KMUP-1 relaxes rabbit corpus cavernosum smooth muscle in vitro and in vivo: involvement of cyclic GMP and K(+) channels.
1. In isolated endothelium-intact or denuded rabbit corpus cavernosum preconstricted with phenylephrine, KMUP-1 (0.001 - 10 microM) caused a concentration-dependent relaxation. 2. This relaxation of KMUP-1 was attenuated by endothelium removed, high K(+) and pretreatments with a soluble guanylyl cyclase (sGC) inhibitor ODQ (1 microM), a NOS inhibitor L-NAME (100 microM), a K(+) channel blocker TEA (10 mM), a K(ATP) channel blocker glibenclamide (1 microM), a voltage-dependent K(+) channel blocker 4-AP (100 microM) and Ca(2+)-dependent K(+) channel blockers apamin (1 microM) and charybdotoxin (ChTX, 0.1 microM). 3. The relaxant responses of KMUP-1 (0.01, 0.05, 0.1 microM) together with a PDE inhibitor IBMX (0.5 microM) had additive actions on rabbit corpus cavernosum smooth muscle (CCSM). 4. KMUP-1 (0.01 - 10 microM) induced increase of intracellular cyclic GMP level in the primary cell culture of rabbit CCSM. This increase in cyclic GMP content was abolished in the presence of ODQ (10 microM). 5. Both KMUP-1 and sildenafil at 0.2, 0.4, 0.6 mg kg(-1) caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. These in vivo activities of ICP for sildenafil and KMUP-1 are consistent with those of in vitro effects of cyclic GMP. 6. KMUP-1 has the following merits: (1) inhibition of PDE or cyclic GMP breakdown, (2) stimulation of NO/sGC/cyclic GMP pathway, and (3) subsequent stimulation of K(+) channels, in rabbit CCSM. We suggest that these merits play prominent roles in KMUP-1-induced CCSM relaxation-associated increases of ICP and penile erection.
Lin
Rong-Jyh
RJ
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Wu
Bin-Nan
BN
Lo
Yi-Ching
YC
Shen
Kuo-Pyng
KP
Lin
Young-Tso
YT
Huang
Chun-Hsiung
CH
Chen
Ing-Jun
IJ
D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D014970:Xanthines / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011687:Purines; D013450:Sulfones; D014970:Xanthines; C439304:KMUP 1; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP