Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue

Objectives. To further investigate the mechanism of action of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phos phodiesterase 5 (PDE5), that has been proved to be effective in the treatme nt of male erectile dysfunction. We assessed the effects of sildenafil on t he in vitro formation of cGMP and cyclic adenosine monophosphate (cAMP) in isolated human corpus cavernosum and cardiac muscle. Methods. Isolated segments of human corpus cavernosum and cardiac muscle we re exposed to increasing concentrations of sildenafil. The dose-dependent a ccumulation of cGMP and cAMP was determined in the tissue samples by means of radioimmunoassays. Responses of the isolated tissue preparations to sild enafil were compared with those obtained with the reference compounds sodiu m nitroprusside, Forskolin, and milrinone. Results. In the concentration range 0.01 to 1 mu M, there was only a minor effect of sildenafil on cGMP levels in isolated human cavernous and cardiac tissues, In contrast, sildenafil was found to increase cAMP significantly in both cavernous and cardiac tissue in physiologic and supraphysiologic co ncentrations. The stimulation of cAMP by sildenafil was more pronounced in cavernous than in cardiac tissue. Concentrations of cGMP in the cardiac str ips were unaltered by milrinone; cAMP was stimulated starring at a concentr ation of 0.05 mu M. In the range of 0.1 to 1.0 mu M, the in vitro effect of sildenafil on cAMP levels in the cardiac samples was almost equivalent to that of milrinone. Conclusions. Our findings provide a potential mechanism for the cardiovascu lar side effects that have been reported with sildenafil use, highlighting the fact that a "cross-talk" between cGMP and cAMP-dependent signal transdu ction pathways might exist in human cavernous and cardiac muscle that may b e of pharmacologic significance. (C) 2000, Elsevier Science Inc.