Role of Nitric Oxide in the Relaxation Elicited by Sildenafil in Penile Resistance Arteries

Abstract

We investigated the role of the vascular endothelium and the L-arginine/nitric oxide pathway in the vasorelaxant effect of the phosphodiesterase type 5 inhibitor sildenafil in penile resistance arteries. Second or third order branches of the horse deep intracavernous penile artery were mounted in microvascular myographs. The vasodilator effects of sildenafil and the NO donor SNAP (S-nitrosoacetyl-D,L-penicillamine) were evaluated in the absence and presence of the endothelium and inhibitors of the NO/cGMP (cyclic guanosine 3',5'-monophosphate) pathway. In phenylephrine precontracted, endothelium intact arteries sildenafil elicited potent relaxations that were markedly decreased by the blockade of soluble guanylate cyclase with ODQ (1H-[1,2,4]oxadiazolo[4-3a]quinoxalin-1-one). Endothelium removal and the inhibition of NO synthase with N(G)-nitro-L-arginine (L-NOARG) caused pronounced inhibition of sildenafil elicited relaxations but not of SNAP induced responses. Combined treatment with the cyclooxygenase blocker indomethacin and L-NOARG caused significantly greater inhibition of sildenafil relaxations than that produced by L-NOARG alone. Inhibitors of the cGMP (PKG) and the cAMP (cyclic adenosine 3',5'-monophosphate) dependent protein kinases Rp-8-Br-PET-cGMPS (beta-phenyl-1, N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer) and Rp-8-CPT-cAMPS (Rp-8-CPT-cAMPS (8-(4-chlorophenylthio) adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer), respectively, inhibited the sildenafil concentration-relaxation curves. The relaxant responses of SNAP were markedly decreased by PKG inhibitor and to a lesser extent by cAMP dependent protein kinase inhibitor. The current results demonstrate a potent relaxant effect of sildenafil in penile resistance arteries due in part to cGMP accumulation and to the enhanced effects of basal released, endothelial derived NO acting through PKG activation. Cross-activation of the cAMP signaling pathway by sildenafil is also suggested.