Exercise conditioning involves adaptations in the heart, peripheral circulation, and trained skeletal muscle that result in improved exercise capacity. Since the specific influence of /3-adrenergic stimulation on these various adaptations has not been clear, we studied the effect of 3,1-selective and nonselective ,B-adrenergic blockade on the exercise conditioning response of 24 healthy, sedentary men after an intensive 6 week aerobic training program. Subjects randomly assigned to receive placebo, 50 mg bid atenolol, or 40 mg bid nadolol were tested before and after training both on and off drugs. Comparable reductions in maximal exercise heart rate occurred with atenolol and nadolol, indicating equivalent /I-adrenergic blockade. Vascular 132-adrenergic selectivity was maintained with atenolol as determined by calf plethysmography during intravenous infusion of epinephrine. All subjects trained at greater than 85% of maximal heart rate and 80% of 'V02max determined on drug. \02max increased after training 16 + 2% (p < .05) in the placebo group and 6 2% (p < .05) in the atenolol group, while there was no change in the nadolol group. At maximal exercise, subjects receiving placebo increased their exercise duration and oxygen pulse significantly greater than those receiving atenolol or nadolol. During submaximal exercise there were reductions in heart rate and heart rate-blood pressure product in all three groups, but these reductions were greater with placebo than with either drug. Leg blood flow during submaximal exercise decreased 24 + 2% (p < .01) in the placebo group but was unchanged in the atenolol and nadolol groups. Lactates in arterialized blood during submaximal exercise were reduced equivalently in all three groups after training. Capillary/fiber ratio in vastus lateralis muscle biopsy specimens increased 31 ± 6% in the placebo group and 21 + 6% in the atenolol group (both p < .05) and tended to increase in the nadolol group. Succinic dehydrogenase and cytochrome oxidase activities in muscle biopsy specimens increased equivalently in all three groups after training. Thus, although exercise conditioning developed to some extent in both drug groups, especially during submaximal exercise, these changes were less marked than that with placebo. While /3-adrenergic blockade attenuated the exercise conditioning response, skeletal muscle adaptations including increases in oxidative enzymes, capillary supply, and decreases in exercise blood lactates were unaffected. Cardiac and peripheral vascular adaptations do appear to be affected by ,3-adrenergic blockade during training. Cardioselectivity does not seem to be important in modifying these effects. Circulation 74, No. 4, 664-674, 1986. AEROBIC EXERCISE TRAINING results in improved function of the heart, peripheral circulation, and skeletal muscle that results in enhanced physical work capacity. [1][2][3][4][5][6] The relative importance of each adaptation and the factors that separately or together in-

Very little is known about the influence of polycythemia on oxygen transport during exercise. We studied chronically instrumented dogs trained to run on a treadmill before and after their hematocrit had been increased by isovolemic exchange transfusion with packed red blood cells. With normovolemic polycythemia, cardiac output fell in a linear fashion as hematocrit was increased to 65%, but these changes were balanced by an increasing oxygen content resulting in constant systemic oxygen transport. Oxygen consumption was unchanged both at rest and during exercise after induction of polycythemia. To investigate the effect of polycythemia on oxygen transport further, we measured both mixed venous Po2 and lactate. Mixed venous Po2 increased and lactate remained unchanged both at rest and in exercising polycythemic dogs. Thus, we conclude that, in conscious animals, systemic oxygen transport is well preserved with increasing hematocrit to at least 65%.

Previous studies have concluded that polycythemia decreases oxygen delivery primarily because of a large fall in cardiac output associated with a rise in systemic vascular resistance that has been attributed to increased blood viscosity. However, because other studies have shown that polycythemia may not reduce oxygen delivery, an alternative hypothesis is that cardiac output falls in response to a rising oxygen content, thereby maintaining oxygen delivery constant. To determine whether oxygen content participates in the regulation of cardiac output during polycythemia, we studied eight chronically instrumented dogs trained to exercise on a treadmill. The dogs underwent exchange transfusion with packed red blood cells containing methemoglobin, which caused an increase in hematocrit from 35 +/- 1 to 50 +/- 1% and in viscosity, with little change in oxygen content. The expected fall in exercise cardiac output failed to occur after exchange transfusion with red blood cells containing methemoglobin (7.5 +/- 4 vs. 6.8 +/- 0.5 l/min; P = not significant), and there was no rise in systemic vascular resistance. Methylene blue was then administered intravenously to facilitate conversion of methemoglobin to oxyhemoglobin, which increased oxygen content (12.8 +/- 0.9 vs. 18.4 +/- 0.9 vol%; P < 0.01) with no change in hematocrit or viscosity. Resting cardiac output did not change significantly, but there was a significant decrease in exercise output (6.8 +/- 0.5 vs. 5.8 +/- 0.4 l/min; P < 0.05). Thus we conclude that the fall in cardiac output seen in acute polycythemia results in part from the regulation of oxygen delivery and is not due solely to increased blood viscosity.

Oxygen radical-induced myocardial lipid peroxidation may cause injury during regional ischemia and reperfusion. However, in vivo detection of lipid peroxidation is difficult. Since conjugated dienes are lipid peroxidation products of unsaturated fatty acids, we evaluated the potential value of detection of these double-bonded fatty acids as a marker of oxygen radical injury. In seven untreated and five superoxide dismutase-treated anesthetized dogs exposed to 90 min of coronary occlusion and subsequent reperfusion, coronary sinus plasma draining the ischemic and reperfused region was assayed for dienes. Lipids were extracted and diene optical density measured at 233 nm wavelength. Superoxide dismutase (5 mg/kg, total dose) was infused into the left atrium during ischemia and the first 30 min of reperfusion. Coronary sinus diene optical density increased in untreated animals at 5 and 10 min of reperfusion (reperfusion optical density (x +/- SEM): 5 min = 1.49 +/- 0.20 absorbance units, 10 min = 1.36 +/- 0.06; both p less than 0.05 vs preocclusion optical density = 1.10 +/- 0.05 and 25 min reperfusion = 1.20 +/- 0.07). No increase in diene optical density occurred in superoxide dismutase-treated dogs. Myocardial lipid peroxidation products, as conjugated dienes, increased in coronary sinus plasma during early reperfusion and this increase was prevented by superoxide dismutase infusion.

Exercise training has been shown to decrease plasma norepinephrine (NE) and epinephrine (EPI) levels during absolute levels of submaximal exercise, which may reflect alterations in sympathetic tone as a result of training. To determine if beta-adrenergic blockade altered these changes in the plasma concentration of catecholamines with exercise conditioning, we studied the effects of beta-adrenergic blockade on NE and EPI at rest and during exercise in 24 healthy, male subjects after a 6-wk exercise training program. The subjects were randomized to placebo (P), atenolol 50 mg twice daily (A), and nadolol 40 mg twice daily (N). There were no changes in resting NE and EPI compared with pretraining values in any subject group. During the same absolute level of submaximal exercise NE decreased in P and A but was unchanged in N, whereas EPI decreased only in P. At maximal exercise all three groups developed significant increases in NE after training that paralleled increases in systolic blood pressure. EPI at maximal exercise increased after training with N but was unchanged with P or A. These training-induced changes in plasma catecholamine levels were masked or blunted when the A and N groups were studied while still on medication after training. Thus beta-adrenergic blockade has important effects on adaptations of the sympathetic nervous system to training, especially during submaximal exercise.