez, Norberto C., Richard L. Clancy, Yoshihiro Moue,and Jean-Paul Richalet. Increasing maximal heart rate increases maximal O₂ uptake in ratsacclimatized to simulated altitude. J. Appl.Physiol. 84(1): 164-168, 1998.Maximal exerciseheart rate (HR_max) is reducedafter acclimatization to hypobaric hypoxia. The lowHR_max contributes to reducemaximal cardiac output(_max) andmay limit maximal O₂ uptake(O_{2 max}). Theobjective of these experiments was to test the hypothesisthat the reduction in_max afteracclimatization to hypoxia, due, in part, to the lowHR_max, limitsO_{2 max}. Ifthis hypothesis is correct, an increase in _max wouldresult in a proportionate increase inO_{2 max}. Rats acclimatized to hypobaric hypoxia [inspiredPO₂(PI_O2) = 69.8 ± 3 Torr for 3 wk] exercised on a treadmill in hypoxic (PI_O2 = 71.7 ± 1.1 Torr) or normoxic conditions(PI_O2 = 142.1 ± 1.1 Torr). Each rat ran twice: in one bout the rat was allowed to reach itsspontaneous HR_max, which was 505 ± 7 and 501 ± 5 beats/min in hypoxic and normoxic exercise,respectively; in the other exercise bout,HR_max was increased by 20% to the preacclimatization value of 600 beats/min by atrial pacing. This resulted in an ~10% increase in_max, since theincrease in HR_max was offset by a10% decrease in stroke volume, probably due to shortening of diastolicfilling time. The increase in_max was accompanied by a proportionate increase in maximal rate of convective O₂ delivery(_max × arterial O₂ content), maximal workrate, and O_{2 max} inhypoxic and normoxic exercise. The data show that increasingHR_max topreacclimatization levels increasesO_{2 max}, supportingthe hypothesis that the lowHR_max tends to limitO_{2 max} after acclimatization to hypoxia.

     

Muscle fatigue and exhaustion during dynamic leg exercise in normoxia and hypobaric hypoxia

Fulco, Charles S., Steven F. Lewis, Peter N. Frykman, RobertBoushel, Sinclair Smith, Everett A. Harman, Allen Cymerman, and Kent B. Pandolf. Muscle fatigue and exhaustion during dynamic leg exercisein normoxia and hypobaric hypoxia. J. Appl. Physiol. 81(5): 1891-1900, 1996.Using anexercise device that integrates maximal voluntary static contraction(MVC) of knee extensor muscles with dynamic knee extension, we comparedprogressive muscle fatigue, i.e., rate of decline in force-generatingcapacity, in normoxia (758 Torr) and hypobaric hypoxia (464 Torr).Eight healthy men performed exhaustive constant work rate kneeextension (21 ± 3 W, 79 ± 2 and 87 ± 2% of 1-leg kneeextension O₂ peak uptake fornormoxia and hypobaria, respectively) from knee angles of90-150° at a rate of 1 Hz. MVC (90° knee angle) wasperformed before dynamic exercise and during 5-s pauses every 2 minof dynamic exercise. MVC force was 578 ± 29 N in normoxia and 569 ± 29 N in hypobaria before exercise and fell, at exhaustion, to similar levels (265 ± 10 and 284 ± 20 N for normoxia andhypobaria, respectively; P > 0.05)that were higher (P < 0.01) thanpeak force of constant work rate knee extension (98 ± 10 N, 18 ± 3% of MVC). Time to exhaustion was 56% shorter for hypobariathan for normoxia (19 ± 5 vs. 43 ± 7 min, respectively;P < 0.01), and rate of right leg MVC fall wasnearly twofold greater for hypobaria than for normoxia (mean slope = 22.3 vs. 11.9 N/min, respectively;P < 0.05). With increasing durationof dynamic exercise for normoxia and hypobaria, integratedelectromyographic activity during MVC fell progressively with MVCforce, implying attenuated maximal muscle excitation. Exhaustion, perse, was postulated to relate more closely to impaired shorteningvelocity than to failure of force-generating capacity.

     

Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du,James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible tochronic mountain sickness. J. Appl.Physiol. 83(1): 25-31, 1997.Hilltop (H) strainSprague-Dawley rats are more susceptible to chronic mountain sicknessthan are the Madison (M) strain rats. It is unclear what role pulmonaryvascular remodeling, polycythemia, and hypoxia-induced vasoconstrictionplay in mediating the more severe pulmonary hypertension that developsin the H rats during chronic hypoxia. It is also unclear whether theincreased sensitivity of the H rats to chronic mountain sickness isspecific for a hypoxia effect or, instead, reflects a generalpropensity toward the development of pulmonary hypertension.Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonaryhypertension. We hypothesized that the difference in the pulmonaryvascular response to chronic hypoxia between H and M rats reflects anincreased sensitivity of the H rats to any pulmonary hypertensivestimuli. Consequently, we expected the two strains to also differ intheir susceptibility to MCT-induced pulmonary hypertension. Pulmonaryarterial pressures in conscious H and M rats were measured 3 wk after asingle dose of MCT, exposure to a simulated high altitude of 18,000 ft(barometric pressure = 380 mmHg), and administration of a single doseof saline as a placebo. The H rats had significantlyhigher pulmonary arterial pressures and right ventricular weights afterMCT and chronic hypoxia than did the M rats. The H rats also had morepulmonary vascular remodeling, i.e., greater wall thickness as apercentage of vessel diameter, after MCT and chronic hypoxia than didthe M rats. The H rats had significantly lower arterialPO₂ than did the M rats after MCT,but the degree of hypoxemia was mild [arterialPO₂ of 72.5 ± 0.8 (SE) Torr for Hrats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H ratshad lower arterial PCO₂ and largerminute ventilation values than did the M rats after MCT. Theseventilatory differences suggest that MCT caused more severe pulmonaryvascular damage in the H rats than in the M rats. These data supportthe hypothesis that the H rats have a general propensity to developpulmonary hypertension and suggest that differences in pulmonaryvascular remodeling account for the increased susceptibility of H rats,compared with M rats, to both MCT and chronic hypoxia-induced pulmonaryhypertension.

     

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.

     

Age-related differences in Na+-dependent Ca2+ accumulation in rabbit hearts exposed to hypoxia and acidification

In this study, we test the hypothesisthat in newborn hearts (as in adults) hypoxia and acidificationstimulate increased Na⁺ uptake, in part via pH-regulatoryNa⁺/H⁺ exchange. Resulting increases inintracellular Na⁺ (Na_i) alter the force drivingthe Na⁺/Ca²⁺ exchanger and lead to increasedintracellular Ca²⁺. NMR spectroscopy measuredNa_i and cytosolic Ca²⁺ concentration([Ca²⁺]_i) and pH (pH_i) inisolated, Langendorff-perfused 4- to 7-day-old rabbit hearts. AfterNa⁺/K⁺ ATPase inhibition, hypoxic hearts gainedNa⁺, whereas normoxic controls did not [19 ± 3.4 to139 ± 14.6 vs. 22 ± 1.9 to 22 ± 2.5 (SE) meq/kg drywt, respectively]. In normoxic hearts acidified using theNH₄Cl prepulse, pH_i fell rapidly and recovered,whereas Na_i rose from 31 ± 18.2 to 117.7 ± 20.5 meq/kg dry wt. Both protocols caused increases in [Ca]_i;however, [Ca]_i increased less in newborn hearts than inadults (P < 0.05). Increases in Na_i and[Ca]_i were inhibited by theNa⁺/H⁺ exchange inhibitormethylisobutylamiloride (MIA, 40 µM; P < 0.05), aswell as by increasing perfusate osmolarity (+30 mosM) immediately before and during hypoxia (P < 0.05). The data supportthe hypothesis that in newborn hearts, like adults, increases inNa_i and [Ca]_i during hypoxia and afternormoxic acidification are in large part the result of increased uptakevia Na⁺/H⁺ and Na⁺/Ca²⁺exchange, respectively. However, for similar hypoxia and acidification protocols, this increase in [Ca]_i is less in newborn thanadult hearts.

     

Hypertonic perfusion inhibits intracellular Na and Ca accumulation in hypoxic myocardium

Muchevidence supports the view that hypoxic/ischemic injury is largely dueto increased intracellular Ca concentration([Ca]_i) resulting from 1) decreasedintracellular pH (pH_i), 2) stimulated Na/H exchangethat increases Na uptake and thus intracellular Na (Na_i),and 3) decreased Na gradient that decreases or reverses net Catransport via Na/Ca exchange. The Na/H exchanger (NHE) is alsostimulated by hypertonic solutions; however, hypertonic media mayinhibit NHE's response to changes in pH_i (Cala PM and Maldonado HM. J Gen Physiol 103: 1035-1054, 1994). Thus wetested the hypothesis that hypertonic perfusion attenuates acid-induced increases in Na_i in myocardium and, thereby, decreasesCa_i accumulation during hypoxia. Rabbit hearts wereLangendorff perfused with HEPES-buffered Krebs-Henseleit solutionequilibrated with 100% O₂ or 100% N₂. Hypertonic perfusion began 5 min before hypoxia or normoxicacidification (NH₄Cl washout). Na_i,[Ca]_i, pH_i, and high-energyphosphates were measured by NMR. Control solutions were 295 mosM, andhypertonic solutions were adjusted to 305, 325, or 345 mosM by additionof NaCl or sucrose. During 60 min of hypoxia (295 mosM),Na_i rose from 22 ± 1 to 100 ± 10 meq/kg dry wt while[Ca]_i rose from 347 ± 11 to 1,306 ± 89 nM.During hypertonic hypoxic perfusion (325 mosM), increases inNa_i and [Ca]_i were reduced by 65 and 60%, respectively (P < 0.05). Hypertonicperfusion also diminished Na uptake after normoxic acidification by87% (P < 0.05). The data are consistent with the hypothesisthat mild hypertonic perfusion diminishes acid-induced Na accumulationand, thereby, decreases Na/Ca exchange-mediated Ca_iaccumulation during hypoxia.

     

Hypoxia, temperature, and pH/CO2 effects on respiratory discharge from a turtle brain stem preparation

Johnson, Stephen M., Rebecca A. Johnson, and Gordon S. Mitchell. Hypoxia, temperature, andpH/CO₂ effects on respiratory discharge from a turtle brain stem preparation. J. Appl. Physiol. 84(2): 649-660, 1998.An in vitrobrain stem preparation from adult turtles (Chrysemyspicta) was used to examine the effects of anoxia andincreased temperature and pH/CO₂on respiration-related motor output. At pH ~7.45, hypoglossal (XII)nerve roots produced patterns of rhythmic bursts (peaks) of discharge(0.74 ± 0.07 peaks/min, 10.0 ± 0.6 s duration) that werequantitatively similar to literature reports of respiratory activity inconscious, vagotomized turtles. Respiratory discharge was stable for 6 h at 22°C; at 32°C, peak amplitude and frequency progressivelyand reversibly decreased with time. Two hours of hypoxia had no effecton respiratory discharge. Acutely increasing bath temperature from 22 to 32°C decreased episode and peak duration and increased peakfrequency. Changes in pH/CO₂increased peak frequency from zero at pH 8.00-8.10 to maxima of0.81 ± 0.01 and 1.44 ± 0.02 peaks/min at 22°C (pH 7.32) and32°C (pH 7.46), respectively;pH/CO₂ sensitivity was similar atboth temperatures. We conclude that1) insensitivity to hypoxiaindicates that rhythmic discharge does not reflect gasping behavior,2) increased temperature altersrespiratory discharge, and 3)central pH/CO₂ sensitivity isunaffected by temperature in this preparation (i.e.,Q₁₀ ~1.0).

     

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.

     

Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs

Moss, T. J., M. G. Davey, G. J. McCrabb, and R. Harding.Development of ventilatory responsiveness to progressive hypoxia and hypercapnia in low-birth-weight lambs. J. Appl.Physiol. 81(4): 1555-1561, 1996.Our aim was todetermine the effects of low birth weight on ventilatory responses toprogressive hypoxia and hypercapnia during early postnatal life. Sevenlow-birth-weight (2.7 ± 0.3 kg) and five normal-birth-weight (4.8 ± 0.2 kg) lambs, all born at term, underwent weekly rebreathingtests during wakefulness while arterialPO₂,PCO₂, and pH were measured. Hypoxicventilatory responsiveness (HOVR; percent increase in ventilation whenarterial PO₂ fell to 60% of resting values) increased in normal lambs from 86.6 ± 7.1% atweek 1 to 227.4 ± 24.9% atweek 6. In low-birth-weight lambs,HOVR was not significantly different at week1 (60.1 ± 18.7%) from that of normal lambs but didnot increase with postnatal age (56.6 ± 19.3% atweek 6). HOVR of all lambs at 6 wkwas significantly correlated with birth weight(r² = 0.8).Hypercapnic ventilatory responsiveness (gradient of ventilation vs.arterial PCO₂) did not change withage and was not significantly different between groups [84.7 ± 7.5 (low-birth-weight lambs) vs. 89.4 ± 6.6 ml ^· min^{1 ·} kg^{1 ·} mmHg¹(normal lambs)]. We conclude that intrauterine conditions that impair fetal growth lead to the failure of HOVR to increase with age.

     

Acute response of the lung mechanics of the rabbit to hypoxia

We measured thechange in total lung resistance(RL) and that in total lungelastance (EL) induced byhypoxia (n = 7) and compared theresults with those by intravenous histamine bolus (n = 5) at three different positiveend-expiratory pressure (PEEP) levels (2, 5, and 8 hPa) in open-chestand vagotomized rabbits. The percent increase ratio ofRL(PIR_R) andEL(PIR_E) was defined as the changein RL andEL, respectively, induced byhypoxia compared with that in the normoxic condition, expressed as apercentage. PIR values for the change inRL andEL induced by bolus injection ofhistamine were also calculated. ThePIR_R andPIR_E induced by hypoxia and byhistamine were positive by a statistically significant amount at everyPEEP level, except for the PIR_Evalue at 8-hPa PEEP in the hypoxic challenge. ThePIR_E-to-PIR_Rratio values in the hypoxic challenge at 2-hPa PEEP were significantlylarger than those in the histamine challenge (hypoxia: 0.91 ± 0.23%; histamine: 0.37 ± 0.065%,P < 0.05). The increasein EL induced by histamine inthe acute phase has been reported to be mainly derived from tissuedistortion secondary to bronchial constriction. Thus our resultssuggest that a part of the increase inEL by hypoxia was originated indifferent parenchymal responses from histamine and imply that thishypoxic response of lung parenchyma is sensitive to the increase inparenchymal tethering at high PEEP levels.

     

Impaired reactivity of rat aorta to phenylephrine and KCl after prolonged hypoxia: role of the endothelium

The hemodynamic response to reductions insystemic oxygen availability serves to redistribute blood flow andmaintain vital organ function. The efficacy of this response depends onthe degree to which hypoxia alters the function of the vascular tissuesthemselves. In this study we have evaluated these effects in ratsexposed to 10% oxygen for 0 (control), 12, and 48 h and for 48 hfollowed by 12 h of normoxic recovery. In aortic segments from eachgroup, the cumulative concentration response relationships wereconstructed for phenylephrine and KCl. Maximum tension generated duringactivation by these agents was reduced after both 12 and 48 h ofhypoxic exposure. After 48 h of hypoxia, the maximum tension duringactivation by phenylephrine was 0.46 ± 0.04 vs. 1.31 ± 0.09 g/mg dry wt for the control group (P < 0.05 for difference). The maximum tension during activation by KClwas similarly affected (0.32 ± 0.02 vs. 0.98 ± 0.06 g/mg dry wt, 48 h of hypoxia vs. control,respectively; P < 0.05 fordifference). Exposure to hypoxia did not alter the EC₅₀ for either agent. Twelvehours of normoxic recovery did not fully restore contractility after 48 h of hypoxia. In aortic rings from control rats, endothelial removalenhanced contraction, whereas, in rings from rats exposed to hypoxia,removal of the endothelium was associated with a decrease in maximumtension. Prolonged exposure to hypoxia results in impairment ofsystemic arterial smooth muscle contractility. This is partlycompensated by the release of vasoconstricting substances from theendothelium.

     

Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery

Verbitsky, O., J. Mizrahi, M. Levin, and E. Isakov.Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery. J. Appl. Physiol. 83(2):333-337, 1997.The influence of acute ingestion ofNaHCO₃ on fatigue and recovery ofthe quadriceps femoris muscle after exercise was studied in six healthymale subjects. A bicycle ergometer was used for exercising under three loading conditions: test A, loadcorresponding to maximal oxygen consumption; testB, load in test A + 17%; test C, load intest B but performed 1 h after acuteingestion of NaHCO₃.Functional electrical stimulation (FES) was applied to provokeisometric contraction of the quadriceps femoris. The resulting kneetorque was monitored during fatigue (2-min chronic FES) and recovery (10-s FES every 10 min, for 40 min). Quadriceps torques were higher inthe presence of NaHCO₃(P < 0.05): withNaHCO₃ the peak, residual, andrecovery (after 40 min) normalized torques were, respectively, 0.68 ± 0.05 (SD), 0.58 ± 0.05, and 0.73 ± 0.05; withoutNaHCO₃ the values were 0.45 ± 0.04, 0.30 ± 0.06, and 0.63 ± 0.06. The increasedtorques obtained after acute ingestion ofNaHCO₃ indicate the possibleexistence of improved nonoxidative glycolysis in isometric contraction,resulting in reduced fatigue and enhanced recovery.

     

Evidence against an increase in capillary permeability in subjects exposed to high altitude

Kleger, Gian-Reto, Peter Bärtsch, Peter Vock, BernhardHeilig, L. Jackson Roberts II, and Peter E. Ballmer. Evidence against an increase in capillary permeability in subjects exposed tohigh altitude. J. Appl. Physiol.81(5): 1917-1923, 1996.A potential pathogenetic cofactor for thedevelopment of acute mountain sickness and high-altitude pulmonaryedema is an increase in capillary permeability, which could occur as aresult of an inflammatory reaction and/or free radical-mediatedinjury to the lung. We measured the systemic albumin escape byintravenously injecting 5 µCi of ¹²⁵I-labeled albumin and theplasma concentrations of cytokines, F₂-isoprostanes (products of lipidperoxidation), and acute-phase proteins in 24 subjects exposed to 4,559 m. Ten subjects developed acute mountain sickness, and four subjectsdeveloped high-altitude pulmonary edema. The transcapillary escaperate of albumin was 6.9 ± 2.0%/h (SD) at low (550 m) and 6.3 ± 1.9%/h at high (4,559 m) altitude (P = 0.23; n = 24). The subjects withhigh-altitude pulmonary edema had a modest but insignificant increasein the transcapillary escape rate of albumin (4.6 ± 1.9%/h at lowvs. 5.7 ± 1.9%/h at high altitude;P = 0.42;n = 4). Plasma concentrations offibrinogen, ₁-acidglycoprotein, C-reactive protein, and interleukin-6 were unchanged inthe early phases and significantly increased by the end of theobservation period in the subjects with high-altitude pulmonary edema,whereas tumor necrosis factor- andF₂-isoprostanes did not change atall. This suggests that the inflammatory reaction was rather aconsequence than a causative factor of high-altitude pulmonary edema.In summary, these data argue against a dominant role for increasedsystemic capillary permeability in the development of acute mountainsickness and high-altitude pulmonary edema.

     

Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats

Bao, Gang, Preet M. Randhawa, and Eugene C. Fletcher.Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J. Appl.Physiol. 82(4): 1071-1078, 1997.Using a ratmodel, we investigated whether episodic eucapnic hypoxia was a morepotent stimulus to acute blood pressure (BP) elevation and bradycardiathan episodic hypocapnic hypoxia. We also investigated therole of sympathetic and parasympathetic nervous system in thiscardiovascular response. Sprague-Dawley (SD) and Wistar Kyoto (WKY)rats were exposed to repetitive 30-s cycles of hypocapnic or eucapnichypoxia before and after intravenous injection of the₁-adrenergic blocker prazosin,₂-adrenergic blocker yohimbine,or atropine. Eucapnic hypoxia caused a threefold elevation in systolicBP from baseline (83.5 ± 3.5 mmHg in WKY, 70.6 ± 4.6 mmHg inSD) and greater bradycardia (178 ± 20 beats/min in WKY,178 ± 21 beats/min in SD) compared with hypocapnic hypoxia (29.8 ± 3.6 mmHg and 43 ± 15 beats/min in WKY,19.0 ± 4.1 mmHg and 45 ± 12 beats/min in SD). Afterprazosin, the BP increase from eucapnic hypoxia was blunted, yohimbineshowed no effect, and atropine blocked the bradycardia. Directmeasurement of sympathetic nerve activity confirmed that addingCO₂ to the hypoxic gas mixture caused a 61% increase in sympathetic nerve activity. WKY rats seemmore vulnerable than SD rats to both hypoxia exposures in terms of theelevation in BP. We conclude that, in the rat, eucapnic hypoxia is amore potent stimulus to acute BP elevation and bradycardia than ishypocapnic hypoxia. An increased sympathetic tone appears to beinvolved in the BP response to acute episodic hypoxia.

     

Recovery of diaphragmatic function in awake sheep after two approaches to thoracic surgery

Imanaka, Hideaki, William R. Kimball, John C. Wain, MasajiNishimura, Kenichi Okubo, Dean Hess, and Robert M. Kacmarek. Recovery of diaphragmatic function in awake sheep after two approaches to thoracic surgery. J. Appl.Physiol. 83(5): 1733-1740, 1997.Video-assistedthoracoscopic surgery (VATS) is replacing thoracotomy, but no study hasaddressed the extent or duration of VATS-induced diaphragmaticalteration. We hypothesized that VATS would impair diaphragmaticfunction less and return diaphragmatic function faster thanthoracotomy. In eight sheep, sonomicrometers were randomly implanted onthe right costal diaphragm via VATS or thoracotomy. Diaphragmaticresting length, shortening fraction, and respiratory function weremeasured weekly during quiet breathing (QB) andCO₂ rebreathing for 4 wk. ForVATS, shortening fraction was smallest onpostoperative days 1 (POD 1) (6.4 ± 3.4 and12.9 ± 8.7% during QB and 10%CO₂ rebreathing, respectively) and7 (6.3 ± 3.4 and 16.9 ± 4.0%during QB and 10% CO₂rebreathing, respectively) and recovered by 3 wk (13.2 ± 1.8 and28.9 ± 8.0% during QB and 10%CO₂ rebreathing, respectively).For thoracotomy, shortening fraction at 10%CO₂ rebreathing was smaller onPODs 1, 7, 14 (15.9 ± 7.1, 13.6 ± 5.4, and 19.0 ± 6.9%) than onPOD 28 (29.9 ± 8.2%), but notduring QB on POD 1 or7 (7.5 ± 3.8 and 3.4 ± 2.6%)compared with POD 28 (10.7 ± 8.7%). Shortening fraction did not differ between surgeries. There wasno group difference in minute ventilation, respiratory rate,transdiaphragmatic pressure, or esophageal and gastric pressures. Inconclusion, although shortening fraction recovered faster for VATS,this translated into insignificant functional differences.

     

Endogenous vasopressin does not mediate hypoxia-induced anapyrexia in rats

The present study was designed to test the hypothesis thatarginine vasopressin (AVP) mediates hypoxia-induced anapyrexia. Therectal temperature of awake, unrestrained rats was measured before andafter hypoxic hypoxia, AVP-blocker injection, or a combination of thetwo. Control animals received saline injections of the same volume.Basal body temperature was 36.52 ± 0.29°C. We observed asignificant (P < 0.05) reduction inbody temperature of 1.45 ± 0.33°C after hypoxia (7% inspiredO₂), whereas systemic andcentral injections of AVP V₁- andAVP V₂-receptor blockers caused nochange in body temperature. When intravenous injection of AVP blockerswas combined with hypoxia, we observed a reduction in body temperatureof 1.49 ± 0.41°C(V₁-receptor blocker) and of 1.30 ± 0.13°C (V₂-receptorblocker), similar to that obtained by application of hypoxia only.Similar results were observed when the blockers were injectedintracerebroventricularly. The data indicate that endogenous AVP doesnot mediate hypoxia-induced anapyrexia in rats.     

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.

     

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.