[Mechanism of the positive inotropic effect of phosphodiesterase inhibitors]

Abstract

Many of newly developed positive inotropic agents are phosphodiesterase inhibitors (PDEI). These are (in contrast to the classical, unselective PDEIs) in most cases selective inhibitors of PDE III which is inhibitable by cGMP. The most important action of PDEIs is a receptor-independent increase in intracellular cAMP, resulting from an inhibition of the degradation of cAMP. An increase in intracellular cAMP levels can also be produced by stimulation of adenylate cyclase, which leads to an increase in cAMP formation. Therefore, the effects of beta-adrenoceptor agonists (e. g., isoprenaline) and PDEIs are rather similar. The main effect of cAMP is to increase the slow Ca inward current during the action potential. This leads to an increase in Ca release from intracellular Ca stores, to an increase in the Ca concentration in the vicinity of the contractile proteins and, hence, to a positive inotropic effect. In addition, PDEIs also produce vasodilatation, which might be of even greater importance than the cardiostimulatory effects of these drugs ("inodilators"). However, two potential disadvantages of PDEIs must also be mentioned: 1) increase in beat frequency and tachyarrhythmias that also result from an increase in intracellular cAMP concentration and 2) decrease in effectiveness or tolerance, which might be due to an increase in inhibitory G proteins.