ores.s11/1/2306-088853.000 NEDICNE AND SCIENCE IN SPORTS AND EXEROSE Copy © 190 by te Amrean Calgoo Spars Meche v.23, No.6 PanesinUSA Effect of beta-blockers on exercise physiology: implications for exercise training NEIL F. GORDON and JOHN J. DUNCAN Institute for Aerobics Research, Dallas, TX 75230 ABSTRACT GORDON, N. F. and J. J. DUNCAN. Effect of beta-blockers on exercise physiology: implications for exercise training. Med. Sci Sports Exerc, Vol. 23, No. 6, pp. 668-676, 1991. We conducted a series of studies aimed at investigating the effect of beta-blockers on ‘exercise physiology. On the bass ofthese and other existing studies, it is possible to draw the following conclusions and to make the following tentative recommendations for patients engaged in exercise training who receive beta-blocker therapy: i) CAD patients treated with beta-blockers are capable of deriving the expected enhancement of cardiorespiratory fitness during training, irespective ofthe type of drug used; i) beta, selective blockers are preferable to nonselective agents for hypertensive patients engaged in exercise training: ii) because beta-slective blockers impair exercise tolerance in some hypertensive patients, physicians should look out for this adverse reaction and, if present, consider alternative antihypertensive therapy: iv) intrinsic sympathomimetic activity confers no advantage during exercise training; v) exercise intensity prescription for patients receiv= ing beta-blockers should bein accordance with traditional guidelines and based on results of individualized exercise testing performed on ‘medication; vi) exercise training is desirable during beta-blocker therapy in that it appears to offset adverse alterations in lipoprotein ‘metabolism; and vii) nonselective beta-blockers may increase predis- position to exertional hyperthermia, and patients must therefore be encouraged to adhere strictly to accepted guidelines for heat injury prevention, EXERCISE, BETA-BLOCKADE, HYPERTENSION, CORONARY ARTERY DISEASE The discovery of beta-adrenoceptor antagonist drugs (beta-blockers) by Black (6) at Imperial Chemical In- dustries in the United Kingdom was a rational phar- macologic extension of Ahiquist’s theory that adrener- gic receptors consist of alpha and beta subgroups, The subsequent introduction in 1965 of propranolol, the first clinically useful beta-blocker, undoubtedly consti tuted one of this century's major advances in cardio- vascular therapeutics. Although originally selected for development as drugs primarily for the treatment of angina pectoris, intensive studies have now confirmed the benefits of beta-blockers not only for this condition, but also for hypertension, arrhythmia, myocardial farction, and a multitude of other cardiac and noncar- diac disorders. Smid for pbleaion December, 1990 ‘Accented for pbaton Feta, 191 In recent years the clinical application of beta-block- ers has been accelerated by the advent of agents with ancillary pharmacologic properties. The most impor- tant advance in this area was the identification by Lands et al. (31) in 1967 of two beta-adrenoceptor subtypes, designated beta; and betaz, and the consequent devel- ‘opment of beta,-selective blockers. In contrast to betay- adrenoceptors, which are the main subtype found in the heart, beta;-adrenoceptors predominate in the pe- ripheral vasculature and lungs, where they mediate vasodilatation and bronchodilatation, respectively. By leaving beta;-adrenoceptors relatively unblocked and responsive to sympathetic stimulation, beta,-selective blockers may therefore be functionally important in patients, for example, with asthma or peripheral vas- cular disease. The clinical value of beta-blockers has also been increased by the synthesis of agents with other ancillary pharmacologic properties, such as intrinsic sympatho- mimetic activity (ISA) and alpha-adrenoceptor block- ing properties. Agents with ISA cause a slight to mod- erate activation of beta-adrenoceptors while preventing ‘the access of catecholamines to these receptor sites. Those with alpha-blocking properties are of potential benefit in that they facilitate arteriolar dilatation. Col- lectively, beta-blockers are the most commonly used drugs in the treatment of cardiovascular diseases in the United States and other Western industrialized nations, At very much the same time, exercise training has also emerged as an important therapeutic modality in the management of patients with cardiovascular dis- eases. In particular, this intervention has proven to be of substantial benefit in hypertensive and coronary artery disease (CAD) patients (39,47). Not surprisingly, many patients with hypertension and CAD who receive beta-blocker therapy now participate in exercise train- ing programs. Because beta-blockers evoke profound alterations in circulatory and metabolic function during exercise, an adequate understanding of the interaction between concomitant beta-blockade and exercise train- ing in these patient populations is therefore of consid- erable clinical relevance. 668BETA-BLOCKERS AND EXERCISE In view of this, we initiated a series of studies in 1982 that were aimed at investigating the effect of beta- blockers on exercise physiology. In this article, we will review certain clinical implications of these studies for patients with hypertension or CAD who exercise on a regular basis and are treated with beta-blockers. Specif- ically, we will use our studies to address five major contemporary issues and concerns: i) the effect of beta- blockers on exercise tolerance; ii) the impact of beta- blockers on the ability to derive a physiologic training effect; iii) the prescription of exercise intensity for pa- tients treated with beta-blockers; iv) the lipid-related benefits of exercise training during chronic beta-blocker therapy; and v) the potentially adverse effects of beta- blockers on exercise thermoregulation. EFFECT OF BETA-BLOCKERS ON EXERCISE TOLERANCE With the possible exception of beta-blockers possess- ing ISA, which may have less cardioprotective value in patients recovering from an acute myocardial infarction (29), no studies have documented a major therapeutic advantage of one beta-blocker over another in the treat- ment of hypertension or CAD. However, depending on, its ancillary pharmacologic properties, a given beta- blocker may be more appropriate in certain speci clinical situations by virtue of a lessening of adverse reactions. One such adverse reaction, which is of con- siderable importance to patients who participate in exercise training, isan impairment of exercise tolerance. To optimize compliance in this particular patient pop- ulation, the appropriate medication is therefore one that reconciles the need for maintenance of exercise tolerance and for therapeutic effectiveness, Patients limited by myocardial ischemia. Beta- blockers increase exercise tolerance in patients with effort-induced myocardial ischemia. This enhancement of functional capability is achieved largely by the com- bination of negative chronotropic and inotropic effects, which serve to attenuate myocardial oxygen require- ments. Acute and chronic studies indicate that, when their dosage is titrated properly, nonselective and beta,- selective agents, as well as those with ISA and/or alpha- blocking properties, are equally effective in enhancing the exercise tolerance of CAD patients who are limited by myocardial ischemia (45,46). Importance of beta,-selectivity for hypertensive patients, In contrast to patients with myocardial ische- mia, exercise tolerance is generally reduced by nonse- lective beta-blocker therapy in those with uncompli- cated essential hypertension (9,18,26). To determine whether beta,-selectivity offers any potential advantage to physically active persons with uncomplicated essen- tial hypertension, we compared the effect of clinically Official Journal ofthe American Collegeof Sports Medicine 669 equipotent doses of propranolol (nonselective beta- blocker) and atenolol (beta,-selective blocker) during maximal graded treadmill testing (24). The drugs were administered, together with a placebo, for 4 d each in a randomized, double-blind, crossover fashion to 12 endurance trained healthy male volunteers. Maximal exercise duration during treadmill testing (propranolol: 8.5% reduction, P < 0.001; atenolol: 3.2% reduction, 0.05 < P<0.1) and maximal oxygen uptake (propran- olol: 9% reduction, P < 0.001; atenolol: 5.4% reduc- tion, P< 0.01) were reduced to a greater degree with propranolol than with atenolol (Fig. 1). These findings have been confirmed in hypertensive patients (26). Z 3 z 8 z g PROP ATEN PLAC 200 ies E aso 5 gs PLAC Figure 1—Erfect of propranolol (PROP), atenolol (ATEN), and pla- cebo (PLAC) on maximal oxygen uptake (VOan) maximal exercise PROP ATEN. oration (TIME), and maximal heart rate (HEART RATE) in 12 healthy men. *P < 0405 vs placebo; **P < 0.05 vs atenolol and placebo, Adapted from Gordoa etal. (24).670 Official Journal of the American College of Sports Medicine Benefits of ISA. The precise mechanisms by which pharmacologic blockade of beta-adrenoceptors attenu- ates maximal exercise tolerance have yet to be fully elucidated. One obvious possibility is a reduction in cardiac output. Because ISA has been shown to limit the reduction in resting and submaximal exercise car- diac output which occurs during beta-blockade (1,41), ISA could theoretically be expected to result in a less- ening of fatigue. To investigate this hypothesis, we compared the effects of propranolol (no ISA) and pin- dolol (nonselective beta-blocker with ISA) on exercise tolerance in 42 men and women with uncomplicated essential hypertension (9). On completion of a single- blind placebo lead-in period, patients were randomly assigned to propranolol (V = 21) or pindolol (NV = 21) therapy for a double-blind parallel study. Drug dosages were titrated to reduce diastolic blood pressure (BP) to <90 mm Hg or by at least 10 mm Hg. Maximal graded ‘treadmill testing was performed on completion of the placebo and titration periods. Maximal exercise dura- tion and maximal oxygen uptake were significantly reduced by both drugs. Contrary to our original hy- pothesis, ISA failed to confer any advantage. Similar observations have been reported by other investigators when comparing beta,-selective blockers with and with- out ISA (30). Impact of arteriolar dilatation. Since the beta-adre- noceptor subtype mediates vasodilatation in peripheral vascular beds, it has been suggested that beta-blockers might impair effort tolerance by directly diminishing local muscle blood flow (26). Ifthis were so, the addition of a calcium antagonist to beta-blocker therapy would be expected to reduce the degree of impairment in effort tolerance by diminishing peripheral vasoconstric- tion, Recent clinical trials have demonstrated that con- comitant treatment with nifedipine, a calcium antago- nist, and a beta-blocker produces antihypertensive ef- fects superior to those observed with either drug alone. In view of this, we studied the effects of dual beta- blockade and nifedipine-induced calcium antagonism on exercise tolerance in 12 healthy, physically active adult males (24). Irrespective of whether nifedipine was combined with atenolol or propranolol, maximal ex- ercise duration during graded maximal treadmill testing and maximal oxygen uptake were equivalent between using a beta-blocker and using its combination with nifedipine. Thus, peripheral vasodilatation with cal- cium antagonism does not offset the adverse effect of beta-blockade on exercise tolerance. In this respect, there is also currently no convincing evidence that alpha-blockade-mediated arteriolar dilatation enhances exercise tolerance during beta-blocker therapy. Comparison with other first-line antihypertensive agents. Since all beta-blockers appear to impair exer- cise tolerance to a certain degree, the question arises as to whether any beta-blocker is in fact desirable for a MEDICINE AND SCIENCE IN SPORTS AND EXERCISE physically active patient with uncomplicated essential hypertension. This issue has recently taken on consid- erable relevance because calcium antagonists and an- giotensin converting enzyme (ACE) inhibitors are now also recommended as initial monotherapy for essential hypertension (47). Preliminary research conducted by us on healthy ‘men failed to demonstrate a significant effect of the calcium antagonist, diltiazem, on exercise tolerance when administered as a single oral dose (20). Conse- quently, we investigated the effect of diltiazem on ex- ercise tolerance when specifically administered to young, physically active hypertensive patients and made a comparison with atenolol (37). Although max- imal exercise duration during treadmill testing was significantly reduced by 16 wk of therapy with atenolol (3% decrease, P < 0.05) but not with diltiazem (1% decrease, P > 0.05), differences between the two drugs in this double-blind parallel study were not statistically significant. Similarly, in another study of ours, maximal exercise duration during cycle ergometer testing was not significantly different afier 7 d of therapy with the ACE inhibitor, captopril, and atenolol (18). Therefore, on the basis of these studies, it is currently not possible to advocate the use of calcium antagonists or ACE inhibitors in preference to beta,-selective blockers in patients with hypertension who are physically active. However, it must be emphasized that beta,-selective blockade did have a considerable negative impact on certain individuals in our studies, and additional re- search is therefore recommended in this area. ABILITY TO DERIVE A PHYSIOLOGIC TRAINING EFFECT DURING BETA-BLOCKER THERAPY ‘The mechanisms by which exercise training improves cardiorespiratory fitness are poorly understood. Studies conducted during the late 1970's suggested a possible physiologic role of sustained adrenergic stimulation (32,48). This postulate was given further credence by the observation by Sable et al. (43) that propranolol markedly attenuates cardiorespiratory adaptations to exercise training in healthy men, The clinical implica- tion of their study, of course, is that CAD and hyper- tensive patients treated with beta-blockers may be inca- pable of deriving a physiologic cardiorespiratory train- ing effect. Trainability of CAD patients. In view of this, we studied the cardiorespiratory responses of seven post- ‘myocardial infarction patients treated with long-term beta-blocker therapy during 4 months of endurance exercise training (16). Observations were obtained, be- fore and after conditioning, during graded levels of treadmill exercise that continued until 85% of the pre- determined symptom-limited heart rate was attained.BETA-BLOCKERS AND EXERCISE This submaximal testing procedure revealed a signifi- cant slowing of the heart rate (by 13%, P < 0.005) together with an increased oxygen pulse (by 13%, P-< 0.05) after training for a given submaximal exercise load. In addition, all patients improved their peak exercise duration (mean increase = 47%, P < 0.005) and oxygen uptake (mean increase = 24%, P< 0.01) with exercise training (Fig. 2). The small patient sample used and lack of a control group do not detract from the findings of this study, which clearly demonstrate that patients with CAD can derive a physiologic cardi- respiratory training effect during chronic beta-blocker therapy. Our observations are supported by those of other investigators who have shown that, in general, CAD patients are capable of deriving the expected 30 ——— 20 177 TIME (min) PRE Post 24 2 20 104 18 16 4 PEAK Vo? (mifkg/min) 2 ° PRE Post Figure 2—Exercise duration (TIME) and peak oxygen uptake (VO:) before (PRE) and after (POST) 4 months of exercise training in seven sien with CAD receiving long-term beta-blocker therapy. *P < 0.01; **P-< 0.005. Adapted from Gordon etal (16). Official Journal of the American Collegeof Sports Medicine 671 enhancement of cardiorespiratory fitness during exer- cise training performed in the presence of beta-blockade (7). To date, no studies have documented an advantage or disadvantage of any specific ancillary pharmacologic property in such patients. Additional research is needed to clarify the effects of beta-blockers on exercise train- lity in specific subgroups of CAD patients, for ex- ample those with and without myocardial ischemia Trainability of hypertensive patients. With the ex- ception of studies conducted at one particular labora- tory (35,43), available research data indicate that nor- ‘mal increases in cardiorespiratory fitness can occur in healthy persons during exercise training performed in the presence of beta-blockade (1 1,36,44,49). Two recent studies conducted at our laboratory (9, unpublished observations) have further shown that hypertensive pa- tients treated with nonselective beta-blockers are also capable of improving their cardiorespiratory fitness by participating in exercise training. However, because the initiation of beta-blocker therapy resulted in an im- paired cardiorespiratory fitness in our studies, exercise ‘raining failed to increase cardiorespiratory fitness to the same absolute level as in patients treated with a placebo (Fig. 3). In reality, our studies show that as many as 20 wk of exercise training only serve to return beta-blocked hypertensive patients to near their pre- drug therapy cardiorespiratory fitness levels. A careful review of the available literature reveals that a similar situation may have occurred in many of the studies z —& w = F PLACEBO PROPRANOLOL, ire 3Effect of propranolol (N = 21) and placebo (N = 17) on ‘maximal exercise duration during treadmill testing (TIME) conducted before (PRE) and after ining in men ‘with uncomplicated esse ducted after 4 wk of placebo therapy significant *P < 0.08. Unpublished observations.672 Official Journal of the American College of Sports Medicine investigating the effect of nonselective beta-blockade on the exercise trainability of healthy persons (11,35,36,43). Recent studies with hypertensive patients suggest that this apparent inability of exercise training to substantially increase cardiorespiratory fitness above pre-drug levels is less marked with beta,-selective blocker therapy than with nonselective agents (2,34). In contrast, one of our studies indicates that ISA is of no advantage in this regard (9). Comparison with other first-line antihypertensive agents. Because beta-blocker therapy limits the mag- nitude of increase in cardiorespiratory fitness from pre- drug levels with exercise training, it may be appropriate to consider alternative antihypertensive agents. We therefore compared the effects of fosinopril (an ACE inhibitor), propranolol, and placebo during 12 wk of exercise training in a randomized, double-blind, parallel study involving 65 sedentary men with uncomplicated essential hypertension (unpublished observations). Pre- drug therapy maximal exercise duration during tread- ‘mill testing increased by 24.6%, 23%, and 5.8% with exercise training in the placebo, fosinopril, and pro- pranolol groups, respectively. The improvement with propranolol was significantly less (P < 0.001) than that with placebo and fosinopril. This study demonstrates that, unlike nonselective beta-blockers, ACE inhibitors do not appear to limit the cardiorespiratory benefits of exercise training. Similar findings have recently been reported by Kelemen etal. (28) with the calcium antag- onist, diltiazem. Additional studies comparing ACE inhibitors and calcium antagonists with beta,-selective blockers are needed to fully clarify the situation. EXERCISE INTENSITY PRESCRIPTION DURING BETA-BLOCKER THERAPY Exercise intensity is frequently prescribed for patients with hypertension or CAD as a percentage of their predetermined maximal heart rate (3). This approach is facilitated primarily by the linear relationship be- tween percentage of maximal oxygen uptake and per- centage of maximal heart rate, Presently, it is widely accepted that exercise training performed at 55-90% of the predetermined maximal heart rate will yield the exercise intensity needed for the stimulation of a car- diorespiratory training effect (3). Effect on maximal heart rate. Clearly, beta-blockers reduce maximal heart rate, and it is therefore not possible to rely on standard age-adjusted heart rate values when prescribing exercise intensity for patients treated with these drugs. Therefore, exercise prescrip- tion should be based on the results of individualized exercise testing performed with the patient on medica- tion, Moreover, since maximal heart rate depends on the amount of time elapsed afier beta-blocker ingestion MEDICINE AND SCIENCE IN SPORTS AND EXERCISE (12,26), exercise testing and subsequent training should take place at a similar time interval after the last drug dose. Ideally, in the event that the beta-blocker dosage is altered at any stage during the course of exercise training, exercise testing should be repeated and the exercise prescription appropriately modified in accord- ance with the new maximal heart rate, We and other researchers have demonstrated that, whereas clinically equipotent doses of propranolol and atenolol produce equivalent reductions in the heart rate response to submaximal exercise, maximal heart rate is, reduced to a greater degree with propranolol (24,27). Although the precise mechanism for this has yet to be conclusively established, blockade of chronotropic car- diac beta,-adrenoceptors by propranolol has been im- plicated (8). Imespective of the actual mechanism, it is evident that exercise testing should also be repeated for the purpose of exercise intensity prescription when a patient is switched from a nonselective to a beta,- selective beta-blocker, and vice versa, even when clini- cally equipotent doses are used. Effect on relationship between percentage of maximal oxygen uptake and percentage of maximal heart rate. In one study involving healthy subjects, we found that propranolol (by 5%, P < 0.05) and atenolol (by 9%, P< 0.05) yielded a somewhat higher than expected percentage of maximal oxygen uptake for 859% of the maximal heart rate (24). Although these data suggest that exercise intensity may be prescribed at a slightly lower percentage of maximal heart rate during beta-blockade, it should be pointed out that, in an earlier study of ours (22), atenolol did not significantly modify the percent maximal oxygen uptake-percent ‘maximal heart rate relationship (Fig. 4), and Hossack etal. (25) have actually documented an opposite finding in CAD patients. Moreover, we have demonstrated that maximal heart rate may be slightly underestimated in healthy persons receiving beta-blockers when continu ous as opposed to intermittent multistage treadmill testing is performed (21). Therefore, while further re- search is needed to fully clarify the situation, it appears that exercise prescribed as a given percentage of the ‘maximal heart rate will probably yield very much the expected percentage of maximal oxygen uptake in per- sons treated with beta-blockers. LIPID-RELATED BENEFITS OF TRAINING DURING BETA-BLOCKADE The major prognostic determinants following an acute myocardial infarction are the extent of residual myocardial ischemia, left ventricular dysfunction, and electrical instability of the myocardium. Beta-blockers lessen myocardial oxygen requirements, improve left ventricular dysfunction that results from myocardialBETA-BLOCKERS AND EXERCISE % of maximal oxygen consumption 0 60 70 80 90 100 % of maximal heart rate Figure 4—Effect of atenolol on the relation of percentage of maximal ‘oxygen consumption to percentage of maximal heart rat in 12 healthy ‘men. Regression lines together with 95% confidence limits are shown, {or placebo (sold fines) and atenolol (dotted lines). From Gordon et 1.22). ischemia, and reduce the propensity toward ventricular arrhythmias, Not surprisingly, prophylactic institution of beta-blockers after an acute myocardial infarction is of documented benefit, the pooled results of placebo- controlled studies showing a very significant reduction of ~25% in mortality at 1-2 yr (29). In contrast, although it has been overwhelmingly demonstrated that an elevated blood pressure increases mortality from CAD, there is presently no convincing evidence that blood pressure lowering with beta-blocker therapy reduces CAD mortality in patients with mild to moderate hypertension. In view of the apparent inability of antihypertensive treatment with beta-block- ers to convincingly reduce CAD mortality (33), it is easily understandable why their adverse effect on serum lipids, particularly high density lipoprotein (HDL) cho- lesterol levels, has raised concern (38,42). Effect of beta-blockade on serum lipoproteins dur- ing exercise training. Exercise training constitutes one of the few potentially effective and physiologically de- sirable means of preventing a shift toward a more atherogenic lipid profile during beta-blocker therapy (15). However, sympathetic stimulation might be nec- essary for exercise training to elicit favorable serum lipid changes. We therefore investigated (unpublished observations) the effect of 12 wk of exercise training on serum lipids in men with uncomplicated essential hy- pertension who were treated with propranolol (/V = 20) or placebo (N = 17). Exercise training resulted in a similar reduction in the total cholesterol:H1DL choles- e672 Official Journal of the American Collegeof Sports Meti terol ratio in the placebo and propranolol groups (7.2% reduction with placebo vs 8.7% reduction with pro- pranolol, P > 0.05). These data suggest that exercise training may indeed offset detrimental effects of chronic beta-blocker therapy on lipoprotein metabolism. How- ever, because conflicting findings have been reported by other investigators (5,50), further research is neces- sary to fully clarify the situation, Lack of benefit of ISA during exercise training. Whereas therapeutic doses of propranolol generally re- duce HDL cholesterol levels by ~10-20%, equipotent doses of pindolol appear to be free of this undesirable effect (4). To determine whether ISA confers any such advantage to patients treated with beta-blockers while participating in exercise training, we compared the effects of propranolol and pindolol on serum lipids during 20 wk of exercise training in 42 patients with uncomplicated essential hypertension (10). No differ- ences were noted between the two drugs with exercise training, The data therefore do not support the prefer- ential use of drugs with ISA in physically active patients who require long-term beta-blocker therapy. Effect of exercise training on CAD mortality in hypertensive patients treated with beta-blockers. Despite its recent precipitous decline, CAD remains the leading cause of mortality in most Western industrial- ized nations. Although the precise role of habitual physical activity as a prophylactic against CAD has yet to be conclusively determined, the results of over 40 ‘major studies support the inference that physical activ ity is inversely and causally related to the risk for CAD (40). However, no data are currently available for hy- pertensive patients receiving beta-blockers or, for that matter, hypertensive patients in general. We have re- cently begun to address this issue by investigating the relationship between baseline cardiorespiratory fitness and mortality during subsequent follow-up in hyperten- sive men evaluated at the Cooper Clinic in Dallas, Texas. Although we have not analyzed data which pertain specifically to beta-blockers at the present time, preliminary analyses in 2823 hypertensive men (some of whom were treated with beta-blockers) indicate a graded relationship of increased physical fitness to de- creased all-cause mortality (13). EFFECT ON EXERCISE THERMOREGULATION The production of mechanical work from chemically bound energy is a relatively inefficient process and results in the formation of various by-products, includ- ing heat. This heat must be adequately dissipated to the environment; otherwise the core temperature may rise excessively. Although most patients with hypertension or CAD do not exercise at an intensity and duration place them at great risk for heat injury, some do.674 Official Journal of the American College of Sports Medicine Effect on sweating, It is conceivable that beta-block- tional heat injury by virtue of an impairment in skin blood flow secondary to a reduction in cardiac output, and/or unopposed alpha-adrenergically mediated cu- taneous vasoconstriction. We therefore investigated the effect of beta-blockade on exercise thermoregulation in a series of studies involving healthy men and those with CAD (14,17,19,23). In two studies (17,23), it was found that propranolol, but not atenolol, significantly in- ‘creased (by ~10%) sweat loss in healthy subjects during prolonged exercise in the heat. However, the observed accentuation of sweating was not accompanied by an. accentuated rectal temperature response in either study. Interestingly, the increase in sweating was not abolished when propranolol was combined with nifedipine in one. of the studies (23). Effect on core temperature. Because the rectum is not the ideal site for core temperature measurement, wwe subsequently investigated the effect of a single oral dose of propranolol on rectal and simultaneously re- corded pulmonary artery temperatures during 30 min of cycling (19), In this study, cycling was performed in, a cool environment at a work rate of 120 W by six men, with documented CAD. Propranolol failed to modify the rectal temperature response to exercise as compared. with a placebo. However, it did cause an alteration of the normal relationship between rectal and pulmonary artery temperatures during exercise. In fact, although the rectal temperature was slightly (but not signifi- cantly) lower on completion of exercise with propran- lol than with placebo, the pulmonary artery tempera- ‘ture was higher in all six patients with propranolol than, with placebo (Fig. 5; mean increase = Wl J lll uw getting + + Uy » ‘TEMPERATURE (%) 35) oo 0 w » TIME (min) Figure 5—Etfect of propranolol on pulmonary artery temperature Fy) at rest (~4 to 0 mia) and during exercise in six men with CAD. ‘ReSulls show are mean SE. From Gordon etal. (19). MEDICINE AND SCIENCE IN SPORTS AND EXERCISE 0.01). Therefore, although research with more chronic therapy is warranted, our thermoregulatory studies sug- gest that nonselective beta-blockade may accentuate the risk for dehydration and hyperthermia and, by implication, their adverse physiologic consequences during prolonged exercise. CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL PRACTICE Although further research is clearly indicated, it is possible to draw the following conclusions and to make the following tentative recommendations regarding beta-blockers and exercise training at the present time, 1. Patients with CAD who are treated with beta- blockers are capable of deriving the expected en- hancement of cardiorespiratory fitness during ex- ercise training, irrespective of the type of beta- blocker used. 2. Where possible, beta,-selective blockers should be prescribed in preference to nonselective beta- blockers for patients with uncomplicated essential hypertension who participate in exercise training, 3. Because beta,-selective blockade may have a con- siderable negative impact on exercise tolerance in certain hypertensive patients, physicians should be on the lookout for this adverse reaction and, if present, consider alternative therapy with an ACE inhibitor or calcium antagonist (unless beta- blocker therapy is specifically indicated). 4, ISA confers no advantage to hypertensive patients who participate in exercise training. 5. Exercise intensity prescription for patients treated with a beta-blocker should be based on the results of individualized exercise testing performed with the patient on medication. Ideally, testing and training should take place at a similar time inter- val after the last drug dose, and testing should be repeated if there is a change in dosage or the type of beta-blocker used. Exercise intensity should be prescribed in accordance with traditional guide- lines. 6. Exercise training is desirable for patients who receive beta-blocker therapy in that it appears to offset adverse beta-blockade-induced alterations in lipoprotein metabolism. 7. Nonselective beta-blocker therapy may increase predisposition toward dehydration and hyperther- mia during exercise. Patients who are treated with these drugs and who participate in prolonged and/ or strenuous exercise must be encouraged to strictly adhere to accepted guidelines for the pre~ vention of exertional heat injury.BETA-BLOCKERS AND EXERCISE We gratefuly acknowledge the contribution made by the coauthors cof our previous manuscripts on beta-blockers and exercise. We thank Linda Robbins and Pam Kerrigan for assistance with the preparation REFERENCES 1. Avis, P. A. Cardiac effects of f.adrenoceptor blockade with intrinsic sympathomimetic activity during submaximal exercise Br. J. Clin. Pharmacol. 24:298-338, 1987, 2, Apis, P. A. P.G. S, GuNTHER, C. P. MEACHAM, M. A. HANDY, and M. M, LeWinrer. 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