The cyclic GMP-specific phosphodiesterase inhibitor, sildenafil, stimulates human sperm motility and capacitation but not acrosome reaction

Capacitation is the series of transformations that spermatozoa undergo in t he female genital tract in order to bind to the zona pellucida, initiate th e acrosome reaction, and fertilize an egg. Cyclic adenosine monophosphate ( cAMP) plays an important role in this process and its levels are regulated by 2 key enzymes, adenylyl cyclase and cyclic nucleotide phosphodiesterase (PDE), the latter being involved in cAMP degradation. Evidence was provided for the involvement of PDE in sperm motility and capacitation. Of the 10 g ene families of PDE that exist in mammalian tissues, the calcium-calmodulin -dependent (type 1) and the cAMP-specific (type 4) have been found in human spermatozoa. Using sildenafil, we investigated a highly potent cyclic guan osine monophosphate (cGMP)-specific PDE (type 5) inhibitor and whether this PDE is present in human spermatozoa and is involved in sperm functions. Si ldenafil inhibited PDE activity of Percoll-washed spermatozoa with an IC50 of 97 +/- 3 and 33 +/- 3 muM when cAMP and cGMP, respectively, were used as substrates. Because the IC50 of sildenafil obtained for PDE type 5 is much lower (2 to 6 nM) than that obtained with sperm PDE, the data suggest that PDE type 5 represents only a small fraction of the whole PDE activity of s permatozoa. Sildenafil causes dose-dependent increases in sperm cAMP levels and capacitation, which are associated with an increase in the levels of t yrosine phosphorylation of 2 fibrous sheath proteins (p105/81). Sperm veloc ity, amplitude of lateral head displacement, and hyperactivation were incre ased at 30-180 minutes. Sildenafil did not trigger the acrosome reaction in capacitated spermatozoa. These results suggest that under our experimental conditions, sildenafil triggers human sperm motility and capacitation, pro bably via its inhibitory action on PDE activity other than type 5 with a re sultant rise in cAMP levels.