The relaxant activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]-pyridazine 1,5,6-trioxide in the mouse corpus cavernosum.
We have studied the effect of an activator of soluble guanylate cyclase 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (FPTO) on the tone and nitrergic relaxation responses of mouse cavernous strips and compared FPTO to a known nitric oxide donor sodium nitroprusside. FPTO thiol-dependently generated nitric oxide measured by polarography and activated purified human soluble guanylate cyclase. FPTO and sodium nitroprusside relaxed the cavernous tissue in a concentration-dependent manner. A nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine did not alter the relaxations to FPTO or sodium nitroprusside, whereas soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) suppressed relaxation to FPTO and sodium nitroprusside. Exogenously added thiols L-cysteine or dithiothreitol inhibited the relaxant responses to FPTO but not to sodium nitroprusside, whereas glutathione did not influence the responses to both agents. Thiol alkylation agent N-ethylmaleimide significantly enhanced FPTO-induced relaxation, and thiol-modifying agent diamide inhibited relaxation to FPTO. The potentiating effect of N-ethylmaleimide was neutralized by coadministration of N-ethylmaleimide with glutathione, L-cysteine, dithiothreitol, or ODQ. N-Ethylmaleimide but not diamide significantly inhibited relaxation induced by sodium nitroprusside. FPTO potently suppressed contraction to electrical field stimulation, which was prevented by glutathione or L-cysteine. In addition, FPTO did not affect relaxation produced by electrical field stimulation in phenylephrine-precontracted tissue. Our results show that FPTO can relax mouse corpus cavernosum and that the relaxant activity of this agent is thiol- and soluble guanylate cyclase-dependent. This effect could be potentiated by N-ethylmaleimide. FPTO does not potentiate nitrergic relaxation induced by electrical field stimulation.
Göçmen
Cemil
C
Department of Pharmacology, Cukurova University Medical School, Adana, Turkey. cgocmen@cu.edu.tr
Büyüknacar
H Sinem
HS
Kots
Alexander Ya
AY
Murad
Ferid
F
Kiroglu
Olcay
O
Kumcu
Eda Karabal
EK
D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004558:Electric Stimulation; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010413:Penis / Q000098:blood supply / Q000187:drug effects*; D011724:Pyridazines / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology
C407739:4,7-dimethyl-1,2,5-oxadiazolo-(3,4-d)pyridazine 1,5,6-trioxide; D003497:Cyclic N-Oxides; D020030:Nitric Oxide Donors; D011724:Pyridazines; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D006162:Guanylate Cyclase