NS11021, a novel opener of large-conductance Ca2+-activated K plus channels, enhances erectile responses in rats

Background and purpose: Large-conductance Ca2+-activated K+ channels (BKCa), located on the arterial and corporal smooth muscle, are potential targets for treatment of erectile dysfunction (ED). This study investigated whether NS11021 (1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-bromo-2-(1H-tetrazol-5-yl)-phenyl]-thiourea), a novel opener of BKCa channels, relaxes erectile tissue in vitro and enhances erectile responses in intact rats. The effects were compared with sildenafil, an inhibitor of phosphodiesterase type 5. Experimental approach: Patch clamp was used to record whole cell current in rat isolated corpus cavernosum smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs). Isometric tension was measured in intracavernous arterial rings and corpus cavernosum strips isolated from rats and men, and simultaneous measurements of intracellular Ca2+ concentration ([Ca2+](i)) and tension were performed in intracavernous arteries. Erectile response was measured in anaesthetized rats. Key results: In patch clamp recordings, NS11021 increased currents sensitive to the selective BKCa channel blocker, iberiotoxin (IbTX) in SMCs, but did not modulate K+ current in HUVECs. NS11021 reduced [Ca2+](i) and tension in penile arteries. IbTX inhibited the vasorelaxation induced by NS11021 and sildenafil in human erectile tissue. NS11021 and sildenafil but not vehicle increased erectile responses in anaesthetized rats, an effect which was abolished after pretreatment with tetraethylammonium. Conclusions and implications: NS11021 leads to relaxation of both intracavernous arteries and corpus cavernosum strips primarily through opening of BKCa channels. It is also effective in facilitating erectile responses in anaesthetized rats. These results suggest a potential for use of BKCa openers in the treatment of ED.