Role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide.

The effects of hypercapnia (CO(2)) confined to either the alveolar space or the intravascular perfusate on exhaled nitric oxide (NO), perfusate NO metabolites (NOx), and pulmonary arterial pressure (Ppa) were examined during normoxia and progressive 20-min hypoxia in isolated blood- and buffer-perfused rabbit lungs. In blood-perfused lungs, when alveolar CO(2) concentration was increased from 0 to 12%, exhaled NO decreased, whereas Ppa increased. Increments of intravascular CO(2) levels increased Ppa without changes in exhaled NO. In buffer-perfused lungs, alveolar CO(2) increased Ppa with reductions in both exhaled NO from 93.8 to 61.7 (SE) nl/min (P < 0.01) and perfusate NOx from 4.8 to 1.8 nmol/min (P < 0.01). In contrast, intravascular CO(2) did not affect either exhaled NO or Ppa despite a tendency for perfusate NOx to decline. Progressive hypoxia elevated Ppa by 28% from baseline with a reduction in exhaled NO during normocapnia. Alveolar hypercapnia enhanced hypoxic Ppa response up to 50% with a further decline in exhaled NO. Hypercapnia did not alter the apparent K(m) for O(2), whereas it significantly decreased the V(max) from 66.7 to 55.6 nl/min. These results suggest that alveolar CO(2) inhibits epithelial NO synthase activity noncompetitively and that the suppressed NO production by hypercapnia augments hypoxic pulmonary vasoconstriction, resulting in improved ventilation-perfusion matching.     

Energy state and vasomotor tone in hypoxic pig lungs

To evaluate the role of energy state in pulmonary vascular responses to hypoxia, we exposed isolated pig lungs to decreases in inspired PO2 or increases in perfusate NaCN concentration. Lung energy state was assessed by 31P nuclear magnetic resonance spectroscopy or measurement of adenine nucleotides by high-pressure liquid chromatography in freeze-clamped biopsies. In ventilated lungs, inspired PO2 of 200 (normoxia), 50 (hypoxia), and 0 Torr (anoxia) did not change adenine nucleotides but resulted in steady-state pulmonary arterial pressure (Ppa) values of 15.5 +/- 1.4, 30.3 +/- 1.8, and 17.2 +/- 1.9 mmHg, respectively, indicating vasoconstriction during hypoxia and reversal of vasoconstriction during anoxia. In degassed lungs, similar changes in Ppa were observed; however, energy state deteriorated during anoxia. An increase in perfusate NaCN concentration from 0 to 0.1 mM progressively increased Ppa and did not alter adenine nucleotides, whereas 1 mM reversed this vasoconstriction and caused deterioration of energy state. These results suggest that 1) pulmonary vasoconstrictor responses to hypoxia or cyanide occurred independently of whole lung energy state, 2) the inability of the pulmonary vasculature to sustain hypoxic vasoconstriction during anoxia might be associated with decreased energy state in some lung compartment, and 3) atelectasis was detrimental to whole lung energy state.     

Effects of indomethacin on estradiol-induced attenuation of hypoxic vasoconstriction in lamb lungs

To determine whether cyclooxygenase products mediated the attenuation of hypoxic pulmonary vasoconstriction induced by estradiol, we measured pulmonary arterial pressure at a flow of 50 ml X min-1 X kg-1 (Ppa50) during steady-state exposures to inspired O2 tensions (PIO2) between 0 and 200 Torr in isolated lungs of juvenile ewes. Intramuscular estradiol (10 mg) 44-60 h before study significantly decreased perfusate concentrations of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator, prostacyclin, but did not significantly affect the stimulus-response relationship between PIO2 and Ppa50. Estradiol (20 mg) 3-5 days before study increased 6-keto-PGF1 alpha concentrations and decreased Ppa50 at PIO2 of 10, 30, and 50 Torr. Indomethacin added to the perfusate of these lungs reduced 6-keto-PGF1 alpha to undetectable levels and altered the estradiol-induced attenuation, increasing Ppa50 at PIO2 of 10 and 30 Torr, but decreasing Ppa50 at PIO2 of 200 Torr. Despite these effects, Ppa50 remained lower than the values measured in lungs not treated with estradiol. These results suggest that the estradiol-induced attenuation of the hypoxic stimulus-response relationship was mediated only in part by cyclooxygenase products, the net effects of which were vasodilation at PIO2 of 10 and 30 Torr, but vasoconstriction at PIO2 of 200 Torr.     

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.     

Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation

Heat shock protein 90 (Hsp90) binding to endothelial nitric oxide synthase (eNOS) is an important step in eNOS activation. The conformational state of bound Hsp90 determines whether eNOS produces nitric oxide (NO) or superoxide (O(2)(*-)). We determined the effects of the Hsp90 antagonists geldanamycin (GA) and radicicol (RA) on basal and ACh-stimulated changes in vessel diameter, cGMP production, and Hsp90:eNOS coimmunoprecipitation in piglet resistance level pulmonary arteries (PRA). In perfused piglet lungs, we evaluated the effects of GA and RA on ACh-stimulated changes in pulmonary arterial pressure (Ppa) and perfusate accumulation of stable NO metabolites (NOx(-)). The effects of GA and RA on ACh-stimulated O(2)(*-) generation was investigated in cultured pulmonary microvascular endothelial cells (PMVEC) by dihydroethidine (DHE) oxidation and confocal microscopy. Hsp90 inhibition with GA or RA reduced ACh-mediated dilation, abolished the ACh-stimulated increase in cGMP, and reduced eNOS:Hsp90 coprecipitation. GA and RA also inhibited the ACh-mediated changes in Ppa and NOx(-) accumulation rates in perfused lungs. ACh increased the rate of DHE oxidation in PMVEC pretreated with GA and RA but not in untreated cells. The cell-permeable superoxide dismutase mimetic M40401 reversed GA-mediated inhibition of ACh-induced dilation in PRA. We conclude that Hsp90 is a modulator of eNOS activity and vascular reactivity in the newborn piglet pulmonary circulation. Uncoupling of eNOS with GA or RA inhibits ACh-mediated dilation by a mechanism that involves O(2)(*-) generation.     

Effects of PEEP on pulmonary hemodynamics in intact dogs with oleic acid pulmonary edema

The effects of positive end-expiratory pressure (PEEP) on the pulmonary circulation were studied in 14 intact anesthetized dogs with oleic acid (OA) lung injury. Transmural (tm) mean pulmonary arterial pressure (Ppa)/cardiac index (Q) plots with transmural left atrial pressure (Pla) kept constant were constructed in seven dogs, and Ppa(tm)/PEEP plots with Q and Pla(tm) kept constant were constructed in seven other dogs. Q was manipulated by using a femoral arteriovenous bypass and a balloon catheter inserted in the inferior vena cava. Pla was manipulated using a balloon catheter placed by thoracotomy in the left atrium. Ppa(tm)/Q plots were essentially linear. Before OA, the linearly extrapolated pressure intercept of the Ppa(tm)/Q relationship approximated Pla(tm). OA (0.09 ml/kg into the right atrium) produced a parallel shift of the Ppa(tm)/Q relationship to higher pressures; i.e., the extrapolated pressure intercept increased while the slope was not modified. After OA, 4 Torr PEEP (5.4 cmH2O) had no effect on the Ppa(tm)/Q relationship and 10 Torr PEEP (13.6 cmH2O) produced a slight, not significant, upward shift of this relationship. Changing PEEP from 0 to 12 Torr (16.3 cmH2O) at constant Q before OA led to an almost linear increase of Ppa(tm) from 14 +/- 1 to 19 +/- 1 mmHg. After OA, Ppa(tm) increased at 0 Torr PEEP but changing PEEP from 0 to 12 Torr did not significantly affect Ppa(tm), which increased from 19 +/- 1 to 20 +/- 1 mmHg. These data suggest that moderate levels of PEEP minimally aggravate the pulmonary hypertension secondary to OA lung injury.     

Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep

We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep. Endotoxin infusion (1.3 micrograms/kg over 0.5 h) caused a rapid, transient rise in pulmonary arterial pressure (Ppa) from 16 +/- 3 to 36 +/- 10 mmHg (P less than 0.001) and pulmonary vascular resistance (PVR) from 187 +/- 84 to 682 +/- 340 dyn.s.cm-5 (P less than 0.05) at 0.5 h, followed by a persistent elevation in Ppa to 22 +/- 3 mmHg and in PVR to 522 +/- 285 dyn.s.cm-5 at 5 h in anesthetized sheep. Arterial PO2 (PaO2) decreased from 341 +/- 79 to 198 +/- 97 (P less than 0.01) and 202 +/- 161 Torr at 0.5 and 5 h, respectively (inspired O2 fraction = 1.0). SRI 63-441, 20 mg.kg-1.h-1 infused for 5 h, blocked the early rise in Ppa and PVR and fall in PaO2, but had no effect on the late phase pulmonary hypertension or hypoxemia. Endotoxin caused a gradual decrease in mean aortic pressure, which was unaffected by SRI 63-441. Infusion of SRI 63-441 alone caused no hemodynamic alterations. In follow-up studies, endotoxin caused an increase in lung lymph flow (QL) from 3.8 +/- 1.1 to 14.1 +/- 8.0 (P less than 0.05) and 12.7 +/- 8.6 ml/h at 1 and 4 h, respectively. SRI 63-441 abolished the early and attenuated the late increase in QL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ambient oxygen regulates epithelial metabolism and nitric oxide production in the human nose.

The effects of ambient O(2) tension on epithelial metabolism and nitric oxide (NO) production (VNO) in the nasal airway were examined in nine healthy volunteers. Nasal VNO, O(2) consumption (VO(2)), and CO(2) production (VCO(2)) were measured during normoxia followed by gradual hypoxia from 21 to 0% O(2) concentration. Nasal VO(2), VCO(2), and respiratory quotient during normoxia were determined to be 1.19 +/- 0.04 ml/min, 1.60 +/- 0.04 ml/min, and 1.35 +/- 0.04, respectively. Hypoxia exposure to the nasal cavity significantly decreased both VCO(2) and VNO [VCO(2): 1.60 +/- 0.04 to 0.96 +/- 0.03 ml/min (P < 0.01), VNO: 530 +/- 15 to 336 +/- 9 nl/min (P < 0.01)]. VNO was reduced commensurately with gradual decline in O(2) tension, and the apparent K(m) value for O(2) was determined to be 23.0 microM. These results indicate that the nasal epithelial cells exchange O(2) and CO(2) with ambient air in the course of their metabolism and that nasal epithelial cells can synthesize NO by using ambient O(2) as a substrate. We conclude that air-borne O(2) diffuses into the epithelium where it may be utilized for either cell metabolism or NO synthesis.     

Living and training in moderate hypoxia does not improve VO2 max more than living and training in normoxia.

The objective of these experiments was to determine whether living and training in moderate hypoxia (MHx) confers an advantage on maximal normoxic exercise capacity compared with living and training in normoxia. Rats were acclimatized to and trained in MHx [inspired PO2 (PI(O2)) = 110 Torr] for 10 wk (HTH). Rats living in normoxia trained under normoxic conditions (NTN) at the same absolute work rate: 30 m/min on a 10 degrees incline, 1 h/day, 5 days/wk. At the end of training, rats exercised maximally in normoxia. Training increased maximal O2 consumption (VO2 max) in NTN and HTH above normoxic (NS) and hypoxic (HS) sedentary controls. However, VO2 max and O2 transport variables were not significantly different between NTN and HTH: VO2 max 86.6 +/- 1.5 vs. 86.8 +/- 1.1 ml x min(-1) x kg(-1); maximal cardiac output 456 +/- 7 vs. 443 +/- 12 ml x min(-1) x kg(-1); tissue blood O2 delivery (cardiac output x arterial O2 content) 95 +/- 2 vs. 96 +/- 2 ml x min(-1) x kg(-1); and O2 extraction ratio (arteriovenous O2 content difference/arterial O2 content) 0.91 +/- 0.01 vs. 0.90 +/- 0.01. Mean pulmonary arterial pressure (Ppa, mmHg) was significantly higher in HS vs. NS (P < 0.05) at rest (24.5 +/- 0.8 vs. 18.1 +/- 0.8) and during maximal exercise (32.0 +/- 0.9 vs. 23.8 +/- 0.6). Training in MHx significantly attenuated the degree of pulmonary hypertension, with Ppa being significantly lower at rest (19.3 +/- 0.8) and during maximal exercise (29.2 +/- 0.5) in HTH vs. HS. These data indicate that, despite maintaining equal absolute training intensity levels, acclimatization to and training in MHx does not confer significant advantages over normoxic training. On the other hand, the pulmonary hypertension associated with acclimatization to hypoxia is reduced with hypoxic exercise training.     

Locus of hypoxic vasoconstriction in isolated ferret lungs

To determine whether hypoxic pulmonary vasoconstriction (HPV) occurs mainly in alveolar or extra-alveolar vessels in ferrets, we used two groups of isolated lungs perfused with autologous blood and a constant left atrial pressure (-5 Torr). In the first group, flow (Q) was held constant at 50, 100, and 150 ml.kg-1 X min-1, and changes in pulmonary arterial pressure (Ppa) were recorded as alveolar pressure (Palv) was lowered from 25 to 0 Torr during control [inspired partial pressure of O2 (PIO2) = 200 Torr] and hypoxic (PIO2 = 25 Torr) conditions. From these data, pressure-flow relationships were constructed at several levels of Palv. In the control state, lung inflation did not affect the slope of the pressure-flow relationships (delta Ppa/delta Q), but caused the extrapolated pressure-axis intercept (Ppa0), representing the mean backpressure to flow, to increase when Palv was greater than or equal to 5 Torr. Hypoxia increased delta Ppa/delta Q and Ppa0 at all levels of Palv. In contrast to its effects under control condition, lung inflation during hypoxia caused a progressive decrease in delta Ppa/delta Q, and did not alter Ppa0 until Palv was greater than or equal to 10 Torr. In the second group of experiments flow was maintained at 100 ml.kg-1 X min-1, and changes in lung blood volume (LBV) were recorded as Palv was varied between 20 and 0 Torr. In the control state, inflation increased LBV over the entire range of Palv. In the hypoxic state inflation decreased LBV until Palv reached 8 Torr; at Palv 8-20 Torr, inflation increased LBV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic sodium cyanate administration on O2 transport and uptake in hypoxic and normoxic exercise.

Systemic O2 transport during maximal exercise at different inspired PO2 (PIO2) values was studied in sodium cyanate-treated (CY) and nontreated (NT) rats. CY rats exhibited increased O2 affinity of Hb (exercise O2 half-saturation pressure of Hb = 27.5 vs. 42.5 Torr), elevated blood Hb concentration, pulmonary hypertension, blunted hypoxic pulmonary vasoconstriction, and normal ventilatory response to exercise. Maximal rate of convective O2 transport was higher and tissue O2 extraction was lower in CY than in NT rats. The relative magnitude of these opposing changes, which determined the net effect of cyanate on maximal O2 uptake (VO2 max), varied at different PIO2: VO2 max (ml. min-1. kg-1) was lower in normoxia (72.8 +/- 1.9 vs. 81. 1 +/- 1.2), the same at 70 Torr PIO2 (55.4 +/- 1.4 vs. 54.1 +/- 1.4), and higher at 55 Torr PIO2 (48 +/- 0.7 vs. 40.4 +/- 1.9) in CY than in NT rats. The beneficial effect of cyanate on VO2 max at 55 Torr PIO2 disappeared when Hb concentration was lowered to normal. It is concluded that the effect of cyanate on VO2 max depends on the relative changes in blood O2 convection and tissue O2 extraction, which vary at different PIO2. Although uptake of O2 by the blood in the lungs is enhanced by cyanate, its release at the tissues is limited, probably because of a reduction in the capillary-to-tissue PO2 diffusion gradient secondary to the increased O2 affinity of Hb.     

Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema

To verify the presence of the constitutional abnormality implicated in the pathogenesis of high-altitude pulmonary edema (HAPE), we evaluated the hemodynamic responses to hypoxia, hypobaria, and exercise in HAPE-susceptible subjects (HAPE-S). HAPE-S were five males with a history of HAPE. Five healthy volunteers who had repeated experiences of mountain climbing without any history of altitude-related problems served as controls. HAPE-S showed much greater increase in pulmonary vascular resistance index (PVRI) than the control subjects, resulting in a much higher level of pulmonary arterial pressure (Ppa), under both acute hypoxia of 15% O2 (Ppa = 29.0 +/- 2.8 vs. 17.8 +/- 0.3 Torr, P less than 0.05) and acute hypobaria of 515 Torr (32.3 +/- 2.8 vs. 19.1 +/- 0.8 Torr, P less than 0.05). Also, PVRI in HAPE-S exhibited a tendency to increase even during light exercise with supine bicycle ergometer (50 W), whereas PVRI in the control subjects significantly decreased, so that HAPE-S showed a greater increase in Ppa (delta Ppa = 16.0 +/- 1.5 vs. 4.9 +/- 1.1 Torr, P less than 0.001) and a greater decrease in arterial oxygen tension (17.8 +/- 4.7 vs. 5.6 +/- 1.7 Torr, P less than 0.05). We thus conclude that HAPE-S have a constitutional abnormality, which can be evaluated at low altitude, in the pulmonary circulatory responses to possible causative factors of HAPE such as hypoxia, hypobaria, and exercise.     

Pulmonary vascular tone is increased by a voltage-dependent calcium channel potentiator

The mechanism of hypoxia-induced pulmonary vasoconstriction remains unknown. To explore the possible dependence of the hypoxic response on voltage-activated calcium (Ca2+) channels, the effects of BAY K 8644 (BAY), a voltage-dependent Ca2+ channel potentiator, were observed on the pulmonary vascular response to hypoxia of both the intact anesthetized dog and the perfused isolated rat lung. In six rat lungs given BAY (1 X 10(-6)M), hypoxia increased mean pulmonary arterial pressure (Ppa) to 30.5 +/- 1.7 (SEM) Torr compared with 14.8 +/- 1.2 Torr for six untreated rat lungs (P less than 0.01). After nifedipine, the maximum Ppa during hypoxia fell 14.1 +/- 2.4 Torr from the previous hypoxic challenge in the BAY-stimulated rats (P less than 0.01). BAY (1.2 X 10(-7) mol/kg) given during normoxia in seven dogs increased pulmonary vascular resistance 2.5 +/- 0.3 to 5.0 +/- 1.2 Torr X 1(-1) X min (P less than 0.05), and systemic vascular resistance 55 +/- 4.9 to 126 +/- 20.7 Torr X 1(-1) X min (P less than 0.05). Systemic mean arterial pressure rose 68 Torr, whereas Ppa remained unchanged. Administration of BAY during hypoxia produced an increase in Ppa: 28 +/- 1.5 to 33 +/- 1.9 Torr (P less than 0.05). Thus BAY, a Ca2+ channel potentiator, enhances the hypoxic pulmonary response in vitro and in vivo. This, together with the effect of nifedipine on BAY potentiation, suggests that increased Ca2+ channel activity may be important in the mechanism of hypoxic pulmonary vasoconstriction.     

PEEP inhibits hypoxic pulmonary vasoconstriction in dogs

The effects of an increase in alveolar pressure on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We therefore studied the effects of positive end-expiratory pressure (PEEP) on pulmonary hemodynamics in 13 pentobarbital-anesthetized dogs ventilated alternately in hyperoxia [inspired O2 fraction (FIO2) 0.4] and in hypoxia (FIO2 0.1). In this intact animal model, HPV was defined as the gradient between hypoxic and hyperoxic transmural (tm) mean pulmonary arterial pressure [Ppa(tm)] at any level of cardiac index (Q). Ppa(tm)/Q plots were constructed with mean transmural left atrial pressure [Pla(tm)] kept constant at approximately 6 mmHg (n = 5 dogs), and Ppa(tm)/PEEP plots were constructed with Q kept constant approximately 2.8 l.min-1.m-2 and Pla(tm) kept constant approximately 8 mmHg (n = 8 dogs). Q was manipulated using a femoral arteriovenous bypass and a balloon catheter in the inferior vena cava. Pla(tm) was held constant by a balloon catheter placed by left thoracotomy in the left atrium. Increasing PEEP, from 0 to 12 Torr by 2-Torr increments, at constant Q and Pla(tm), increased Ppa(tm) from 14 +/- 1 (SE) to 19 +/- 1 mmHg in hyperoxia but did not affect Ppa(tm) (from 22 +/- 2 to 23 +/- 1 mmHg) in hypoxia. Both hypoxia and PEEP, at constant Pla(tm), increased Ppa(tm) over the whole range of Q studied, from 1 to 5 l/min, but more at the highest than at the lowest Q and without change in extrapolated pressure intercepts. Adding PEEP to hypoxia did not affect Ppa(tm) at all levels of Q.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary prostacyclin production with increased flow and sympathetic stimulation

We evaluated the effects of an abrupt increase in flow and of a subsequent sympathetic nerve stimulation on the pulmonary production of prostacyclin (PGI2) and thromboxane A2 (TXA2) in canine isolated left lower lobes perfused in situ with pulsatile flow. When flow was abruptly increased from 50 +/- 3 to 288 +/- 2 ml/min, mean pulmonary arterial pressure (Ppa) increased by 15 +/- 2 Torr and then declined by 2.4 Torr over the next 5 min. This secondary decrease in Ppa was associated with a significant 0.26 +/- 0.11 ng/ml increase in the pulmonary venous concentration of the stable PGI2 hydrolysis product 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) as determined by radioimmunoassay. Stimulation of the left stellate ganglion usually resulted in an increase in Ppa which peaked at 1.1 +/- 0.6 Torr above its prestimulus level and then declined over the next 5 min. Associated with this decline was a 0.24 +/- 0.11 ng/ml increase in 6-keto-PGF1 alpha at 1 min. We suggest that the decline in Ppa is due to the synthesis and release of PGI2 by the endothelial cells in response to an increase in perfusion pressure.     

Effects of altitude acclimatization on pulmonary gas exchange during exercise

Pulmonary gas exchange was studied in eight normal subjects both before and after 2 wk of altitude acclimatization at 3,800 m (12,470 ft, barometric pressure = 484 Torr). Respiratory and multiple inert gas tensions, ventilation, cardiac output (Q), and hemoglobin concentration were measured at rest and during three levels of constant-load cycle exercise during both normoxia [inspired PO2 (PIO2) = 148 Torr] and normobaric hypoxia (PIO2 = 91 Torr). After acclimatization, the measured alveolar-arterial PO2 difference (A-aPO2) for any given work rate decreased (P less than 0.02). The largest reductions were observed during the highest work rates and were 24.8 +/- 1.4 to 19.7 +/- 0.8 Torr (normoxia) and 22.0 +/- 1.1 to 19.4 +/- 0.7 Torr (hypoxia). This could not be explained by changes in ventilation-perfusion inequality or estimated O2 diffusing capacity, which were unaffected by acclimatization. However, Q for any given work rate was significantly decreased (P less than 0.001) after acclimatization. We suggest that the reduction in A-aPO2 after acclimatization is a result of more nearly complete alveolar/end-capillary diffusion equilibration on the basis of a longer pulmonary capillary transit time.     

Lung endothelial and epithelial permeability after platelet-activating factor

We investigated whether platelet-activating factor (PAF) increased epithelial or endothelial permeability in isolated-perfused rabbit lungs. PAF was either injected into the pulmonary artery or instilled into the airway of lungs perfused with Tyrode's solution containing 1% bovine serum albumin. The effect of adding neutrophils or platelets to the perfusate was also tested. Perfusion was maintained 20-40 min after adding PAF and then a fluid filtration coefficient (Kf) was determined to assess vascular permeability. At the end of each experiment, one lung was lavaged, and the lavagate protein concentration (BALP) was determined. Wet weight-to-dry weight ratios (W/D) were determined on the other lung. PAF added to the vascular space increased peak pulmonary arterial pressure (Ppa) from 13.5 +/- 3.1 (mean +/- SE) to 24.2 +/- 3.3 cmH2O (P less than 0.05). The effect was amplified by platelets [Ppa to 70.8 +/- 8.0 cmH2O (P less than 0.05)] but not by neutrophils [Ppa to 22.0 +/- 1.4 cmH2O (P less than 0.05)]. Minimal changes in Ppa were observed after instilling PAF into the airway. The Kf, W/D, and BALP of untreated lungs were not increased by injecting PAF into the vasculature or into the air space. The effect of PAF on Kf, W/D, and BALP was unaltered by adding platelets or neutrophils to the perfusate. PAF increases intravascular pressure (at a constant rate of perfusion) but does not increase epithelial or endothelial permeability in isolated-perfused rabbit lungs.     

Chronic administration of sodium cyanate decreases O2 extraction ratio in dogs

It has been proposed that an increase in the affinity of hemoglobin for O2 may be beneficial in severe hypoxemia. To test this hypothesis, we compared the response to progressive hypoxemia in dogs with normal hemoglobin affinity (P50 = 32.4 +/- 0.7 Torr) to dogs with a left shift of the oxyhemoglobin dissociation curve (P50 = 21.9 +/- 0.5 Torr) induced by chronic oral administration of sodium cyanate. Animals were anesthetized, paralyzed, and mechanically ventilated. The inspired O2 fraction was progressively lowered by increasing the inspired fraction of N2. The lowest level of O2 transport required to maintain base-line O2 consumption (VO2) was 9.3 +/- 0.8 ml.min-1.kg-1 for control and 16.5 +/- 1.1 ml.min-1.kg-1 for the sodium cyanate-treated dogs (P less than 0.01). Other measured parameters at this level of O2 transport were, for experimental vs. control: arterial PO2 19.3 +/- 2.4 (SE) Torr vs. 21.8 +/- 1.6 Torr (NS); arterial O2 content 10.0 +/- 1.2 ml/dl vs. 4.9 +/- 0.4 ml/dl (P less than 0.01); mixed venous PO2 14.0 +/- 1.5 Torr vs. 13.8 +/- 1.0 Torr (NS); mixed venous O2 content 6.8 +/- 1.0 ml/dl vs. 2.3 +/- 0.2 ml/dl (P less than 0.01); and O2 extraction ratio 32.7 +/- 2.8% vs. 51.2 +/- 3.8% (P less than 0.01). We conclude that chronic administration of sodium cyanate appears to be detrimental to O2 transport, since the experimental dogs were unable to increase their O2 extraction ratios to the same level as control, thus requiring a higher level of O2 transport to maintain their base-line VO2 values.     

Effect of high-frequency ventilation on gas exchange and pulmonary vascular resistance in lambs

We studied the effects of conventional mechanical ventilation (CMV) (15 ml/kg tidal volume delivered at 18-25 breaths/min) and high-frequency oscillatory ventilation (HFOV) (less than or equal to 2 ml/kg delivered at 10 Hz) on pulmonary hemodynamics and gas exchange during ambient air breathing and hypoxic gas breathing in 10 4-day-old lambs. After instrumentation and randomization to either HFOV or CMV the animals breathed first ambient air and then hypoxic gas (inspired O2 fraction = 0.13) for 20 min. The mode of ventilation was then changed, and the normoxic and hypoxic gas challenges were repeated. The multiple inert gas elimination technique was utilized to assess gas exchange. There was a significant increase with HFOV in mean pulmonary arterial pressure (Ppa) (20.1 +/- 4.2 vs. 22 +/- 3.8 Torr, CMV vs. HFOV, P less than 0.05) during ambient air breathing. During hypoxic gas breathing Ppa was also greater with HFOV than with CMV (29.5 +/- 5.7 vs. 34 +/- 3.1 Torr, CMV vs. HFOV, P less than 0.05). HFOV reduced pulmonary blood flow (Qp) during ambient air breathing (0.33 +/- 0.11 vs. 0.28 +/- 0.09 l . kg-1 . min-1, CMV vs. HFOV, P less than 0.05) and during hypoxic gas breathing (0.38 +/- 0.11 vs. 0.29 +/- 0.09 l . kg-1 . min-1, P less than 0.05). There was no significant difference in calculated venous admixture for sulfur hexafluoride or in the index of low ventilation-perfusion lung regions with HFOV compared with CMV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Operation Everest II: oxygen transport during exercise at extreme simulated altitude

A decrease in maximal O2 uptake has been demonstrated with increasing altitude. However, direct measurements of individual links in the O2 transport chain at extreme altitude have not been obtained previously. In this study we examined eight healthy males, aged 21-31 yr, at rest and during steady-state exercise at sea level and the following inspired O2 pressures (PIO2): 80, 63, 49, and 43 Torr, during a 40-day simulated ascent of Mt. Everest. The subjects exercised on a cycle ergometer, and heart rate was recorded by an electrocardiograph; ventilation, O2 uptake, and CO2 output were measured by open circuit. Arterial and mixed venous blood samples were collected from indwelling radial or brachial and pulmonary arterial catheters for analysis of blood gases, O2 saturation and content, and lactate. As PIO2 decreased, maximal O2 uptake decreased from 3.98 +/- 0.20 l/min at sea level to 1.17 +/- 0.08 l/min at PIO2 43 Torr. This was associated with profound hypoxemia and hypocapnia; at 60 W of exercise at PIO2 43 Torr, arterial PO2 = 28 +/- 1 Torr and PCO2 = 11 +/- 1 Torr, with a marked reduction in mixed venous PO2 [14.8 +/- 1 (SE) Torr]. Considering the major factors responsible for transfer of O2 from the atmosphere to the tissues, the most important adaptations occurred in ventilation where a fourfold increase in alveolar ventilation was observed. Diffusion from alveolus to end-capillary blood was unchanged with altitude. The mass circulatory transport of O2 to the tissue capillaries was also unaffected by altitude except at PIO2 43 Torr where cardiac output was increased for a given O2 uptake. Diffusion from the capillary to the tissue mitochondria, reflected by mixed venous PO2, was also increased with altitude. With increasing altitude, blood lactate was progressively reduced at maximal exercise, whereas at any absolute and relative submaximal work load, blood lactate was higher. These findings suggest that although glycogenolysis may be accentuated at low work loads, it may not be maximally activated at exhaustion.