Phosphodiesterase inhibition by new cardiotonic agents: Mechanism of action and possible clinical relevance in the therapy of congestive heart failure

Abstract

Cyclic AMP is known as a secondary messenger regulating the myocardial force of contraction. For the degradation of cAMP multiple forms of PDE within the cell are described, which vary according to substrate specificity, kinetic characterization, and cellular localization. One of these isoenzymes, the low Km cAMP-specific PDE (PDE III), which seems to be closely related to cardiotonic effects of PDE inhibitors, exists either in a particulate form (in dogs), probably associated with the sarcoplasmic reticulum, or in a soluble form (in guinea pig). The existence of different forms of PDE III possibly reflects a different pooling or compartmentalization of cAMP. Many agents selectively inhibiting PDE III are described which potently increase the force of contraction and which exert vasodilatory effects. Besides PDE inhibition some of these agents possess additional cAMP-independent actions, e.g., sensitization of the contractile proteins to Ca²⁺, prolongation of the action potential, or prolongation of the open state of the Na⁺-channel. Since agents which nonselectively inhibit PDE are known as potent positive inotropic agents (e.g., IBMX), PDE III inhibition itself, but not a selectivity for PDE III inhibition, seems to be a prerequisite for this mechanisms of action of cardiotonic drugs. Investigations with preparations from diseased human myocardium show that the β-adrenoceptor agonist isoprenaline as well as the PDE inhibitor IBMX increase the force of contraction to only about one-third of the maximal effect of the cardiac glycoside dihydro-ouabain or Ca²⁺. In nonfailing human heart preparations all agents had equal activity. Possible reasons for these differences may be a decreased responsiveness to β-adrenoceptor stimulation (β-receptor down-regulation) or an inappropriate increase in cAMP levels due to increased activity of inhibitory G_i-proteins with resulting decrease of adenylate cyclase activity in the failing heart. Besides a short-term clinical and hemodynamic improvement of congestive heart failure, uncontrolled long-term administration of PDE III-inhibitor agents failed to produce sustained clinical benefit and had no effect on survival. Controlled long-term studies with new cardiotonic agents in patients with severe CHF are still lacking.