Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone.
The 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 EC(50) of 15 microM. The effects of nicorandil were only partially reversed by the K(ATP) channel blocker glyburide (10 microM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 microM). 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 K(ATP) channels and stimulation of soluble guanylate cyclase.
Hsieh
G C
GC
Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. gin.c.hsieh@abbott.com
Kolasa
T
T
Sullivan
J P
JP
Brioni
J D
JD
D000255:Adenosine Triphosphate / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D020108:Nicorandil / Q000378:metabolism / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010413:Penis / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D015221:Potassium Channels; D011810:Quinoxalines; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D020108:Nicorandil; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D005905:Glyburide