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International Journal of Impotence Research (2001) 13, 240246
2001 Nature Publishing Group All rights reserved 0955-9930/01 $15.00
www.nature.com/ijirDual mechanism of action of nicorandil on rabbit corpus cavernosal
smooth muscle toneGC Hsieh1*, T Kolasa1, JP Sullivan1 and JD Brioni11Neurological and Urological Diseases Research, Abbott Laboratories, Illinois, USAThe potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male
erectile dysfunction has recently been suggested based on positive clinical outcomes following
intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation
of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function
preclinically and clinically. The aim of the present study was to determine the effects and
mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of
smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenylephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC50 of 15 mM. The effects of nicorandil were only partially reversed
by the KATP channel blocker glyburide (10 mM) or by a soluble guanylate cyclase (sGC) inhibitor
1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 mM). However, a combination of ODQ and
glyburide completely blocked the relaxant effects of nicorandil. The results of the present study
indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves
activation of KATP channels and stimulation of soluble guanylate cyclase. International Journal of
Impotence Research (2001) 13, 240246.Keywords: nicorandil; erectile dysfunction; KATP channel; guanylate cyclaseIntroductionCorpus cavernosal smooth muscle tone is controlled
by a number of discrete signaling pathways coordinated at the level of the peripheral and central
nervous system. This smooth muscle tone ultimately regulates penile accidity and erection.1
Contraction is primarily mediated by alphaadrenoceptor stimulation1,2 while relaxation is
mediated by the interaction of several types of
neurotransmission, including nonadrenergic noncholinergic (NANC) neural input and the release of
nitric oxide,1,3 Nitric oxide, released from NANC
nerve terminals and from cholinergically-activated
endothelial cells, diffuses into adjacent smooth
muscle cells where it activates soluble guanylate
cyclase. This increases the intracellular levels of
cyclic guanosine monophosphate (cGMP) that leads
to the relaxation of cavernosal smooth muscle. The
increased blood ow and engorgement of the
trabecular spaces results in veno-occlusion and
penile erection. Nitrovasodilators (organic nitrates
...