CLINICAL INVESTIGATION Effects of selective and nonselective ,3-adrenergic blockade on mechanisms of exercise conditioning

Exercise conditioning involves adaptations in the heart, peripheral circulation, and trained skeletal muscle that result in improved exercise capacity. Since the specific influence of /3adrenergic stimulation on these various adaptations has not been clear, we studied the effect of 3,1selective 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 ,3adrenergic 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. 1-6 The relative importance of each adaptation and the factors that separately or together inFrom the Divisions of Cardiology and General Internal Medicine of the Department of Medicine and the Department of Neurology. University of Colorado Health Sciences Center, Denver. Supported by a Research and Training Center Grant (GOOBOUJ049) from the National Institute for Handicapped Research, Department of Education, Washington, DC. Dr. Wolfel was a recipient of National Research Service Award HL 07459 04 from the NHLBI. Dr. Hiatt is a Henry J. Kaiser Family Foundation Scholar in General Internal Medicine. Address for correspondence: Eugene E. Wolfel, M.D., Division of Cardiology, Box 4000, Denver General Hospital, 777 Bannock St., Denver, CO 80204-4507. Received Feb. 7, 1986; revision accepted July 3, 1986. 664 fluence these adaptations have been incompletely understood. The role of the adrenergic nervous system in intense aerobic exercise is of considerable interest, since sympathetic stimulation affects heart rate, myocardial contractility, vascular tone, and substrate utilization in skeletal and cardiac muscle and other tissues.7 There is also evidence that exercise conditioning may be substantially influenced by sympathetic stimulation. Regular infusions of sympathetic agonists in animals have been reported to induce conditioning effects similar to those that occur with exercise.""In rats trained while receiving propranolol, a nonselective /-adrenergic blocker, conditioning was altered. 12 Similar studies of healthy, previously sedentary, young men in our laboCIRCULATION by gest on A ril 0, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATURAL HISTORY-EXERCISE PHYSIOLOGY ratory have shown that propranolol attenuates exercise conditioning.'3' 14 However, other investigators have not observed effects of /3-blockade on exercise conditioning in healthy men.'--8 These conflicting results could represent differences in study design but may also reflect a differential effect of 3-adrenergic blockade on the various mechanisms involved in exercise conditioning. Since high heart rates and myocardial oxygen consumption during training appear to be requisites for optimal conditioning, 19 the attenuation of exercise con~ ditioning by propranololl3' 14 could be caused in part by direct /3-cardiac receptor blockade that inhibited cardiac adaptations. Since nonselective /3-adrenergic receptor blockade also may alter skeletal muscle metabolism and peripheral vascular function, we considered the possibility that extracardiac adaptations could also be impaired. If so, cardioselective /3-adrenergic blockers would be expected to be less detrimental during exercise training, since 032-adrenergic receptors, which are modulators of peripheral vascular reactivity and carbohydrate metabolism in skeletal muscle,20' 21 would be minimally affected. In prior studies, lactate metabolism during exercise was influenced more by nonselective than by /,-selective adrenergic blockade,22 whereas hemodynamic and antilipolytic effects were similar with selective and nonselective ,8-adrenergic blockade.20' 23, 24 We compared specific training-induced adaptations of skeletal muscle and the peripheral vasculature in healthy young men randomly assigned to groups with intact sympathetic control, cardioselective ,81-adrenergic blockade, or nonselective /3-adrenergic blockade. We hypothesized that if skeletal muscle metabolic and vascular adaptations were inhibited by loss of /8-sympathetic stimulation, selective /,1-adrenergic receptor blockade would attenuate exercise conditioning less than nonselective /-adrenergic blockade.