The proconvulsant effect of sildenafil in mice: role of nitric oxide–cGMP pathway

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)‐mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO‐mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)–cGMP pathway. The effect of sildenafil (1–40 mg kg −1 ) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil‐induced effects with NO–cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N (G)‐nitro‐ L ‐arginine methyl ester ( L ‐NAME), NOS substrate L ‐arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose‐dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L ‐NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO–cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L ‐arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO–cGMP pathway.British Journal of Pharmacology (2006) 147 , 935–943. doi: 10.1038/sj.bjp.0706680