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

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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 G,). It has been proved that functionally active β-adrenoceptors may be restored by treatment with β-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 β-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, β-adrenoceptors, and α-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 β-adrenoceptors in the human cardiac muscle. The lack of spare β-adrenoceptors has consequences for the therapeutic approach in patients with heart failure. At least initially, the administration of β-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 β-adrenoceptors after β-blockade may lead to restored physiological regulation of force of contraction by norepinephrine.