Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue.
OBJECTIVE
To further investigate the mechanism of action of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5), that has been proved to be effective in the treatment of male erectile dysfunction. We assessed the effects of sildenafil on the 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 were exposed to increasing concentrations of sildenafil. The dose-dependent accumulation of cGMP and cAMP was determined in the tissue samples by means of radioimmunoassays. Responses of the isolated tissue preparations to sildenafil were compared with those obtained with the reference compounds sodium nitroprusside, forskolin, and milrinone.


RESULTS
In the concentration range 0.01 to 1 microM, 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 concentrations. The stimulation of cAMP by sildenafil was more pronounced in cavernous than in cardiac tissue. Concentrations of cGMP in the cardiac strips were unaltered by milrinone; cAMP was stimulated starting at a concentration of 0.05 microM. In the range of 0.1 to 1.0 microM, 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 cardiovascular side effects that have been reported with sildenafil use, highlighting the fact that a "cross-talk" between cGMP and cAMP-dependent signal transduction pathways might exist in human cavernous and cardiac muscle that may be of pharmacologic significance.
Stief
C G
CG
Department of Urology, Hannover Medical School, Germany.
Uckert
S
S
Becker
A J
AJ
Harringer
W
W
Truss
M C
MC
Forssmann
W G
WG
Jonas
U
U
D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000096:biosynthesis*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010413:Penis / Q000187:drug effects* / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D005576:Colforsin; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D006152:Cyclic GMP; D020105:Milrinone