The relaxant activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]-pyridazine 1,5,6-trioxide in the mouse corpus cavernosum

J Pharmacol Exp Ther. 2006 Feb;316(2):753-61. doi: 10.1124/jpet.105.094250. Epub 2005 Oct 27.

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(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.

MeSH terms

  • Animals
  • Cyclic N-Oxides / pharmacology*
  • Electric Stimulation
  • Guanylate Cyclase / metabolism*
  • In Vitro Techniques
  • Male
  • Mice
  • Muscle Relaxation / drug effects*
  • Muscle, Smooth, Vascular / drug effects*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Penis / blood supply
  • Penis / drug effects*
  • Pyridazines / pharmacology*
  • Sulfhydryl Compounds / pharmacology

Substances

  • 4,7-dimethyl-1,2,5-oxadiazolo-(3,4-d)pyridazine 1,5,6-trioxide
  • Cyclic N-Oxides
  • Nitric Oxide Donors
  • Pyridazines
  • Sulfhydryl Compounds
  • Nitric Oxide
  • Guanylate Cyclase