Different preconditioning stimuli invoke disparate electromechanical and energetic responses to global ischemia in rat hearts.

One hypothesized mechanism of the cardioprotection provided by preconditioning is decreased utilization of ATP during ischemia. Although ATP levels in preconditioned heart during ischemia have been previously studied, contractile activity during ischemia has not been investigated. Contractile activity accounts for significant ATP consumption during ischemia. We hypothesized that preconditioning stimuli may conserve energy during the ischemic period by decreasing myocardial contractile energy expenditure prior to asystolic cardiac arrest. We studied three preconditioning stimuli: (i) four cycles of 5-min periods of ischemia (4 x 5' CI), (ii) 2 min of alpha 1-adrenergic stimulation (phenylephrine; PE), and (iii) 2 min of P1-purinergic stimulation (adenosine). The effects of these stimuli on myocardial ATP, ventricular contractility, and the time to cessation of electromechanical function (asystole) during the sustained ischemic period were then examined. Preconditioning stimuli (4 x 5' CI, phenylephrine, and adenosine) improved postischemic functional recovery compared with nonpreconditioned controls. Myocardial ATP contents at the end of 20 min of global ischemia were higher for adenosine-treated (9.0 +/- 1.5 mumol/g dry weight; p < 0.05) and PE-treated (9.9 +/- 1.9 mumol/g dryweight; p < 0.05) hearts than for controls (6.6 +/- 1.2 mumol/g dry weight). The CI hearts began with lower myocardial ATP levels (9.9 +/- 1.2 mumol/g dry weight; p < 0.05) than other groups prior to the sustained ischemic period (control 13.4 +/- 1.0 mumol/g dry weight). As a result of a lower rate of ATP depletion, ATP levels in the CI group were similar to the untreated control after 20 min of sustained ischemia (5.5 +/- 0.7 mumol/g dry weight). Preconditioning with 4 x 5' CI or adenosine (but not PE) led to earlier ventricular arrest. Only adenosine-treated hearts demonstrated a more rapid decline in ventricular contractility during sustained ischemia than did nonpreconditioned control hearts. We conclude that while the final recovery of ventricular contractility after asystolic arrest and reperfusion is improved by preconditioning with different stimuli (4 x 5' CI, adenosine, or PE), each stimulus conferred a characteristic electromechanical and energy conservation strategy during sustained ischemia. Adenosine conserved myocardial ATP content and reduced total cardiac work (developed pressure and heart beats). CI conserved myocardial ATP and minimized the number of ischemic cardiac beats. PE preserved myocardial ATP during ischemia without changing contractile behavior. Thus, energy conservation strategies during ischemia could contribute to the protection afforded by preconditioning stimuli, but the mechanisms appear to differ among stimuli.

Serum potassium concentration as a predictor of resuscitation outcome in hypothermic cardiac arrest.

The purpose of this study was to determine whether serum potassium concentration (SK) can predict resuscitation outcome in a canine model of severe hypothermic cardiac arrest. Fifteen adult mongrel anesthetized dogs were immersed to the neck in a 4 degrees C water bath and ventilated with room air, with ventilation halved at 45 min and stopped at 90 min. After cardiac arrest, 14 of the dogs were kept in the water bath for periods of 2-7 h, and another was held in arrest for 13 h. Following 10 min of closed chest cardiopulmonary resuscitation (CPR) (simulating a short transport time to a hospital), animals were placed on cardiopulmonary bypass and rapidly rewarmed. With appearance of ventricular fibrillation, animals were defibrillated up to three times. Standard advanced cardiac life support was initiated at a core temperature (Tc) of 30 degrees C. Eight of the 15 dogs had return of spontaneous circulation (ROSC), at Tc ranging from 30.4 to 36.5 degrees C. The eight dogs with ROSC did not differ from the seven without ROSC in time to arrest (128 +/- 48 versus 128 +/- 23 min) (mean +/- SD) or Tc at arrest (18.1 +/- 2.2 versus 17.9 +/- 3.1 degrees C), but had higher Tc at the end of the arrest period (9.7 +/- 3.0 versus 5.2 +/- 2.0 degrees C), reflecting a shorter arrest period in the dogs with ROSC (225 +/- 95 versus 420 +/- 193 min). SK (mEq liter(-1)) did not differ between dogs with and without ROSC at baseline (3.5 +/- 0.4 versus 3.7 +/- 0.4) or at arrest (3.4 +/- 0.7 versus 4.3 +/- 2.2), but there was a trend toward higher SK at the end of arrest in the group without ROSC (4.6 +/- 1.5 versus 9.4 +/- 6.3; range 3.2-7.8 versus 3.5-21.4; p = .053). SK was similar after 10 min of CPR in the groups with and without ROSC (6.6 +/- 2.9 versus 9.0 +/- 2.4; range 2.5-11.1 versus 4.5-11.0; p = .107). SK after 10 min of CPR was higher in some animals with ROSC (9.6 and 11.1) than in others which did not have ROSC (4.5 and 7.9). We conclude that very high SK following prolonged hypothermic cardiac arrest may be suggestive of an inability to resuscitate. However, SK after both prolonged hypothermic cardiac arrest and a brief period of CPR is not a good predictor of resuscitation using cardiopulmonary bypass rewarming in an animal model.

Muscle accounts for glucose disposal but not blood lactate appearance during exercise after acclimatization to 4,300 m.

We hypothesized that the increased blood glucose disappearance (Rd) observed during exercise and after acclimatization to high altitude (4,300 m) could be attributed to net glucose uptake (G) by the legs and that the increased arterial lactate concentration and rate of appearance (Ra) on arrival at altitude and subsequent decrease with acclimatization were caused by changes in net muscle lactate release (L). To evaluate these hypotheses, seven healthy males [23 +/- 2 (SE) yr, 72.2 +/- 1.6 kg], on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6-D2]glucose (Brooks et al., J. Appl. Physiol. 70: 919-927, 1991) and [3-13C]lactate (Brooks et al., J. Appl. Physiol. 71:333-341, 1991) and rested for a minimum of 90 min, followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 uptake (65 +/- 2% of both acute altitude and acclimatization peak O2 uptake). Glucose and lactate arteriovenous differences across the legs and arms and leg blood flow were measured. Leg G increased during exercise compared with rest, at altitude compared with sea level, and after acclimatization. Leg G accounted for 27-36% of Rd at rest and essentially all glucose Rd during exercise. A shunting of the blood glucose flux to active muscle during exercise at altitude is indicated. With acute altitude exposure, at 5 min of exercise L was elevated compared with sea level or after acclimatization, but from 15 to 45 min of exercise the pattern and magnitude of L from the legs varied and followed neither the pattern nor the magnitude of responses in arterial lactate concentration or Ra. Leg L accounted for 6-65% of lactate Ra at rest and 17-63% during exercise, but the percent Ra from L was not affected by altitude. Tracer-measured lactate extraction by legs accounted for 10-25% of lactate Rd at rest and 31-83% during exercise. Arms released lactate under all conditions except during exercise with acute exposure to high altitude, when the arms consumed lactate. Both active and inactive muscle beds demonstrated simultaneous lactate extraction and release. We conclude that active skeletal muscle is the predominant site of glucose disposal during exercise and at high altitude but not the sole source of blood lactate during exercise at sea level or high altitude.

Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure.

Exercise at high altitude is a stress that activates the sympathoadrenal systems, which could affect responses to acute altitude exposure and promote adaptations during chronic altitude exposure. However, catecholamine levels are not clearly described over time at high altitude. In seven male volunteers (23 yr, 72 kg), resting arterial norepinephrine concentrations (ng/ml) on arrival at Pikes Peak (0.338 +/- 0.041) decreased compared with sea-level values (0.525 +/- 0.034) but increased to above sea-level values after 21 days at 4,300 m (0.798 +/- 0.052). Furthermore, during 45 min of constant submaximal exercise, values were similar at sea level (1.670 +/- 0.221) and on acute exposure to 4,300 m (2.123 +/- 0.086) but increased after 21 days of chronic exposure (2.693 +/- 0.216). By contrast, resting arterial epinephrine values (ng/ml) during acute and chronic exposure (0.708 +/- 0.033 vs. 0.448 +/- 0.026) both exceeded those of sea level (0.356 +/- 0.020). During exercise values on arrival were greater than at sea level (0.921 +/- 0.024 vs. 0.397 +/- 0.035) but fell to 0.612 +/- 0.025 ng/ml after 21 days. Exercise norepinephrine levels were related to systemic vascular resistance measurements (r = 0.93), whereas epinephrine levels were related to circulating lactate (r = 0.95). We conclude that during exercise at altitude there is a dissociation between norepinephrine, an indicator of sympathetic neural activity, and epinephrine, an indicator of adrenal medullary response. These actions may account for different metabolic and physiological responses to acute vs. chronic altitude exposure.

Internal carotid flow velocity with exercise before and after acclimatization to 4,300 m.

Cerebral blood flow and O2 delivery during exercise are important for well-being at altitude but have not been studied. We expected flow to increase on arrival at altitude and then to fall as O2 saturation and hemoglobin increased, thereby maintaining cerebral O2 delivery. We used Doppler ultrasound to measure internal carotid artery flow velocity at sea level and on Pikes Peak, CO (4,300 m). In an initial study (1987, n = 7 men) done to determine the effect of brief (5-min) exercises of increasing intensity, we found at sea level that velocity [24.8 +/- 1.4 (SE) cm/s rest] increased by 15 +/- 7, 30 +/- 6, and 22 +/- 8% for cycle exercises at 33, 71, and 96% of maximal O2 uptake, respectively. During acute hypobaric hypoxia in a decompression chamber (inspired PO2 = 83 Torr), velocity (23.2 +/- 1.4 cm/s rest) increased by 33 +/- 6, 20 +/- 5, and 17 +/- 9% for exercises at 45, 72, and 98% of maximal O2 uptake, respectively. After 18 days on Pikes Peak (inspired PO2 = 87 Torr), velocity (26.6 +/- 1.5 cm/s rest) did not increase with exercise. A subsequent study (1988, n = 7 men) of the effect of prolonged exercise (45 min at approximately 100 W) found at sea level that velocity (24.8 +/- 1.7 cm/s rest) increased by 22 +/- 6, 13 +/- 5, 17 +/- 4, and 12 +/- 3% at 5, 15, 30, and 45 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen transport during steady-state submaximal exercise in chronic hypoxia.

Arterial O2 delivery during short-term submaximal exercise falls on arrival at high altitude but thereafter remains constant. As arterial O2 content increases with acclimatization, blood flow falls. We evaluated several factors that could influence O2 delivery during more prolonged submaximal exercise after acclimatization at 4,300 m. Seven men (23 +/- 2 yr) performed 45 min of steady-state submaximal exercise at sea level (barometric pressure 751 Torr), on acute ascent to 4,300 m (barometric pressure 463 Torr), and after 21 days of residence at altitude. The O2 uptake (VO2) was constant during exercise, 51 +/- 1% of maximal VO2 at sea level, and 65 +/- 2% VO2 at 4,300 m. After acclimatization, exercise cardiac output decreased 25 +/- 3% compared with arrival and leg blood flow decreased 18 +/- 3% (P less than 0.05), with no change in the percentage of cardiac output to the leg. Hemoglobin concentration and arterial O2 saturation increased, but total body and leg O2 delivery remained unchanged. After acclimatization, a reduction in plasma volume was offset by an increase in erythrocyte volume, and total blood volume did not change. Mean systemic arterial pressure, systemic vascular resistance, and leg vascular resistance were all greater after acclimatization (P less than 0.05). Mean plasma norepinephrine levels also increased during exercise in a parallel fashion with increased vascular resistance. Thus we conclude that both total body and leg O2 delivery decrease after arrival at 4,300 m and remain unchanged with acclimatization as a result of a parallel fall in both cardiac output and leg blood flow and an increase in arterial O2 content.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased exercise muscle lactate release after high altitude acclimatization.

Blood lactate concentration during exercise decreases after acclimatization to high altitude, but it is not clear whether there is decreased lactate release from the exercising muscle or if other mechanisms are involved. We measured iliac venous and femoral arterial lactate concentrations and iliac venous blood flow during cycle exercise before and after acclimatization to 4,300 m. During hypoxia, at a given O2 consumption the venous and arterial lactate concentrations, the venous and arterial concentration differences, and the net lactate release were lower after acclimatization than during acute altitude exposure. While breathing O2-enriched air after acclimatization at a given O2 consumption the venous and arterial lactate concentrations and the venous and arterial concentration differences were significantly lower, and the net lactate release tended to be lower than while breathing ambient air at sea level before acclimatization. We conclude that the lower lactate concentration in venous and arterial blood during exercise after altitude acclimatization reflected less net release of lactate by the exercising muscles, and that this likely resulted from the acclimatization process itself rather than the hypoxia per se.

Increased exercise SaO2 independent of ventilatory acclimatization at 4,300 m.

Arterial O2 saturation (Sao2) decreases in hypoxia in the transition from rest to moderate exercise, but it is unknown whether other several weeks at high altitude SaO2 in submaximal exercise follows the same time course and pattern as that of ventilatory acclimatization in resting subjects. Ventilatory acclimatization is essentially complete after approximately 1 wk at 4,300 m, such that improvement in submaximal exercise SaO2 would then require other mechanisms. On days 2, 8, and 22 on Pikes Peak (4,300 m), 6 male subjects performed prolonged steady-state cycle exercise at 79% maximal O2 uptake (VO2 max). Resting SaO2 rose from day 1 (78.4 +/- 1.6%) to day 8 (87.5 +/- 1.4%) and then did not increase further by day 20 (86.4 +/- 0.6%). During exercise, SaO2 values (mean of 5-, 15-, and 30-min measurements) were 72.7% (day 2), 78.6% (day 8), and 82.3% (day 22), meaning that all of the increase in resting SaO2 occurred from day 1 to day 8, but exercise SaO2 increased from day 2 to day 8 (5.9%) and then increased further from day 8 to day 22 (3.7%). On day 22, the exercise SaO2 was higher than on day 8 despite an unchanged ventilation and O2 consumption. The increased exercise SaO2 was accompanied by decreased CO2 production. The mechanisms responsible for the increased exercise SaO2 require further investigation.

Combined effects of female hormones and metabolic rate on ventilatory drives in women.

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.

Oxygen transport to exercising leg in chronic hypoxia.

Residence at high altitude could be accompanied by adaptations that alter the mechanisms of O2 delivery to exercising muscle. Seven sea level resident males, aged 22 +/- 1 yr, performed moderate to near-maximal steady-state cycle exercise at sea level in normoxia [inspired PO2 (PIO2) 150 Torr] and acute hypobaric hypoxia (barometric pressure, 445 Torr; PIO2, 83 Torr), and after 18 days' residence on Pikes Peak (4,300 m) while breathing ambient air (PIO2, 86 Torr) and air similar to that at sea level (35% O2, PIO2, 144 Torr). In both hypoxia and normoxia, after acclimatization the femoral arterial-iliac venous O2 content difference, hemoglobin concentration, and arterial O2 content, were higher than before acclimatization, but the venous PO2 (PVO2) was unchanged. Thermodilution leg blood flow was lower but calculated arterial O2 delivery and leg VO2 similar in hypoxia after vs. before acclimatization. Mean arterial pressure (MAP) and total peripheral resistance in hypoxia were greater after, than before, acclimatization. We concluded that acclimatization did not increase O2 delivery but rather maintained delivery via increased arterial oxygenation and decreased leg blood flow. The maintenance of PVO2 and the higher MAP after acclimatization suggested matching of O2 delivery to tissue O2 demands, with vasoconstriction possibly contributing to the decreased flow.

Breathing pattern in hypoxic exposures of varying duration.

The relative contributions of breathing frequency and tidal volume to the increase in ventilation during acute or prolonged exposure to hypoxia is uncertain. We examined the changes in breathing pattern during hypoxic exposures lasting minutes, hours, and days using data from previous studies. Increased tidal volume accounted for the increased ventilation during 7-10 and 30 min of isocapnic and poikilocapnic (no CO2 added) hypoxic exposures as well as during 7 h of poikilocapnic hypobaric hypoxia (4,800 m). Tidal volume was also a greater overall contributor than frequency to increased ventilation in sea-level residents during 3 days of isocapnic hypobaric hypoxia (4,100-4,600 m) and in Denver (1,600 m) residents during 5 days on Pikes Peak (4,300 m). In sea-level residents during 3 days of poikilocapnic hypobaric hypoxia (3,600-4,300 m) and during 7-8 days on Pikes Peak, increased frequency accounted for the rise in ventilation. Tidal volume thus contributed more than frequency to increasing ventilation during brief hypoxia, whereas the contribution of frequency was increased in prolonged hypoxia involving a 4,300-m altitude ascent and hypocapnia.

Ventilatory and treadmill endurance during acute semistarvation.

Little is known about respiratory muscle function in acute undernutrition, although an inadequate caloric intake is common in numerous disease states. Twelve young-adult, healthy female volunteers performed two familiarization experiments and were then studied after 7 days of consuming 40% of normal daily caloric intake as well as after 1 wk of normal caloric intake. In each experiment subjects performed tests of resting pulmonary function, inspiratory muscle strength, and ventilatory endurance, the last of which involved two 60-s and two 6-min isocapnic maximum voluntary ventilation maneuvers. Subjects then walked to exhaustion in 8-20 min on a treadmill. The caloric restriction did not affect performance of any breathing test but did lower endurance time in severe treadmill exercise (P less than 0.05). Basal metabolic rate was lowered, resting blood levels of free fatty acids and beta-hydroxybutyrate elevated, and glucose lowered following the caloric restriction (P less than 0.05). Blood lactate levels were lower during and after exercise following caloric restriction (P less than 0.05). We conclude that ventilatory muscle strength and endurance are fully preserved in caloric restriction severe enough to cause mild ketoacidosis and hypoglycemia, lowered basal metabolic rate, and decreased endurance in severe treadmill exercise.

Stress hormonal response to exercise after sleep loss.

While prolonged loss of sleep is unpleasant and demanding, it remains unclear if it blunts or enhances the physiological stress imposed by subsequent exercise. To investigate this, we deprived eight subjects of sleep prior to exercise to see if this altered the stress hormonal response to that exercise. In a first series of experiments, two fragmented nights of sleep preceded 30 min of heavy treadmill walking exercise. While sleep loss disturbed mood before and during exercise (p less than 0.05), it left stress hormonal levels (cortisol and beta-endorphin) in blood identical to control. In a second series, subjects performed light treadmill walking exercise for 3 h after 36 sleepless hours. As before, sleep deprivation disturbed mood before and throughout exercise (p less than 0.05), but failed to change blood levels of stress hormones. In both series, sleeplessness left heart rate, oxygen uptake, minute ventilation, and body core temperature unchanged in exercise. We conclude that sleep loss provokes psychological changes during subsequent exercise without measurably altering the stress hormonal response to that exercise.

Maximal ventilation after exhausting exercise.

It remains unclear whether the hyperpnea of exercise severely stresses the ventilatory musculature. We hypothesized that the ability to ventilate maximally is decreased during and immediately following exhausting exercise. Subjects performed isocapnic maximal voluntary ventilations (60-s MVV) before, during the final minute, and after exhausting treadmill exercise lasting either 3-10 min or 60 min. Severe exercise lasting 3-10 min failed to change the 60-s MVV. In contrast, during the final minute and 5 and 10 min after 60 min of exhausting exercise, eight non-runners showed significantly lower (P less than 0.01) 60-s MVV values in comparison to control values. Eight runners had a lower (P less than 0.05) 60-s MVV 10 min post-exercise as compared with control and exercise values. Our data suggest that the capacity to ventilate maximally declines only in long-term exhausting exercise and that this decrement in most pronounced in non-runners.

Skeletal muscle capillarity during recovery from chronic hypoxic exposure.

Young male Sprague-Dawley rats were randomly assigned to one of three groups (Chronically Hypoxic, N = 15; Age-Control, N = 15; Weight-Control, N = 15) and studied immediately following a 36-day exposure at a simulated altitude of 5846m or after recovery periods of one, three or seven days. Following preincubation at pH 3.8, cross-sections of soleus muscle were stained by the calcium ATPase method and analyzed for six indices of skeletal muscle capillarity: capillary density (CD), fiber density, number of capillaries around each fiber (CAF), Capillary/fiber ratio (C:F), fiber cross-sectional area (FCSA), and fiber diameter. No differences in skeletal muscle capillarity were observed in chronically hypoxic rats at the termination of exposure or during the seven day recovery period. The Chronically Hypoxics differed significantly (p less than or equal to .05) from both control groups in three different measures of physiologic stress, but showed a definite trend toward recovery in the post-exposure period. This recovery was most apparent in body weight comparisons. The Chronically Hypoxics weighed less than the Age-Controls immediately following the exposure period but gained rapidly during the first three days post-exposure. These rapid body weight increases in rats recovering from chronic exposure to hypoxia suggest that age-controls should not be excluded in favor of weight-controls in similar studies.

A Developmental Explanation For Children's Motor behavior.

Two experiments were conducted to test the application of Pascual-Leone's (1970) neo-Piagetian theory for explaining children's acquisition of skill in a curvilinear positioning task. Two groups of children (late pre-operational 6 yr olds and early concrete 8 yr olds) were identified and from each group 10 low M-processors and 10 high M-processors were selected (total n=40) through use of the Children's Embedded Figures Test. The 6 yr olds were administered 2-and 3-scheme curvilinear positioning tasks while the 8 yr olds performed 3-and 4-scheme tasks. The difference between the two experiments was the nature of the positioning tasks, i.e., one task allowed visual processing of information, while the other did not. Both experiments supported the neo-Piagetian predictions of structural mental space as explaining the developmental nature of motor skill acquisition, and functional mental space as explaining individual differences within stages in children's performance.