Phosphodiesterase inhibitors: The inotropes of choice for the new millennium?

Abstract

PHOSPHODIESTERASE (PDE) functions to terminate the actions of cyclic 3′,5′-nucleotides (ie, cyclic adenosine monophosphate [AMP] and cyclic guanosine monophosphate [GMP]) by catalyzing their hydrolysis. PDE enzymes are ubiquitous in the cardiovascular system and have different substrate specificities, kinetic characteristics, and responses to pharmacologic agents. 1 Beavo JA Reifsnyder DH Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990; 11: 150-155 Abstract Full Text PDF PubMed Scopus (822) Google Scholar , 2 Huraux C Makita T Montes F et al. A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology. 1998; 88: 1654-1659 Crossref PubMed Scopus (31) Google Scholar PDE inhibitors are a unique class of pharmacologic agents that have a broad spectrum of effects and are used more widely than is often realized. Perhaps the currently most often prescribed PDE inhibitor is sildenafil (Viagra), a type V cyclic GMP—specific inhibitor that was developed originally for the problems of nitroglycerin tolerance. When a cardiac surgeon injects papaverine, a benzylisoquinoline derivative of opium, into an internal mammary artery, the mechanism of vasodilation is by PDE inhibition. 2 Huraux C Makita T Montes F et al. A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology. 1998; 88: 1654-1659 Crossref PubMed Scopus (31) Google Scholar Milrinone is the newest of the cyclic AMP—specific PDE inhibitors (also called fraction III or low-Km cyclic AMP) that can produce positive inotropic effects and vasodilation independent of β1-adrenergic receptor stimulation. Several forms of these drugs are currently approved in different countries. The bipyridines (milrinone and amrinone) and the imidazolones (enoximone) are the intravenous PDE inhibitors used clinically for ventricular dysfunction.