Xanthine‐analog,KMUP‐2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erection

The pharmacological properties of KMUP‐2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP‐2 caused relaxations that were attenuated by removed endothelium, high K⁺, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 μM) and ODQ (1 μM), a NOS inhibitor, L‐NAME (100 μM), a K⁺ channel blocker TEA (10 mM), a K_ATP channel blocker glibenclamide (1 μM), a voltage‐dependent K⁺ channel blocker 4‐AP (100 μM), and the Ca²⁺‐dependent K⁺ channel blockers apamin (1 μM) and charybdotoxin (ChTX, 0.1 μM). The relaxant responses of KMUP‐2 (0.01, 0.05, 0.1 μM) together with a PDE inhibitor, IBMX (0.5 μM), had additive effects on rabbit aorta and CCSM. Additionally, KMUP‐2 (100 μM) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP‐2 (0.1–100 μM) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 μM) and ODQ (10 μM). Obviously, the relaxant effects of KMUP‐2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP‐2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K⁺ channels in rabbit aorta and CCSM. KMUP‐2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP‐1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose‐dependent manner. It is concluded that both the increases of cGMP and the opening activity of K⁺ channels play prominent roles in KMUP‐2‐induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162–172, 2002. © 2002 Wiley‐Liss, Inc.