KMUP‐1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo : involvement of cyclic GMP and K + channels

In isolated endothelium‐intact or denuded rabbit corpus cavernosum preconstricted with phenylephrine, KMUP‐1 (0.001 – 10 μ M ) caused a concentration‐dependent relaxation. This relaxation of KMUP‐1 was attenuated by endothelium removed, high K + and pretreatments with a soluble guanylyl cyclase (sGC) inhibitor ODQ (1 μ M ), a NOS inhibitor L ‐NAME (100 μ M ), a K + channel blocker TEA (10 m M ), a K ATP channel blocker glibenclamide (1 μ M ), a voltage‐dependent K + channel blocker 4‐AP (100 μ M ) and Ca 2+ ‐dependent K + channel blockers apamin (1 μ M ) and charybdotoxin (ChTX, 0.1 μ M ). The relaxant responses of KMUP‐1 (0.01, 0.05, 0.1 μ M ) together with a PDE inhibitor IBMX (0.5 μ M ) had additive actions on rabbit corpus cavernosum smooth muscle (CCSM). KMUP‐1 (0.01 – 10 μ M ) induced increase of intracellular cyclic GMP level in the primary cell culture of rabbit CCSM. This increase in cyclic GMP content was abolished in the presence of ODQ (10 μ M ). Both KMUP‐1 and sildenafil at 0.2, 0.4, 0.6 mg kg −1 caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose‐dependent manner. These in vivo activities of ICP for sildenafil and KMUP‐1 are consistent with those of in vitro effects of cyclic GMP. KMUP‐1 has the following merits: (1) inhibition of PDE or cyclic GMP breakdown, (2) stimulation of NO/sGC/cyclic GMP pathway, and (3) subsequent stimulation of K + channels, in rabbit CCSM. We suggest that these merits play prominent roles in KMUP‐1‐induced CCSM relaxation‐associated increases of ICP and penile erection.British Journal of Pharmacology (2002) 135 , 1159–1166; doi: 10.1038/sj.bjp.0704554