Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease.

Several families of phosphodiesterases (PDE), the enzymes catalyzing hydrolysis of cyclic (c) nucleoside monophosphates, namely, 3 5 -cAMP (cAMP) and 3 5 cGMP (cGMP), have been identified and characterized in recent years.1 Since selective pharmacological inhibitors of isoform 5 (a cGMP-specific PDE), such as sildenafil, tadalafil, or vardenafil, have become available, the physiological function and interaction of different PDE isoforms,2 their tissue distribution,2 and the therapeutic potential of PDE 5 inhibition have attracted increasing interest.3 The discovery in 1989 of sildenafil, a highly selective inhibitor of PDE 5, was the result of extensive research on chemical agents targeting PDE 5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, a remarkable side effect was reported by a number of volunteers participating in these investigations; sildenafil seemed to enhance penile erections, which soon thereafter became the main focus of further studies. PDE 5 is found in high concentration in smooth muscle cells of the corpora cavernosa.2 Relaxation of smooth muscle cells of penile arteries, arterioles, and sinusoids in response to sexual stimulation results in an increase in blood volume within the rigid tunica albuginea and compression of draining venules, and hence a penile erection. Relaxation of the arterial smooth muscles occurs after stimulation of the enzyme guanylate cyclase by nitric oxide released from nonadrenergic-noncholinergic nerves and endothelial cells, with subsequent formation of cGMP4 (Figure 1). cGMP activates a cGMP-dependent protein kinase, which leads to phosphorylation of ion channels with the final consequence of a reduced cytosolic calcium concentration.5 Thus, sildenafil inhibiting the breakdown of cGMP was found to be effective in a high percentage of male patients suffering from erectile dysfunction.3,6 However, as PDE 5 is expressed in various other tissues, such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, visceral and tracheobronchial muscles, and platelets,1,2,7,8 effects in patients are complex. In this review, we try to outline the effects of PDE 5 inhibition in addition to its efficacy in erectile dysfunction. Potential implications, and whether some of these effects are therapeutically exploitable, will be discussed. Because of limited information on newer agents, the main conclusions will be drawn from results obtained with sildenafil treatment.