EFFECTS OF SILDENAFIL, A TYPE-5 CGMP PHOSPHODIESTERASE INHIBITOR, ANDPAPAVERINE ON CYCLIC-GMP AND CYCLIC-AMP LEVELS IN THE RABBIT CORPUS CAVERNOSUM IN-VITRO

Objective To investigate further the mechanisms of action of sildenafi l, a highly selective and potent inhibitor of type 5 cGMP phosphodiest erase (PDE5) that has proved effective in the treatment of erectile dy sfunction, by assessing its effect on the in vitro formation of cGMP a nd cAMP in the corpus cavernosum of the rabbit. Materials and methods Male New Zealand White rabbits (2.5 kg) were killed and their penises rapidly excised, cut into segments and pooled. Penile segments were th en incubated with various concentrations of sildenafil or papaverine. The formation of cGMP was stimulated with increasing concentrations of sodium nitroprusside (SNP) and the cGMP and cAMP concentrations measu red by radioimmunoassay. Responses were compared to those obtained wit h papaverine, which is used therapeutically as an erectogen. Results i n the presence or absence of SNP, sildenafil increased cGMP concentrat ions in rabbit penile tissue with increasing dose; the increase was gr eatest (about 28-fold) when cGMP was stimulated with SNP (up to 10 mu mol/L). At all stimulatory concentrations of SNP, the effective concen trations for 50% stimulation (EC50) of sildenafil were 430-520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhan ced cGMP formation in response to SNP, but at much higher concentratio ns than did sildenafil (greater than or equal to 10 mu mol/L). Conclus ions Sildenafil specifically increases cGMP levels in rabbit corpora c avernosa; the increase is greater in the presence of SNP indicating th at, in vivo, sildenafil may enhance erection by the augmentation of ni tric oxide-mediated relaxation pathways. The erectogenic effect of sil denafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafi l as a potent and highly selective inhibitor of cGMP-specific PDE.