Effect of hypoxia on percent of arteriolar and capillary beds perfused in the rat brain

The effects of moderate and severe hypoxia on quantitative regional morphometric indexes of the total and perfused arteriolar and capillary network were studied in the rat brain to determine whether diffusion distances were reduced in hypoxia. Fluorescein isothiocyanate (FITC)-labeled dextran was injected into the femoral vein of conscious control and hypoxic rats. After 20 s, the animal was decapitated and the head was frozen in liquid N2. Sections from eight brain regions were photographed to detect the perfused microvessels and then stained for alkaline phosphatase to visualize the total vascular network. There were significant increases in percent perfused arteriolar and capillary morphology between the two groups of hypoxic animals and control animals. In control rats, the percent of capillaries perfused averaged 45.6 +/- 0.6% (mean +/- SE). In moderate hypoxia 63.4 +/- 1.8% of the vessels were perfused and in severe hypoxia 89.4 +/- 0.1% were perfused. The percentage of arterioles perfused changed similarly. There were no significant differences in any index of total or percent perfused arteriolar or capillary morphometry among the regions within any group. During severe hypoxia, a greater percentage of the capillary reserves was utilized. These results demonstrate a uniform response to hypoxia in the capillary and arteriolar network of the conscious rat brain.     

Effect of hemorrhage on regional morphometric indexes of cerebral capillarity

This study was performed to determine whether the brain can increase the number of perfused capillaries and arterioles supplying it regionally during hemorrhage. This was done using a technique to simultaneously determine total and perfused regional arteriolar and capillary morphology. Conscious Long-Evans rats served as unbled controls or were bled 65 mmHg or to 40-45 mmHg and stabilized for 30 min. Regional cerebral blood flow was determined using [14C]iodoantipyrine in half of these animals and fluorescein isothiocyanate-dextran was injected in the other half for determination of perfused cerebral microvascular morphometric indexes. The total microvasculature was labeled postmortem via an alkaline phosphatase stain. Regional cerebral blood flow was significantly increased in animals bled to 65 mmHg. During hemorrhage to 40-45 mmHg, cerebral blood flow was reduced 50% (from 59 +/- 28 to 26 +/- 11 ml X min-1 X 100 g-1, mean +/- SD) with no regional redistribution. For all treatments, total capillary density ranged from 400 to 500 capillaries/mm2, and in controls 47% were perfused. Animals bled to 65 mmHg did not mobilize their unperfused microvascular reserve even though they showed a slight tendency to do so. During hemorrhage to 40-45 mmHg, this percent increased significantly to 57% with the largest increase occurring in the pons. Approximately 51% of arterioles were perfused in controls and this was not different compared with the percent perfused during hemorrhage. Despite the overall lack of mobilization of unperfused arterioles, some regions within the brain significantly mobilized their reserves with severe hemorrhage, e.g., hippocampus (78%), hypothalamus (67%), and medulla (73%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary arterial and venous constriction during hypoxia in 3- to 5-wk-old and adult ferrets

We have determined the sites of hypoxic vasoconstriction in ferret lungs. Lungs of five 3- to 5-wk-old and five adult ferrets were isolated and perfused with blood. Blood flow was adjusted initially to keep pulmonary arterial pressure at 20 cmH2O and left atrial and airway pressures at 6 and 8 cmH2O, respectively (zone 3). Once adjusted, flow was kept constant throughout the experiment. In each lung, pressures were measured in subpleural 20- to 50-microns-diam arterioles and venules with the micropipette servo-nulling method during normoxia (PO2 approximately 100 Torr) and hypoxia (PO2 less than 50 Torr). In normoxic adult ferret lungs, approximately 40% of total vascular resistance was in arteries, approximately 40% was in microvessels, and approximately 20% was in veins. With hypoxia, the total arteriovenous pressure drop increased by 68%. Arterial and venous pressure drops increased by 92 and 132%, respectively, with no change in microvascular pressure drop. In 3- to 5-wk-old ferret lungs, the vascular pressure profile during normoxia and the response to hypoxia were similar to those in adult lungs. We conclude that, in ferret lungs, arterial and venous resistances increase equally during hypoxia, resulting in increased microvascular pressures for fluid filtration.     

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

Acute hypoxia alters eicosanoid production of perfused pulmonary artery endothelial cells in culture.

Hypoxia alters vascular tone which regulates regional blood flow in the pulmonary circulation. Endothelial derived eicosanoids alter vascular tone and blood flow and have been implicated as modulators of hypoxic pulmonary vasoconstriction. Eicosanoid production was measured in cultured bovine pulmonary endothelial cells during constant flow and pressure perfusion at two oxygen tensions (hypoxia: 4% O2, 5% CO2, 91% N2; normoxia: 21% O2, 5% CO2, 74% N2). Endothelial cells were grown to confluence on microcarrier beads. Cell cartridges (N = 8) containing 2 ml of microcarrier beads (congruent to 5 x 10(6) cells) were constantly perfused (3 ml/min) with Krebs' solutions (pH 7.4, T 37 degrees C) equilibrated with each gas mixture. After a ten minute equilibration period, lipids were extracted (C18 Sep Pak) from twenty minute aliquots of perfusate over three hours (nine aliquots per cartridge). Eicosanoids (6-keto PGF1 alpha; TXB2; and total leukotriene [LT - LTC4, LTD4, LTE4, LTF4]) were assayed by radioimmunoassay. Eicosanoid production did not vary over time. 6-keto PGF1 alpha production was increased during hypoxia (normoxia 291 +/- 27 vs hypoxia 395 +/- 35 ng/min/gm protein; p less than 0.01). Thromboxane production (normoxia 19 +/- 2 vs hypoxia 20 +/- 2 ng/min/gm protein) and total leukotriene production (normoxia 363 +/- 35 vs hypoxia 329 +/- 29 ng/min/gm protein) did not change with hypoxia. These data demonstrated that oxygen increased endothelial prostacyclin production but did not effect thromboxane or leukotriene production.     

Microvascular pressures during hypoxia in isolated lungs of newborn rabbits

The purpose of this study was to determine the sites of hypoxic vasoconstriction in lungs of newborn rabbits. We isolated and perfused with blood the lungs from 19 rabbit pups, 7-23 days old. We maintained blood flow constant, continuously monitored pulmonary arterial and left atrial pressures, and alternated ventilation of the lungs with 95% O2-5% CO2 (control), and 95% N2-5% CO2 (hypoxia). Using micropipettes and a servonulling device, we measured pressures in 20-60-micron-diam subpleural arterioles and venules during control and hypoxic conditions. We inflated the lungs to a constant airway pressure of 5-7 cmH2O and kept left atrial pressure greater than airway pressure (zone 3) during micropuncture. In eight lungs we measured microvascular pressures first during control and then during hypoxia. We reversed this order in four lungs. In seven lungs we measured microvascular pressures only during hypoxia. We found a significant increase in pulmonary arterial pressure with no change in microvascular pressures. These results indicate that the site of hypoxic vasoconstriction in lungs of newborn rabbits is arteries greater than 60 micron in diameter.     

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis

We previously demonstrated that, in awake goats, 6 h of hypoxic carotid body perfusion during systemic normoxia produced time-dependent hyperventilation that is typical of ventilatory acclimatization to hypoxia (VAH). The hypocapnic alkalosis that occurred could have produced VAH by inducing cerebral vasoconstriction and brain lactic acidosis even though systemic arterial normoxia was maintained. In the present study we tested the hypothesis that hypocapnic alkalosis is a necessary component of VAH. Goats were prepared so that one carotid body could be perfused, from an extracorporeal circuit, with blood in which gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Using this preparation we carried out 4 h of hypoxic carotid body perfusion while maintaining systemic arterial (and brain) normoxia in awake goats. Expired minute ventilation (VE) was measured while CO2 was added to inspired air to maintain normocapnia. Carotid body PCO2 and PO2 were maintained near 40 Torr during the 4-h carotid body perfusion. Control mean VE was 8.65 +/- 0.48 l/min (mean +/- SE). With acute carotid body hypoxia (30 min) VE increased to 21.73 +/- 2.02 l/min (P less than 0.05); over the ensuing 3.5 h of carotid body hypoxia, VE progressively increased to 39.14 +/- 4.14 l/min (P less than 0.05). These data indicate that neither cerebral hypoxia nor hypocapnic alkalosis are required to produce VAH. After termination of the 4-h carotid body stimulation, hyperventilation was not maintained in these studies, i.e., there was no deacclimatization. This suggests that acclimatization and deacclimatization are produced by different mechanisms.     

Effect of alpha adrenergic blockade on brain blood flow and ventilation during hypoxia in newborn piglets.

The influence of cardiovascular changes on ventilation has been demonstrated in adult animals and humans (Jones, French, Weissman & Wasserman, 1981; Wasserman, Whipp & Castagna 1974). It has been suggested that neonatal hypoxic ventilatory depression may be related to some of the hemodynamic changes that occur during hypoxia (Brown & Lawson, 1988; Darnall, 1985; Suguihara, Bancalari, Bancalari, Hehre & Gerhardt, 1986). To test the possible relationship between the cardiovascular and ventilatory response to hypoxia in the newborn, eleven sedated spontaneously breathing piglets (age: 5.9 +/- 1.6 days; weight: 1795 +/- 317 g; SD) were studied before and after alpha adrenergic blockade with phenoxybenzamine. Minute ventilation (VE) was measured with a pneumotachograph, cardiac output (CO) by thermodilution and total and regional brain blood flow (BBF) with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10% O2. Hypoxia was again induced one hour after infusion of phenoxybenzamine (6 mg/kg over 30 min). After 10 min of hypoxia, in the absence of phenoxybenzamine, the animals responded with marked increases in VE (P less than 0.001), CO (P less than 0.001), BBF, and brain stem blood flow (BSBF) (P less than 0.02). However, the normal hemodynamic response to hypoxia was eliminated after alpha adrenergic blockade. There were significant decreases in systemic arterial blood pressure, CO, and BBF during hypoxia after phenoxybenzamine infusion; nevertheless, VE increased significantly (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of five consecutive nocturnal hypoxic exposures on the cerebrovascular responses to acute hypoxia and hypercapnia in humans.

The effects of discontinuous hypoxia on cerebrovascular regulation in humans are unknown. We hypothesized that five nocturnal hypoxic exposures (8 h/day) at a simulated altitude of 4,300 m (inspired O2 fraction = approximately 13.8%) would elicit cerebrovascular responses that are similar to those that have been reported during chronic altitude exposures. Twelve male subjects (26.6 +/- 4.1 yr, mean +/- SD) volunteered for this study. The technique of end-tidal forcing was used to examine cerebral blood flow (CBF) and regional cerebral O2 saturation (Sr(O2)) responses to acute variations in O2 and CO2 twice before, immediately after, and 5 days after the overnight hypoxic exposures. Transcranial Doppler ultrasound was used to assess CBF, and near-infrared spectroscopy was used to assess Sr(O2). Throughout the nocturnal hypoxic exposures, end-tidal Pco2 decreased (P < 0.001) whereas arterial O2 saturation increased (P < 0.001) compared with overnight normoxic control measurements. Symptoms associated with altitude illness were significantly greater than control values on the first night (P < 0.001) and second night (P < 0.01) of nocturnal hypoxia. Immediately after the nocturnal hypoxic intervention, the sensitivity of CBF to acute variations in O2 and CO2 increased 116% (P < 0.01) and 33% (P < 0.05), respectively, compared with control values. Sr(O2) was highly correlated with arterial O2 saturation (R2 = 0.94 +/- 0.04). These results show that discontinuous hypoxia elicits increases in the sensitivity of CBF to acute variations in O2 and CO2, which are similar to those observed during chronic hypoxia.     

Hypercapnia and response of cerebral blood flow to hypoxia in newborn lambs

Individual effects of hypoxic hypoxia and hypercapnia on the cerebral circulation are well described, but data on their combined effects are conflicting. We measured the effect of hypoxic hypoxia on cerebral blood flow (CBF) and cerebral O2 consumption during normocapnia (arterial PCO2 = 33 +/- 2 Torr) and during hypercapnia (60 +/- 2 Torr) in seven pentobarbital-anesthetized lambs. Analysis of variance showed that neither the magnitude of the hypoxic CBF response nor cerebral O2 consumption was significantly related to the level of arterial PCO2. To determine whether hypoxic cerebral vasodilation during hypercapnia was restricted by reflex sympathetic stimulation we studied an additional six hypercapnic anesthetized lambs before and after bilateral removal of the superior cervical ganglion. Sympathectomy had no effect on base-line CBF during hypercapnia or on the CBF response to hypoxic hypoxia. We conclude that the effects of hypoxic hypoxia on CBF and cerebral O2 consumption are not significantly altered by moderate hypercapnia in the anesthetized lamb. Furthermore, we found no evidence that hypercapnia results in a reflex increase in sympathetic tone that interferes with the ability of cerebral vessels to dilate during hypoxic hypoxia.     

Role of nitric oxide in capillary perfusion and oxygen delivery regulation during systemic hypoxia

The role of nitric oxide (NO) and reactive oxygen species (ROS) in regulating capillary perfusion was studied in the hamster cheek pouch model during normoxia and after 20 min of exposure to 10% O2-90% N2. We measured PO2 by using phosphorescence quenching microscopy and ROS production in systemic blood. Identical experiments were performed after treatment with the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) and after the reinfusion of the NO donor 2,2'-(hydroxynitrosohydrazono)bis-etanamine (DETA/NO) after treatment with L-NMMA. Hypoxia caused a significant decrease in the systemic PO2. During normoxia, arteriolar intravascular PO2 decreased progressively from 47.0 +/- 3.5 mmHg in the larger arterioles to 28.0 +/- 2.5 mmHg in the terminal arterioles; conversely, intravascular PO2 was 7-14 mmHg and approximately uniform in all arterioles. Tissue PO2 was 85% of baseline. Hypoxia significantly dilated arterioles, reduced blood flow, and increased capillary perfusion (15%) and ROS (72%) relative to baseline. Administration of L-NMMA during hypoxia further reduced capillary perfusion to 47% of baseline and increased ROS to 34% of baseline, both changes being significant. Tissue PO2 was reduced by 33% versus the hypoxic group. Administration of DETA/NO after L-NMMA caused vasodilation, normalized ROS, and increased capillary perfusion and tissue PO2. These results indicate that during normoxia, oxygen is supplied to the tissue mostly by the arterioles, whereas in hypoxia, oxygen is supplied to tissue by capillaries by a NO concentration-dependent mechanism that controls capillary perfusion and tissue PO2, involving capillary endothelial cell responses to the decrease in lipid peroxide formation controlled by NO availability during low PO2 conditions.     

Reversal of pulmonary hypoxic vasoconstriction with pentoxifylline and aminophylline in isolated lungs

Pentoxifylline (Pent) is a xanthine known to improve erythrocyte deformability and thought to have little effect on smooth muscle tone. In this study I examined the direct effects of Pent on the pulmonary vasculature of isolated lungs and compared them with the effects of aminophylline. The object was to study whether Pent can reverse the hypoxic pressor response (HPR) by its hemorheological property. Changes in pulmonary arterial pressure (Pa) of isolated lungs (pigs and rats) perfused at constant flow rate were monitored to reflect changes in vascular resistance. During normoxia, injection of Pent (5 mg/kg animal weight) in pig lungs depressed the Pa from 12.8 +/- 1.8 to 8.1 +/- 0.8 mmHg (1 mmHg = 133.3 Pa); whereas during hypoxia, Pa was depressed from 34.0 +/- 2.3 to 12.3 +/- 1.4 mmHg. To identify the mechanism of this vasodepressor effect (being either vasodilation or improved erythrocyte deformability), I tested the effect of Pent in lungs perfused with cell-free perfusate. In these plasma-perfused lungs, the vasodepressor effects of Pent were similar to those observed during blood perfusion (slight depression in Pa during normoxia, but large during hypoxia). Similar experiments in blood and plasma perfused pig lungs revealed that aminophylline (5 mg/kg) also produced similar vasodepressor responses. The effects of Pent in rat lungs were comparable; no effect during normoxia, but a depressor effect during hypoxia. Vasoconstriction in pig lungs induced by angiotensin infusion was also abolished by Pent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide mediates hypoxia-induced cerebral vasodilation in humans.

Nitric oxide (NO) plays a pivotal role in the regulation of peripheral vascular tone. Its role in the regulation of cerebral vascular tone in humans remains to be elucidated. This study investigates the role of NO in hypoxia-induced cerebral vasodilatation in young healthy volunteers. The effect of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) on the cerebral blood flow (CBF) was assessed during normoxia and during hypoxia (peripheral O(2) saturation 97 and 80%, respectively). Subjects were positioned in a magnetic resonance scanner, breathing normal air (normoxia) or a N(2)-O(2) mixture (hypoxia). The CBF was measured before and after administration of L-NMMA (3 mg/kg) by use of phase-contrast magnetic resonance imaging techniques. Administration of L-NMMA during normoxia did not affect CBF. Hypoxia increased CBF from 1,049 +/- 113 to 1,209 +/- 143 ml/min (P < 0.05). After L-NMMA administration, the augmented CBF returned to baseline (1,050 +/- 161 ml/min; P < 0.05). Similarly, cerebral vascular resistance declined during hypoxia and returned to baseline after administration of L-NMMA (P < 0.05 for both). Use of phase-contrast magnetic resonance imaging shows that hypoxia-induced cerebral vasodilatation in humans is mediated by NO.     

Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle.

Exercise blunts sympathetic alpha-adrenergic vasoconstriction (functional sympatholysis). We hypothesized that sympatholysis would be augmented during hypoxic exercise compared with exercise alone. Fourteen subjects were monitored with ECG and pulse oximetry. Brachial artery and antecubital vein catheters were placed in the nondominant (exercising) arm. Subjects breathed hypoxic gas to titrate arterial O2 saturation to 80% while remaining normocapnic via a rebreath system. Baseline and two 8-min bouts of rhythmic forearm exercise (10 and 20% of maximum) were performed during normoxia and hypoxia. Forearm blood flow, blood pressure, heart rate, minute ventilation, and end-tidal CO2 were measured at rest and during exercise. Vasoconstrictor responsiveness was determined by responses to intra-arterial tyramine during the final 3 min of rest and each exercise bout. Heart rate was higher during hypoxia (P < 0.01), whereas blood pressure was similar (P = 0.84). Hypoxic exercise potentiated minute ventilation compared with normoxic exercise (P < 0.01). Forearm blood flow was higher during hypoxia compared with normoxia at rest (85 +/- 9 vs. 66 +/- 7 ml/min), at 10% exercise (276 +/- 33 vs. 217 +/- 27 ml/min), and at 20% exercise (464 +/- 32 vs. 386 +/- 28 ml/min; P < 0.01). Arterial epinephrine was higher during hypoxia (P < 0.01); however, venoarterial norepinephrine difference was similar between hypoxia and normoxia before (P = 0.47) and during tyramine administration (P = 0.14). Vasoconstriction to tyramine (%decrease from pretyramine values) was blunted in a dose-dependent manner with increasing exercise intensity (P < 0.01). Interestingly, vasoconstrictor responsiveness tended to be greater (P = 0.06) at rest (-37 +/- 6% vs. -33 +/- 6%), at 10% exercise (-27 +/- 5 vs. -22 +/- 4%), and at 20% exercise (-22 +/- 5 vs. -14 +/- 4%) between hypoxia and normoxia, respectively. Thus sympatholysis is not augmented by moderate hypoxia nor does it contribute to the increased blood flow during hypoxic exercise.     

N omega-nitro-L-arginine influences cerebral metabolism in awake sheep.

Cerebral vasodilation in hypoxia may involve endothelium-derived relaxing factor-nitric oxide (NO). An inhibitor of NO formation, N omega-nitro-L-arginine (LNA, 100 micrograms/kg i.v.), was given to conscious sheep (n = 6) during normoxia and again in hypocapnic hypoxia (arterial PO2 approximately 38 Torr). Blood samples were obtained from the aorta and sagittal sinus, and cerebral blood flow (CBF) was measured with 15-microns radiolabeled microspheres. During normoxia, LNA elevated (P < 0.05) mean arterial pressure from 82 +/- 3 to 88 +/- 2 (SE) mmHg and cerebral perfusion pressure (CPP) from 72 +/- 3 to 79 +/- 3 mmHg, CBF was unchanged, and cerebral lactate release (CLR) rose temporarily from 0.0 +/- 1.9 to 13.3 +/- 8.7 mumol.min-1 x 100 g-1 (P < 0.05). The glucose-O2 index declined (P < 0.05) from 1.67 +/- 0.16 to 1.03 +/- 0.4 mumol.min-1 x 100 g-1. Hypoxia increased CBF from 59.9 +/- 5.4 to 122.5 +/- 17.5 ml.min-1 x 100 g-1 and the glucose-O2 index from 1.75 +/- 0.43 to 2.49 +/- 0.52 mumol.min-1 x 100 g-1 and decreased brain CO2 output, brain respiratory quotient, and CPP (all P < 0.05), while cerebral O2 uptake, CLR, and CPP were unchanged. LNA given during hypoxia decreased CBF to 77.7 +/- 11.8 ml.min-1 x 100 g-1 and cerebral O2 uptake from 154 +/- 22 to 105.2 +/- 12.4 mumol.min-1 x 100 g-1 and further elevated mean arterial pressure to 98 +/- 2 mmHg (all P < 0.05), CLR was unchanged, and, surprisingly, brain CO2 output and respiratory quotient were reduced dramatically to negative values (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise delays the hypoxic thermal response in rats.

Exercise exacerbates acute mountain sickness. In infants and small mammals, hypoxia elicits a decrease in body temperature (Tb) [hypoxic thermal response (HTR)], which may protect against hypoxic tissue damage. We postulated that exercise would counteract the HTR and promote hypoxic tissue damage. Tb was measured by telemetry in rats (n = 28) exercising or sedentary in either normoxia or hypoxia (10% O2, 24 h) at 25 degrees C ambient temperature (Ta). After 24 h of normoxia, rats walked at 10 m/min on a treadmill (30 min exercise, 30 min rest) for 6 h followed by 18 h of rest in either hypoxia or normoxia. Exercising normoxic rats increased Tb ( degrees C) vs. baseline (39.68 +/- 0.99 vs. 38.90 +/- 0.95, mean +/- SD, P < 0.05) and vs. sedentary normoxic rats (38.0 +/- 0.09, P < 0.05). Sedentary hypoxic rats decreased Tb (36.15 +/- 0.97 vs. 38.0 +/- 0.36, P < 0.05) whereas Tb was maintained in the exercising hypoxic rats during the initial 6 h of exercise (37.61 +/- 0.55 vs. 37.72 +/- 1.25, not significant). After exercise, Tb in hypoxic rats reached a nadir similar to that in sedentary hypoxic rats (35.05 +/- 1.69 vs. 35.03 +/- 1.32, respectively). Tb reached its nadir significantly later in exercising hypoxic vs. sedentary hypoxic rats (10.51 +/- 1.61 vs. 5.36 +/- 1.83 h, respectively; P = 0.002). Significantly greater histopathological damage and water contents were observed in brain and lungs in the exercising hypoxic vs. sedentary hypoxic and normoxic rats. Thus exercise early in hypoxia delays but does not prevent the HTR. Counteracting the HTR early in hypoxia by exercise exacerbates brain and lung damage and edema in the absence of ischemia.     

Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules.

Systemic hypoxia, produced by lowering inspired Po2, induces a rapid inflammation in several microcirculations, including cremaster muscle. Mast cell activation is a necessary element of this response. Selective reduction of cremaster microvascular Po2 (PmO2) with normal systemic arterial Po2 (PaO2; cremaster hypoxia/systemic normoxia), however, does not elicit increased leukocyte-endothelial adherence (LEA) in cremaster venules. This could be due to a short time of leukocyte exposure to the hypoxic cremaster environment. Conversely, LEA increases when PaO2 is lowered, while cremaster PmO2 remains high (cremaster normoxia/systemic hypoxia). An alternative explanation of these results is that a mediator released from a central site during systemic hypoxia initiates the inflammatory cascade. We hypothesized that if this is the case, cremaster mast cells would be activated during cremaster normoxia/systemic hypoxia, but not during cremaster hypoxia/systemic normoxia. The microcirculation of rat cremaster muscles was visualized by using intravital microscopy. Cremaster PmO2 was measured with a phosphorescence quenching method. Cremaster hypoxia/systemic normoxia (PmO2 7 +/- 1 Torr, PaO2 87 +/- 2 Torr) did not increase LEA; however, topical application of the mast cell activator compound 48/80 under these conditions did increase LEA. The effect of compound 48/80 on LEA was blocked by topical cromolyn, a mast cell stabilizer. LEA increased during cremaster normoxia/systemic hypoxia, (PmO2 64 +/- 5 Torr, PaO2 33 +/- 2 Torr); this increase was blocked by topical cromolyn. The results suggest that mast cell stimulation occurs only when PaO2 is reduced, independent of cremaster PmO2, and support the idea of a mediator that is released during systemic hypoxia and initiates the inflammatory cascade.     

Clinical evidence for myocardial derecruitment downstream from severe stenosis: pressure-flow control interaction

To verify the interaction between coronary pressure (CP) and blood flow (CBF) control, we studied nine candidates for angioplasty of an isolated lesion of the left anterior descending coronary artery [i.e. , percutaneous transluminal coronary angioplasty (PTCA)]. CBF (i.e., flow velocity x coronary cross-sectional area at the Doppler tip) and CP were monitored during washout of 2-5 mCi of (133)Xe after bolus injection into the left main artery before and after PTCA. Xe mean transit time (MTT) was calculated as the area under the time-activity curve, acquired by a gamma camera, divided by the dose obtained from a model fit of the Xe curve in the anterior wall. CBF response to intracoronary adenosine (2 mg) was also assessed. PTCA increased baseline CBF (from 14.5 +/- 9.4 to 20 +/- 8 ml/min, P < 0.01), coronary flow reserve (from 1.52 +/- 0.24 to 2.33 +/- 0.8, P < 0.01), and CP (from 64 +/- 9 to 100 +/- 10 mmHg, P < 0.05). MTT decreased from 89 +/- 32 to 70 +/- 19 s (P < 0.05) after PTCA; however, MTT and CBF changes were not correlated (r = -0.09, not significant). Inasmuch as MTT is the ratio of distribution volume to CBF, MTT x CBF was used as an index of perfused myocardial volume. Volume increased after PTCA from 23 +/- 18 to 56 +/- 30 ml. A direct correlation was observed between the percent increase in distal CP and percent increase in perfused volume (r = 0.91, P < 0.01). Thus low CP was not associated with exhaustion of flow reserve but, rather, with reduction of perfused myocardial volume. These data suggest that, in the presence of a severe coronary stenosis, derecruitment of vascular units occurs that is proportional to the decrease in driving pressure. Residual perfused units maintain a vasomotor tone, thus explaining the paradoxical persistence of coronary reserve.     

Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs.

We hypothesized that chronic intermittent hypoxia (CIH) would induce a predisposition to apnea in response to induced hypocapnia. To test this, we used pressure support ventilation to quantify the difference in end-tidal partial pressure of CO(2) (Pet(CO(2))) between eupnea and the apneic threshold ("CO(2) reserve") as an index of the propensity for apnea and unstable breathing during sleep, both before and following up to 3-wk exposure to chronic intermittent hypoxia in dogs. CIH consisted of 25 s of Pet(O(2)) = 35-40 Torr followed by 35 s of normoxia, and this pattern was repeated 60 times/h, 7-8 h/day for 3 wk. The CO(2) reserve was determined during non-rapid eye movement sleep in normoxia 14-16 h after the most recent hypoxic exposure. Contrary to our hypothesis, the slope of the ventilatory response to CO(2) below eupnea progressively decreased during CIH (control, 1.36 +/- 0.18; week 2, 0.94 +/- 0.12; week 3, 0.73 +/- 0.05 l.min(-1).Torr(-1), P < 0.05). This resulted in a significant increase in the CO(2) reserve relative to control (P < 0.05) following both 2 and 3 wk of CIH (control, 2.6 +/- 0.6; week 2, 3.7 +/- 0.8; week 3, 4.5 +/- 0.9 Torr). CIH also 1) caused no change in eupneic, air breathing Pa(CO(2)); 2) increased the slope of the ventilatory response to hypercapnia after 2 wk but not after 3 wk compared with control; and 3) had no effect on the ventilatory response to hypoxia. We conclude that 3-wk CIH reduced the sensitivity of the ventilatory response to transient hypocapnia and thereby increased the CO(2) reserve, i.e., the propensity for apnea was reduced.     

Cardiovagal regulation during combined hypoxic and orthostatic stress: fainters vs. nonfainters.

We tested the hypothesis that individual differences in the effect of acute hypoxia on the cardiovagal arterial baroreflex would determine individual susceptibility to hypoxic syncope. In 16 healthy, nonsmoking, normotensive subjects (8 women, 8 men, age 20-33 yr), we assessed orthostatic tolerance with a 20-min 60 degrees head-upright tilt during both normoxia and hypoxia (breathing 12% O(2)). On a separate occasion, we assessed baroreflex control of heart rate (cardiovagal baroreflex gain) using the modified Oxford technique during both normoxia and hypoxia. When subjects were tilted under hypoxic conditions, 5 of the 16 developed presyncopal signs or symptoms, and the 20-min tilt had to be terminated. These "fainters" had comparable cardiovagal baroreflex gain to "nonfainters" under both normoxic and hypoxic conditions (normoxia, fainters: -1.2 +/- 0.2, nonfainters: -1.0 +/- 0.2 beats.min(-1).mmHg(-1), P = 0.252; hypoxia, fainters: -1.3 +/- 0.2, nonfainters: -1.0 +/- 0.1 beats.min(-1).mmHg(-1), P = 0.208). Furthermore, hypoxia did not alter cardiovagal baroreflex gain in either group (both P > 0.8). It appears from these observations that hypoxic syncope results from the superimposed vasodilator effects of hypoxia on the cardiovascular system and not from a hypoxia-induced maladjustment in baroreflex control of heart rate.