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

Abstract

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. NEthylmaleimide 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.The modulatory role of nitric oxide in penile erection has recently been the subject of extensive investigations. Nitric oxide is synthesized by erectile-autonomic nerves and vascular endothelium of the cavernous tissue, and nitric oxidemediated transmission is defined as nitrergic transmission (Saenz de Tejada, 1992). Nitric oxide is a potent activator of soluble guanylate cyclase (sGC), which catalyzes the biosynthesis of cGMP. cGMP causes a trabecular smooth muscle relaxation in the penis, facilitating blood flow into the cavernous tissue and thus eliciting an erection (Saenz de Tejada, 1992).Certain conditions, including aging and vascular and metabolic diseases, can result in the impaired synthesis, release, or bioavailability of NO in the autonomic nerves or endothelium in penile tissue (Saenz de Tejada, 2004). This results in erectile dysfunction due to insufficient relaxation of cavernous smooth muscle and dilation of penile arteries. Certain prodrugs, which can release nitric oxide or nitric oxide-like species under physiological conditions (nitric oxide donors), have been widely used in the therapy of erectile dysfu...

Pyridopyrimidine derivatives as inhibitors of cyclic nucleotide synthesis: Application for treatment of diarrhea

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A Class of Semiconducting Polymers as Potential Materials for Polymer Solar Cells

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