The role of .BETA.-adrenoceptor subtypes in cardiac contractility.

Since the existence of beta 3-adrenoceptors in various organs has been established, it is necessary to re-evaluate the subtypes of beta-adrenoceptors in cardiac muscle. We have demonstrated the possible existence of three subtypes of beta-adrenoceptors: beta 2-adrenoceptors, high-affinity beta 1-adrenoceptors (the so-called beta 1-adrenoceptors) and the low-affinity beta 1-adrenoceptors (akin to beta 3-adrenoceptors) in canine cardiac muscle, which are coupled with increases in myocardial cyclic AMP content and positive inotropic effects. Cyclic AMP generated by the activation of the high-affinity beta 1-adrenoceptors seems to be coupled with the positive inotropic effect much more effectively than via beta 2- or low-affinity beta 1-adrenoceptors. Stimulation of beta 2-adrenoceptors or the low affinity beta 1-adrenoceptor is causally related to the development of tolerance and to the adverse effects of nonselective beta-full agonists. It is conceivable that with denopamine, unlike with isoproterenol, tolerance can hardly develop, and there are no adverse effects resulting from its partial agonistic property and its selectivity for the high-affinity beta 1-adrenoceptors. The selective stimulation of the high-affinity beta 1-adrenoceptors would be beneficial for the management of mild congestive heart failure. In contrast, stimulation of the low-affinity beta 1-adrenoceptors by endogenous catecholamines or nonselective beta-agonists will contribute to deteriorating hemodynamic, symptomatic and prognostic consequences in patients with congestive heart failure.