CARDIOVASCULAR EFFECTS OF CLENBUTEROL ARE BETA(2)-ADRENOCEPTOR-MEDIATED IN STEERS

The mechanism through which the repartitioning agent clenbuterol incre ases heart rate was investigated. First, the relative importance of th e beta(1)- and beta(2)-adrenoceptors was established in rat and bovine right atria in vitro. The positive chronotropic and inotropic effects of (+/-)isoproterenol in rat and bovine right atria, respectively, we re markedly antagonized (P < .001) by the beta(1)-adrenoceptor antagon ist CGP 20712A but were antagonized less by the beta(2)-adrenoceptor a ntagonist ICI 118 551 in rat (P < .01), but not in bovine atria, indic ating a major role of the beta(1)-adrenoceptors. Clenbuterol was only a partial agonist in rat right atria, increasing heart rate at high co ncentrations through stimulation of beta(1)-adrenoceptors. In studies in vivo, clenbuterol decreased the plasma potassium concentration (P < .05) and increased the plasma glucose concentration (P < .05). Clenbu terol also reduced diastolic blood pressure (P < .01) and increased he art rate (P < .001). The increase in heart rate was not due to direct stimulation of cardiac beta(1)-adrenoceptors by clenbuterol but was co nsistent with a reflex response to beta(2)-adrenoceptor-mediated hypot ension. This would have caused the activation of baroreceptors, which in turn would have resulted in both the release of norepinephrine to s timulate cardiac beta(1)-adrenoceptors and the inhibition of cholinerg ic input to the heart. Thus, the effects of clenbuterol could be elimi nated completely by ICI 118 551 or reduced by approximately 50% using CGP 20712A. The combination of treatment of clenbuterol and CGP 20712A could be useful. It may allow the full repartitioning effects seen wi th the beta(2)-agonist alone, but with a markedly attenuated effect on the heart. Such a treatment regimen may also help reduce the increase d energy expenditure and loss of appetite seen following the initial a dministration of clenbuterol.