SILDENAFIL, A NOVEL INHIBITOR OF PHOSPHODIESTERASE TYPE-5 IN HUMAN CORPUS CAVERNOSUM SMOOTH-MUSCLE CELLS

In human corpus cavernosum, release of nitric oxide from the non-adren ergic, noncholinergic nerves and/or the endothelium activates guanylyl cyclase and increases intracellular cGMP levels. The increase in intr acellular cGMP modulates intracellular calcium and in turn regulates s mooth muscle contractility and erectile function. Phosphodiesterases p lay an important physiological role by regulating the intracellular le vels of cyclic nucleotides. In this study, we investigated the kinetic parameters of inhibition of phosphodiesterase (PDE) type 5 (E.C. 3.1. 4.35 3', 5'-cyclic GMP phosphodiesterase) by a novel, high affinity, s elective PDE type 5 inhibitor, sildenafil, in soluble extracts of huma n corpus cavernosum smooth muscle cells. Sildenafil inhibited PDE type 5 cGMP-hydrolytic activity, in the crude extract (K-i=4-6 nM) and in partially purified preparations (K-i=2 nM) in a competitive manner, as determined by Dixon plots. Sildenafil (K-i=2-4 nM) was a more effecti ve PDE type 5 inhibitor than zaprinast (K-i=250 nM). Stimulation of in tracellular cGMP synthesis by the nitric oxide donor, sodium nitroprus side, resulted in less than a 5% increase in cGMP levels in the absenc e of sildenafil and a 35% increase in cGMP levels in the presence of s ildenafil, in intact cells at physiological temperatures. These result s are in accord with the clinical observations that sildenafil, taken orally, promotes penile erection through increased intracellular cGMP in response to sexual stimulation, potentiating smooth muscle relaxati on. (C) 1998 Elsevier Science Inc.