Effects of sildenafil, a type‐5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro

Abstract

Objective To investigate further the mechanisms of action of sildenafil, a highly selective and potent inhibitor of type 5 cGMP phosphodiesterase (PDE5) that has proved effective in the treatment of erectile dysfunction, by assessing its effect on the in vitro formation of cGMP and 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 then 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 measured by radioimmunoassay. Responses were compared to those obtained with papaverine, which is used therapeutically as an erectogen. Results In the presence or absence of SNP, sildenafil increased cGMP concentrations in rabbit penile tissue with increasing dose; the increase was greatest (about 28‐fold) when cGMP was stimulated with SNP (up to 10 μmol/L). At all stimulatory concentrations of SNP, the effective concentrations for 50% stimulation (EC50 ) of sildenafil were 430–520 nmol/L. Concentrations of cAMP were unaltered by sildenafil. Papaverine enhanced cGMP formation in response to SNP, but at much higher concentrations than did sildenafil (≥10 μmol/L). Conclusions Sildenafil specifically increases cGMP levels in rabbit corpora cavernosa; the increase is greater in the presence of SNP indicating that, in vivo, sildenafil may enhance erection by the augmentation of nitric oxide‐mediated relaxation pathways. The erectogenic effect of sildenafil is mediated by a specific enhancement of cGMP accumulation in the corpus cavernosum, consistent with the known activity of sildenafil as a potent and highly selective inhibitor of cGMP‐specific PDE.

Sexual dysfunction after pelvic surgery

“…It is a nonspecific phosphodiesterase (PDE) inhibitor that increases cyclic AMP and cyclic GMP. 78 Phentolamine, another vasoactive agent, is a direct a-adrenoceptor blocker. However, phentolamine alone cannot produce rigid erections, so it is commonly used in combination with other agents.…”

Synergistic effects of sildenafil on relaxation of rabbit and rat cavernosal smooth muscles when combined with various vasoactive agents

“…Therefore, the combination of sildena®l plus intraurethral or intracavernosal PGE 1 , or intracavernosal forskolin or VIP, might be effective in patients with ED in whom monotherapy with these agents has failed. That papaverine and sildena®l were not synergistic in this study might be because they have similar mechanisms of action on the relaxation of cavernosal smooth muscles [20,26,27]. To ascertain why there are different synergistic effects of cAMP-mediated agents plus sildena®l, the intracellular cAMP level should be measured, and expression and functional studies of receptors of VIP and PGE 1 after treatment with forskolin, VIP and PGE 1 conducted in cavernosal smooth muscles.…”

“…Doherty et al [19] reported that direct injection of various PGE 5 inhibitors into cat corpus cavernosum caused dose-dependent increases in intracorporal pressure. Furthermore, Jeremy et al [20] reported that 10 mmol/L sildena®l alone increased the cGMP level up to ®ve-fold in rabbit corpus cavernosum tissue, and up to 28-fold in the presence of 1 mmol/L SNP. Reportedly, sildena®l alone signi®cantly reduced the basal tone in unstimulated rabbit cavernosal smooth muscle [18].…”

Effects of the specific phosphodiesterase inhibitors on alloxan-induced diabetic rabbit cavernous tissue in vitro

“…20 It has a very de®nite effect upon erectile activity in humans 21 and sildena®l promotes penile erection through increased intracellular cGMP in response to sexual stimulation potentiating smooth muscle relaxation. 22 In this study, papaverine was used as a standard inhibitor, and all results obtained with other more speci®c inhibitors were compared with papaverine. Zaprinast and sulmazole, cGMP-speci®c PDE inhibitors, 23 relaxed corpus cavernosum with pD 2 Figure 2 (a) Zaprinast concentration ± response curves in isolated rabbit corpus cavernosum strips precontracted with phenylephrine 10 76 ± 3610 76 M. Each point is expressed as a percentage of the contraction induced by phenylephrine and is given as the mean AE s.e.m.…”