Enhancement of motility and acrosome reaction in human spermatozoa: differential activation by type-specific phosphodiesterase inhibitors

Inhibition of sperm phosphodiesterase (PDE) has been shown to increase cAMPconcentrations and stimulate motility and the acrosome reaction. Whileseveral PDE genes exist in mammals, little is known about the physiologicalrole of PDE forms expressed in human spermatozoa. Using type-selectiveinhibitors, we identified two of the PDE forms expressed in humanspermatozoa and studied their involvement in sperm function. Selectiveinhibitors of calcium-calmodulin-regulated PDE1 (8-methoxy-isobutyl-methylxanthine) and cAMP-specific PDE4 (RS-25344, Rolipram) wereused to study PDE forms in human sperm extracts. 8-MeIBMX andRolipram/RS-25344 inhibited sperm PDE activity by 35-40 and 25-30%respectively. Subcellular fractionation of the sperm homogenate suggeststhese pharmacologically distinct forms may be located in separate cellularregions. To evaluate the functional significance of different PDE forms,the effect of type-specific PDE inhibition on sperm motility and theacrosome reaction was examined. PDE4 inhibitors enhanced sperm motilityover controls without affecting the acrosome reaction, while PDE1inhibitors selectively stimulated the acrosome reaction. These dataindicate at least two distinct PDE types exist in human spermatozoa. Ourfindings also support the hypothesis that PDE subtypes affect spermfunction by regulating separate pools of cAMP and may ultimately offernovel treatments to infertile couples with abnormal semen parameters.