Clinical Use of Phosphodiesterase-5 Inhibitors in Chronic Heart Failure

Abstract

Received June 25, 2008; accepted September 16, 2008. Nowadays, the inhibitors of the phosphodiesterase enzyme type 5 (PDE5), thanks to a sustained relaxant activity on smooth muscles of the corpus cavernosum, are a widely used remedy for erectile dysfunction in man. This class of compounds was originally developed for the treatment of angina pectoris, based on the ability of oversignaling the pathway originated from nitric oxide (NO) and pursued via cGMP signaling. Because the clinical effects were not as promising as initially reported by experimental studies, PDE5 inhibitors1 were not regarded as a remarkable advancement over commonly used nitrates. Subsequently, however, it was realized that the clinical applicability of the enhanced NO/cGMP pathway by inhibiting the PDE5 activity could be larger than previously thought. Over the last few years, the use of PDE5 inhibitors has been expanded to the therapeutic management of other cardiovascular disorders, including chronic heart failure (CHF). Their clinical applicability to CHF is the subject of this review. The homeostatic role of phosphodiesterases (PDEs) as related to the intracellular levels of cAMP and cGMP was first described by Sutherland,2 who, because of this, was awarded the Nobel Prize for Physiology and Medicine in 1971. These enzymes hydrolyze the phosphodiester bond of cAMP and cGMP to form the inactive 5′-AMP and 5′-GMP. In optimizing the intracellular levels of cAMP and cGMP, breakdown is predominant over synthesis. PDEs comprise a superfamily with 11 subfamilies, which have been characterized on the basis of amino acid sequence, substrate specificity, pharmacological properties and allosteric regulation. Within these families, more than 40 isoforms are expressed either by different genes or as expression of the same gene through alternative splicing.3 The substrate specificities include the enzymes that are specific for cAMP hydrolysis, those for cyclic GMP hydrolysis,4 and those that …