β-Blocking Agents and Positive Inotropic Agents in the Therapy of Chronic Heart Failure

Abstract

Positive inotropic stimulation of the failing cardiac muscle seems to be useful, if certain requirements are met: (a) there is some cardiac contractile reserve left, (b) the positive inotropic agent of choice is able to mobilize this contractile reserve, and (c) peripheral vascular resistance is not increased permanently by this agent. On the other hand, the physiological response (i.e., positive inotropic effect) to circulating catecholamines in heart failure is decreased or even absent due to receptor desensitization and an alteration of guanine nucleotide-binding proteins (increased Gi). It has been proved that functionally active beta-adrenoceptors may be restored by treatment with beta-adrenoceptor antagonists. However, these agents necessarily will have negative inotropic effects in the failing cardiac muscle, if the force of contraction is largely dependent on a permanent stimulation by catecholamines and if there are no spare beta-adrenoceptors. To clarify these as-yet unresolved problems, we have determined the contractile reserve as well as its utilization by positive inotropic agents in human cardiac muscles of failing and nonfailing hearts. The number and functional activity of cardiac glycoside receptors, beta-adrenoceptors, and alpha-adrenoceptors were measured as well as the positive inotropic and negative inotropic effects of partial agonists. Furthermore, we have accumulated evidence that, in fact, there are no spare beta-adrenoceptors in the human cardiac muscle. The lack of spare beta-adrenoceptors has consequences for the therapeutic approach in patients with heart failure. At least initially, the administration of beta-adrenoceptor-blocking agents to patients with heart failure depending on agonist-induced stimulation will lead to a worsening of cardiac function. If this situation can be tolerated, however, the subsequent restoration of functionally active beta-adrenoceptors after beta-blockade may lead to restored physiological regulation of force of contraction by norepinephrine.