YC-1 potentiates the nitric oxide/cyclic GMP pathway in corpus cavernosum and facilitates penile erection in rats.
The aim of present study was to characterize the in vitro and in vivo pharmacological effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a soluble guanylate cyclase activator, on corpus cavernosal smooth muscle and penile erectile activity. YC-1 relaxed phenylephrine precontracted cavernosal smooth muscle (EC(50)=4.4 microM) and this effect was partially antagonized by 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ). ODQ is a selective soluble guanylate cyclase inhibitor that completely blocked the relaxation induced by sodium nitroprusside, suggesting that YC-1 binds to soluble guanylate cyclase at a different site from nitric oxide (NO). Both YC-1 and sodium nitroprusside, but not sildenafil (1-100 microM) caused concentration-dependent increases in cyclic GMP levels in cultured rabbit cavernosal smooth muscle cells and produced synergistic effects. Intraperitoneal administration of YC-1 (10 micromol/kg) evoked penile erection in rats with 70% incidence. More importantly, YC-1 was able to significantly augment the pro-erectile effects of a suboptimal dose of apomorphine. These results suggest that the soluble guanylate cyclase activator YC-1 increases cyclic GMP levels, leading to relaxation of cavernosal smooth muscle. These biochemical events may be related to the pro-erectile properties of YC-1 in vivo.
Hsieh
Gin C
GC
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6119, USA. gin.c.hsieh@abbott.com
O'Neill
Alyssa B
AB
Moreland
Robert B
RB
Sullivan
James P
JP
Brioni
Jorge D
JD
D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D007191:Indazoles; D010069:Oxadiazoles; D011810:Quinoxalines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP