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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

The Relaxant Activity of 4,7-Dimethyl-1,2,5-oxadiazolo[3,4-d]-pyridazine 1,5,6-Trioxide in the Mouse Corpus Cavernosum

Cemil Göçmen, H. Sinem Büyüknacar, Alexander Ya Kots, Ferid Murad, Olcay Kirolu, and Eda Karabal Kumcu

Department of Pharmacology, Çukurova University Medical School, Adana, Turkey (C.G., H.S.B., O.K., E.K.K.); and Department of Integrative Biology and Pharmacology, The University of Texas at Houston Medical School, Houston, Texas (A.Y.K., F.M.)

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-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.

Address correspondence to: Dr. Cemil Göçmen, Department of Pharmacology, Çukurova University Medical School, TR-01330 Adana, Turkey. E-mail: cgocmen{at}cu.edu.tr

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