Adrenergic and local control of O2 uptake during and after severe hypoxia

The distribution of whole-body O2 supply during severe hypoxia and recovery and its relation to the regional distribution of O2 deficit and repayment was studied. Mongrel dogs were anesthetized, paralyzed, and ventilated to maintain an end-tidal PCO2 between 35 and 40 Torr. In one group, the alpha- and beta-adrenergic receptors were blocked to eliminate neural and humoral adrenergic influences. In a second group, alpha-adrenergic receptors were stimulated to decrease O2 delivery by excessive vasoconstriction. In a third group, beta-adrenergic receptors were stimulated to increase O2 delivery. Whole-body and hindlimb muscle O2 uptake and vascular responses were measured during normoxic control, 15 or 30 min of severe hypoxia (9% O2 in N2), and 20 or 30 min of normoxic recovery, respectively. The whole-body O2 deficit and excess O2 uptake in recovery were partitioned into muscle and nonmuscle areas. The data showed that neural or humoral influences had little effect on the regional distribution of the total O2 deficit and O2 excess in recovery. The O2 deficit could be decreased somewhat by increasing delivery, but the amount of excess O2 used in recovery was unaffected. This suggested that the excess O2 use in recovery was more a function of an energy deficit during hypoxia and not an O2 deficit.     

Regional O2 uptake during hypoxia and recovery in hypermetabolic dogs

The regional distribution of O2 deficit in muscle and nonmuscle tissues was measured in hypermetabolic dogs ventilated with a low inspired O2 fraction and was compared with excess O2 used in these regions during normoxic recovery. O2 uptake was stimulated by 2,4-dinitrophenol (DNP). Arterial, mixed venous, and muscle venous blood samples were drawn before, during, and after severe hypoxia (9% O2-91% N2) for the calculation of hindlimb O2 uptake and cardiac output. The O2 deficit and excess O2 uptake in recovery were calculated as the cumulative differences between normoxic control and respective hypoxic and recovery O2 uptake values. The DNP data were compared with data previously obtained in our laboratory. A greater whole-body O2 deficit was incurred in the DNP group during hypoxia and was associated with a larger O2 use in recovery. The total O2 deficit was equally distributed between muscle and nonmuscle tissues, but more excess O2 use occurred in nonmuscle tissues. The greater excess O2 used by nonmuscle tissues may have been associated with the restoration of intracellular ion concentrations brought about by the increased activity of energy-using membrane pumps.     

Regional hemodynamic responses to hypoxia in polycythemic dogs

Polycythemia increases blood viscosity so that systemic O2 delivery (QO2) decreases and its regional distribution changes. We examined whether hypoxia, by promoting local vasodilation, further modified these effects in resting skeletal muscle and gut in anesthetized dogs after hematocrit had been raised to 65%. One group (CON, n = 7) served as normoxic controls while another (HH, n = 6) was ventilated with 9% O2--91% N2 for 30 min between periods of normoxia. Polycythemia decreased cardiac output so that QO2 to both regions decreased approximately 50% in both groups. In compensation, O2 extraction fraction increased to 65% in muscle and to 50% in gut. When QO2 was reduced further during hypoxia, blood flow increased in muscle but not in gut. Unlike previously published normocythemic studies, there was no initial hypoxic vasoconstriction in muscle. Metabolic vasodilation during hypoxia was enhanced in muscle when blood O2 reserves were first lowered by increased extraction with polycythemia alone. The increase in resting muscle blood flow during hypoxia with no change in cardiac output may have decreased O2 availability to other more vital tissues. In that sense and under these experimental conditions, polycythemia caused a maladaptive response during hypoxic hypoxia.     

Regional hemodynamic responses to hypoxia and hypermetabolism in polycythemic dogs

Normovolemic polycythemia did not improve the ability of either resting muscle or gut to maintain O2 uptake (VO2) during severe hypoxia because of the adverse effects of increased viscosity on blood flow to those regions. The present study tested whether increased metabolic demand would promote vasodilation sufficiently to overcome those effects. We measured whole body, muscle, and gut blood flow, O2 extraction, and VO2 in anesthetized dogs after increasing hematocrit to 65% and raising O2 demand with 2,4-dinitrophenol (n = 8). We also tested whether regional denervation (n = 8) and hypervolemia (n = 6) affected these responses. After raising hematocrit and metabolism, the dogs were ventilated with air, with 9% O2-91% N2, and again with air for 30-min periods. Reduced blood flow and increased O2 demand, caused by increased blood viscosity and 2,4-dinitrophenol, respectively, increased O2 extraction so that muscle VO2 was nearly supply limited in normoxia. Denervation showed that vasoconstriction had increased in gut and muscle with hypoxia onset but this was overcome after 15 min. By then, muscle was receiving a major portion of cardiac output, whereas gut showed little change. With hypervolemia cardiac output increased in hypoxia but neither gut nor muscle increased blood flow in those experiments. Because regional and whole body VO2 fell in all groups during hypoxia to the same extent found earlier in normocythemic dogs, any real benefit of polycythemia under the conditions of these experiments was dubious at best.     

Muscle O2 deficit during hypoxia and two levels of O2 demand

We have examined the relative deficits in tension development and O2 uptake in contracting skeletal muscle during severe hypoxic hypoxia. Anesthetized mongrel dogs were ventilated to maintain an end-tidal PCO2 between 35 and 40 Torr. Venous outflow from the gastrocnemius muscle was measured using an electromagnetic flow probe. The tendon was cut and attached to a strain gauge. The muscle was stimulated to contract isometrically at 2 or 4 Hz for 20 min. Hypoxia (9% O2 in N2) was then imposed for 30 min, followed by 30 min of normoxia. Blood flow first increased in proportion to the contraction frequency and then increased further a similar amount in both groups during hypoxia. O2 extraction and blood flow reached maximal levels during hypoxia in the 2-Hz group. The further O2 deficit that was accumulated during 4 Hz and hypoxia was, therefore, a result of the greater discrepancy between O2 supply and demand. O2 uptake decreased more in hypoxia than did developed tension. These results are best explained by ATP supplementation from nonaerobic energy sources that was promoted by the free-flow condition of hypoxic hypoxia.     

Hindlimb vascular responses to sympathetic augmentation during acute anemia

The effect of increased sympathetic activity on skeletal muscle blood flow during acute anemic hypoxia was studied in 16 anesthetized dogs. Sympathetic activity was altered by clamping the carotid arteries bilaterally below the carotid sinus. One group (n = 8) was beta blocked by administration of propranolol (1 mg/kg); a second group (n = 8) was untreated. Venous outflow from the left hindlimb was isolated for measurement of blood flow and O2 uptake (VO2). After a 20-min control period, both carotid arteries were clamped (CC) for 20 min followed by a 20-min recovery period. The sequence was repeated after hematocrit was lowered to about 15% by dextran exchange for blood. Prior to anemia, CC did not alter cardiac output or limb blood flow in either group. After induction of anemia, hindlimb resistance was higher with CC in the beta block than in the no block group. Both limb blood flow and VO2 fell in the beta-block group with CC during anemia. Beta block also prevented the additive increases in whole body VO2 seen with CC and induction of anemia. The data showed that the increased vasoconstrictor tone that was obtained with beta block during anemia was successful in redistributing the lower viscosity blood away from resting skeletal muscle, even to the point that muscle VO2 was decreased.     

The role aortic chemoreceptors during severe CO hypoxia

The importance of aortic chemoreceptors in the circulatory responses to severe carbon monoxide (CO) hypoxia was studied in anesthetized dogs. The aortic chemoreceptors were surgically denervated in eight dogs prior to the induction of CO hypoxia, with nine other dogs serving as intact controls. Values for both whole body and hindlimb blood flow, vascular resistance, and O2 uptake were determined prior to and at 30 min of CO hypoxia in the two groups. Arterial O2 content was reduced 65% using an in situ dialysis method to produce CO hypoxia. At 30 min of hypoxia, cardiac output increased but limb blood flow remained at prehypoxic levels in both groups. This indicated that aortic chemoreceptor input was not necessary for the increase in cardiac output during severe CO hypoxia, nor for the diversion of this increased flow to nonmuscle tissues. Limb O2 uptake decreased during CO hypoxia in the aortic-denervated group but remained at prehypoxic levels in the intact group. The lower resting values for limb blood flow in the aortic-denervated animals required a greater level of O2 extraction to maintain resting O2 uptake. When CO hypoxia was superimposed upon this compensation, an O2 supply limitation occurred because the limb failed to vasodilate even as maximal levels for O2 extraction were approached.     

The role of alpha-adrenergic receptors in carbon monoxide hypoxia

The importance of alpha-adrenergic receptors in the cardiac output and peripheral circulatory responses to carbon monoxide (CO) hypoxia was studied in anesthetized dogs. Phenoxybenzamine (3 mg/kg i.v.) was injected to block alpha-receptor activity and the data obtained were then compared with those from a previous study of CO hypoxia in unblocked animals. Values for cardiac output, hindlimb blood flow, vascular resistance, and oxygen uptake were obtained prior to and at 30 and 60 min of CO hypoxia which reduced arterial oxygen content by approximately 50%. alpha-Adrenergic blockade resulted in a lower (p less than 0.05) control value for cardiac output than observed in unblocked animals, but no differences were present between the two groups at 30 or 60 min of CO hypoxia. Similarly, limb blood flow was lower (p less than 0.05) during the control period in the alpha-blocked group but rose to the same level as that in the unblocked animals at 60 min of COH. No change in limb blood flow occurred during CO hypoxia in the unblocked group. These findings demonstrated that during CO hypoxia alpha-receptor mediated venoconstriction does not contribute to the cardiac output response and alpha-receptor mediated vasoconstriction probably does prevent a rise in hindlimb skeletal muscle blood flow.     

Muscle perfusion and oxygenation during local hyperoxia

Ventilation with O2 was previously shown to decrease whole-body and hindlimb muscle O2 uptake (VO2) in anesthetized dogs, particularly during anemia. To determine whether this was a purely local effect of hyperoxia (HiOx), we pump perfused isolated dog hindlimb muscles with autologous blood made hyperoxic (PO2 greater than 500 Torr) in a membrane oxygenator while the animals were ventilated with room air. Both constant-flow and constant-pressure protocols were used, and half the dogs were made anemic by exchange transfusion of dextran to hematocrit (Hct) approximately 15%. Thus there were four groups of n = 6 dogs each. A 30-min period of HiOx was preceded and followed by similar periods of perfusion with normoxic blood. In HiOx all four groups showed increased leg hindrance, increased leg venous PO2, and no significant changes in leg O2 inflow. Limb blood flow and VO2 decreased approximately 20% in HiOx with constant-pressure perfusion, regardless of Hct. In the constant-flow protocol, leg VO2 in HiOx was maintained by the anemic animals and actually increased in the normocythemic group. We conclude that HiOx directly affected vascular smooth muscle to cause flow restriction and maldistribution. Constant flow offset these effects, but the increased limb VO2 may have been a toxic effect. Anemia appeared to exaggerate the microcirculatory maldistribution caused by HiOx.     

O2 delivery to contracting muscle during hypoxic or CO hypoxia

The consequences of a decreased O2 supply to a contracting canine gastrocnemius muscle preparation were investigated during two forms of hypoxia: hypoxic hypoxia (HH) (n = 6) and CO hypoxia (COH) (n = 6). Muscle O2 uptake, blood flow, O2 extraction, and developed tension were measured at rest and at 1 twitch/s isometric contractions in normoxia and in hypoxia. No differences were observed between the two groups at rest. During contractions and hypoxia, however, O2 uptake decreased from the normoxic level in the COH group but not in the HH group. Blood flow increased in both groups during hypoxia, but more so in the COH group. O2 extraction increased further with hypoxia (P less than 0.05) during concentrations in the HH group but actually fell (P less than 0.05) in the COH group. The O2 uptake limitation during COH and contractions was associated with a lesser O2 extraction. The leftward shift in the oxyhemoglobin dissociation curve during COH may have impeded tissue O2 extraction. Other factors, however, such as decreased myoglobin function or perfusion heterogeneity must have contributed to the inability to utilize the O2 reserve more fully.     

Effect of lowered muscle temperature on the physiological response to exercise in men

The effect of low muscle temperature on the response to dynamic exercise was studied in six healthy men who performed 42 min of exercise on a cycle ergometer at an intensity of 70% of their maximal O2 uptake. Experiments were performed under control conditions, i.e. from rest at room temperature, and following 45 min standing with legs immersed in a water bath at 12 degrees C. The water bath reduced quadriceps muscle temperature (at 3 cm depth) from 36.4 (SD 0.5) degrees C to 30.5 (SD 1.7) degrees C. Following cooling, exercise heart rate was initially lower, the mean difference ranged from 13 (SD 4) beats.min-1 after 6 min of exercise, to 4 (SD 2) beats.min-1 after 24 min of exercise. Steady-state oxygen uptake was consistently higher (0.2 l.min-1). However, no difference could be discerned in the kinetics of oxygen uptake at the onset of exercise. During exercise after cooling a significantly higher peak value was found for the blood lactate concentration compared to that under control conditions. The peak values were both reached after approximately 9 min of exercise. After 42 min of exercise the blood lactate concentrations did not differ significantly, indicating a faster rate of removal during exercise after cooling. We interpreted these observations as reflecting a relatively higher level of muscle hypoxia at the onset of exercise as a consequence of a cold-induced vasoconstriction. The elevated steady-state oxygen uptake may in part have been accounted for by the energetic costs of removal of the extra lactate released into the blood consequent upon initial tissue hypoxia.     

Effects of exercise in normoxia and acute hypoxia on respiratory muscle metabolites

We determined changes in rat plantaris, diaphragm, and intercostal muscle metabolites following exercise of various intensities and durations, in normoxia and hypoxia (FIO2 = 0.12). Marked alveolar hyperventilation occurred during all exercise conditions, suggesting that respiratory muscle motor activity was high. [ATP] was maintained at rest levels in all muscles during all normoxic and hypoxic exercise bouts, but at the expense of creatine phosphate (CP) in plantaris muscle and diaphragm muscle following brief exercise at maximum O2 uptake (VO2max) in normoxia. In normoxic exercise plantaris [glycogen] fell as exercise exceeded 60% VO2max, and was reduced to less than 50% control during exhaustive endurance exercise (68% VO2max for 54 min and 84% for 38 min). Respiratory muscle [glycogen] was unchanged at VO2max as well as during either type of endurance exercise. Glucose 6-phosphate (G6P) rose consistently during heavy exercise in diaphragm but not in plantaris. With all types of exercise greater than 84% VO2max, lactate concentration ([LA]) in all three muscles rose to the same extent as arterial [LA], except at VO2max, where respiratory muscle [LA] rose to less than half that in arterial blood or plantaris. Exhaustive exercise in hypoxia caused marked hyperventilation and reduced arterial O2 content; glycogen fell in plantaris (20% of control) and in diaphragm (58%) and intercostals (44%). We conclude that respiratory muscle glycogen stores are spared during exhaustive exercise in the face of substantial glycogen utilization in plantaris, even under conditions of extreme hyperventilation and reduced O2 transport. This sparing effect is due primarily to G6P inhibition of glycogen phosphorylase in diaphragm muscle. The presence of elevated [LA] in the absence of glycogen utilization suggests that increased lactate uptake, rather than lactate production, occurred in the respiratory muscles during exhaustive exercise.     

Responses of innervated and denervated gut to whole-body hypoxia

As a significant user of O2 at rest (20% of whole body), the gut may be subject to more severe limitation of O2 supply during global hypoxia than more vital areas because of preferential redistribution of blood flow. Accordingly, its accumulation of O2 deficit during hypoxia and its excess O2 use during normoxic recovery might be altered by extrinsic neural activity. We measured blood flow and O2 uptake in whole body (WB) and gut segments while anesthetized dogs were ventilated with 9% O2-91% N2 for 30 min followed by 30-min normoxic recovery. In six dogs extrinsic innervation to the gut segment was left intact and it was severed in another six animals. O2 deficit and excess were the accumulated differences from the normoxic O2 uptake for both gut and WB corrected for O2 stores changes. The intact gut, although only 4% body wt, incurred 22% of WB O2 deficit but contributed only 8% to WB O2 excess. The imbalance (gut excess was only 44% of gut deficit) implied that O2 using functions were curtailed during hypoxia without obligating an energy stores deficit. Denervation did not alter these quantitative relationships. Blood flow responses to transition between normoxia and hypoxia were only transiently altered. Extrinsic innervation apparently plays no major role in gut responses to WB hypoxia.     

Circulatory responses to 2,4-dinitrophenol in dog limb during normoxia and hypoxia

We tested whether blood flow to skeletal muscle would increase in proportion to an increase in O2 uptake caused by 2,4-dinitrophenol (DNP). We further tested the metabolic control in the face of a central challenge, hypoxic hypoxia. Three injections of DNP were made at 30-min intervals into the arterial supply of the left hindlimb in anesthetized dogs. Similar experiments were done on a second group of dogs ventilated with 12% O2-88% N2 (DNP and hypoxia). A third group served as time controls. Limb O2 uptake increased in a linear fashion in the DNP group with each injection. The increase in limb O2 uptake fell off with the second and third injections in the DNP and hypoxia group and appeared to be limited by the hypoxia. Limb blood flow increased only with the last injection in that group and not at all in the DNP group. Limb vascular resistance decreased in both the experimental groups relative to the time-related changes in the control group. This became more marked as the O2 extraction ratio exceeded 0.5. Even in the absence of nerve stimulation and active muscle contractions, both distribution and resistance control vessels responded in a coordinated fashion to an increase in O2 uptake. Mild hypoxia enhanced these responses but also appeared to limit a fraction of O2 uptake that may not have been concerned with maintaining tissue energy levels.     

Peripheral vascular responses to hypoxic hypoxia after aortic denervation

We wished to see whether aortic chemoreceptors and other vagal afferent traffic played an essential role in the circulatory adjustments to hypoxic hypoxia. Aortic chemoreceptors were denervated (AD) in one group (n = 6) of anesthetized dogs, bilateral cervical vagotomy (V) was done on a second group (n = 6), and a third group (n = 6) was sham-operated to serve as a control. Venous outflow from the left hindlimb was isolated. After a 20-min control period of ventilation with room air, the animals were ventilated for 60 min with 9% of O2 in N2. Arterial, mixed venous, and hindlimb venous blood samples were taken every 20 min. The cardiac output response to hypoxic hypoxia was attenuated at 40 and 60 min in both the AD and V groups (p less than 0.05). Hindlimb blood flow increased equally in all three groups during hypoxia. The pressor response at the onset of hypoxia (20 min) was abolished in the AD and V groups, but mean arterial pressure fell to similar levels in all three groups by 60 min of hypoxia. We concluded that reflex aortic chemoreceptor stimulation during hypoxia augmented cardiac output mostly by effects on the venous side of the circulation but played no role in skeletal muscle vascular responses to hypoxic hypoxia.     

Plasma from conscious hypoxic rats stimulates leukocyte-endothelial interactions in normoxic cremaster venules.

Systemic hypoxia results in rapid increases in leukocyte-endothelial adherence (LEA) and emigration, vascular permeability, and mast cell activation in several microcirculations. Observations in cremaster muscle suggest that this response is initiated by a mediator released from a distant site (Dix R, Orth T, Allen JA, Wood JG, and Gonzalez NC. J Appl Physiol 95: 2495-2502, 2003). The present experiments in rat cremaster muscle tested the hypothesis that, if a circulating mediator triggers hypoxia-induced inflammation, then plasma from hypoxic rats should elicit LEA in normoxic cremaster venules. Plasma from conscious donor rats breathing 10% O2-90% N2 for 5 min was applied topically to the cremaster of normoxic anesthetized rats. In this and all other groups described below, the donor plasma had attained normoxic PO2 when applied to the cremaster. LEA (leukocytes/100-microm venule) increased from 2.7 +/- 0.8 to 12.3 +/- 2.4, and venular shear rate and arteriolar diameter decreased to 79 +/- 9% (P < 0.05, n = 6) and 77 +/- 5% of control (P < 0.05, n = 5), respectively, 10 min after application of plasma from hypoxic donors. The decrease in venular shear rate was exclusively due to a reduction of venular blood flow, secondary to the upstream arteriolar vasoconstriction. Plasma from normoxic donors had no effects. Plasma from blood equilibrated in vitro for 5 min with 5% CO2-95% N2 did not alter LEA or shear rate of normoxic cremasters, suggesting that the putative mediator does not originate in blood cells. The effects of plasma from hypoxic rats persisted when the donors were pretreated with the mast cell stabilizer cromolyn, which prevents hypoxia-induced LEA. This suggests that the effects of hypoxic plasma are not due to inflammatory mediators released by adherent leukocytes in the donor rat. There was a positive correlation between LEA and mast cell degranulation observed histologically. These results support the idea that systemic hypoxia produces the release of a substance transported by the circulation that initiates the microvascular inflammation.     

Limitations to vasodilatory capacity and .VO2 max in trained human skeletal muscle

To further explore the limitations to maximal O(2) consumption (.VO(2 max)) in exercise-trained skeletal muscle, six cyclists performed graded knee-extensor exercise to maximum work rate (WR(max)) in hypoxia (12% O(2)), hyperoxia (100% O(2)), and hyperoxia + femoral arterial infusion of adenosine (ADO) at 80% WR(max). Arterial and venous blood sampling and thermodilution blood flow measurements allowed the determination of muscle O(2) delivery and O(2) consumption. At WR(max), O(2) delivery rose progressively from hypoxia (1.0 +/- 0.04 l/min) to hyperoxia (1.20 +/- 0.09 l/min) and hyperoxia + ADO (1.33 +/- 0.05 l/min). Leg .VO(2 max) varied with O(2) availability (0.81 +/- 0.05 and 0.97 +/- 0.07 l/min in hypoxia and hyperoxia, respectively) but did not improve with ADO-mediated vasodilation (0.80 +/- 0.09 l/min in hyperoxia + ADO). Although a vasodilatory reserve in the maximally working quadriceps muscle group may have been evidenced by increased leg vascular conductance after ADO infusion beyond that observed in hyperoxia (increased blood flow but no change in blood pressure), we recognize the possibility that the ADO infusion may have provoked vasodilation in nonexercising tissue of this limb. Together, these findings imply that maximally exercising skeletal muscle may maintain some vasodilatory capacity, but the lack of improvement in leg .VO(2 max) with significantly increased O(2) delivery (hyperoxia + ADO), with a degree of uncertainty as to the site of this dilation, suggests an ADO-induced mismatch between O(2) consumption and blood flow in the exercising limb.     

Exercise training in normobaric hypoxia in endurance runners. I. Improvement in aerobic performance capacity.

This study investigates whether a 6-wk intermittent hypoxia training (IHT), designed to avoid reductions in training loads and intensities, improves the endurance performance capacity of competitive distance runners. Eighteen athletes were randomly assigned to train in normoxia [Nor group; n = 9; maximal oxygen uptake (VO2 max) = 61.5 +/- 1.1 ml x kg(-1) x min(-1)] or intermittently in hypoxia (Hyp group; n = 9; VO2 max = 64.2 +/- 1.2 ml x kg(-1) x min(-1)). Into their usual normoxic training schedule, athletes included two weekly high-intensity (second ventilatory threshold) and moderate-duration (24-40 min) training sessions, performed either in normoxia [inspired O2 fraction (FiO2) = 20.9%] or in normobaric hypoxia (FiO2) = 14.5%). Before and after training, all athletes realized 1) a normoxic and hypoxic incremental test to determine VO2 max and ventilatory thresholds (first and second ventilatory threshold), and 2) an all-out test at the pretraining minimal velocity eliciting VO2 max to determine their time to exhaustion (T(lim)) and the parameters of O2 uptake (VO2) kinetics. Only the Hyp group significantly improved VO2 max (+5% at both FiO2, P < 0.05), without changes in blood O2-carrying capacity. Moreover, T(lim) lengthened in the Hyp group only (+35%, P < 0.001), without significant modifications of VO2 kinetics. Despite similar training load, the Nor group displayed no such improvements, with unchanged VO2 max (+1%, nonsignificant), T(lim) (+10%, nonsignificant), and VO2 kinetics. In addition, T(lim) improvements in the Hyp group were not correlated with concomitant modifications of other parameters, including VO2 max or VO2 kinetics. The present IHT model, involving specific high-intensity and moderate-duration hypoxic sessions, may potentialize the metabolic stimuli of training in already trained athletes and elicit peripheral muscle adaptations, resulting in increased endurance performance capacity.     

Chronic hypoxia attenuates nitric oxide-dependent hemodynamic responses to acute hypoxia

Alterations in the nitric oxide (NO) pathway have been implicated in the pathogenesis of chronic hypoxia-induced pulmonary hypertension. Chronic hypoxia can either suppress the NO pathway, causing pulmonary hypertension, or increase NO release in order to counteract elevated pulmonary arterial pressure. We determined the effect of NO synthase inhibitor on hemodynamic responses to acute hypoxia (10% O(2)) in anesthetized rats following chronic exposure to hypobaric hypoxia (0.5 atm, air). In rats raised under normoxic conditions, acute hypoxia caused profound systemic hypotension and slight pulmonary hypertension without altering cardiac output. The total systemic vascular resistance (SVR) decreased by 41 +/- 5%, whereas the pulmonary vascular resistance (PVR) increased by 25 +/- 6% during acute hypoxia. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) attenuated systemic vasodilatation and enhanced pulmonary vasoconstriction. In rats with prior exposure to chronic hypobaric hypoxia, the baseline values of mean pulmonary and systemic arterial pressure were significantly higher than those in the normoxic group. Chronic hypoxia caused right ventricular hypertrophy, as evidenced by a greater weight ratio of the right ventricle to the left ventricle and the interventricular septum compared to the normoxic group (46 +/- 4 vs. 28 +/- 3%). In rats which were previously exposed to chronic hypoxia (half room air for 15 days), acute hypoxia reduced SVR by 14 +/- 6% and increased PVR by 17 +/- 4%. Pretreatment with L-NAME further inhibited the systemic vasodilatation effect of acute hypoxia, but did not enhance pulmonary vasoconstriction. Our results suggest that the release of NO counteracts pulmonary vasoconstriction but lowers systemic vasodilatation on exposure to acute hypoxia, and these responses are attenuated following adaptation to chronic hypoxia.     

Changes in HIF-1α protein, pyruvate dehydrogenase phosphorylation, and activity with exercise in acute and chronic hypoxia

Exercise under acute hypoxia elicits a large increase in blood lactate concentration ([La](b)) compared with normoxic exercise. However, several studies in humans show that with the transition to chronic hypoxia, exercise [La](b) returns to normoxic levels. Although extensively examined over the last decades, the muscle-specific mechanisms responsible for this phenomenon remain unknown. To assess the changes in skeletal muscle associated with a transition from acute to chronic hypoxia, CD-1 mice were exposed for 24 h (24H), 1 wk (1WH), or 4 wk (4WH) to hypobaric hypoxia (equivalent to 4,300 m), exercised under 12% O(2), and compared with normoxic mice (N) at 21% O(2). Since the enzyme pyruvate dehydrogenase (PDH) plays a major role in the metabolic fate of pyruvate (oxidation vs. lactate production), we assessed the changes in its activity and regulation. Here we report that when run under hypoxia, 24H mice exhibited the highest blood and intramuscular lactate of all groups, while the 1WH group approached N group values. Concomitantly, the 24H group exhibited the lowest PDH activity, associated with a higher phosphorylation (inactive) state of the Ser(232) residue of PDH, a site specific to PDH kinase-1 (PDK1). Furthermore, protein levels of PDK1 and its regulator, the hypoxia inducible factor-1α (HIF-1α), were both elevated in the 24H group compared with N and 1WH groups. Overall, our results point to a novel mechanism in muscle where the HIF-1α pathway is desensitized in the transition from acute to chronic hypoxia, leading to a reestablishment of PDH activity and a reduction in lactate production by the exercising muscles.