CGMP MEDIATES THE VASCULAR AND PLATELET ACTIONS OF NITRIC-OXIDE - CONFIRMATION USING AN INHIBITOR OF THE SOLUBLE GUANYLYL CYCLASE

The L-arginine:nitric oxide (NO) pathway is believed to exert many of its physiological effects via stimulation of the soluble guanylyl cycl ase (SGC); however, the lack of a selective inhibitor of this enzyme h as prevented conclusive demonstration of this mechanism of action, We have found that the compound 1H-[1,2,4]oxadiazolo [4,3,-a] quinoxalin- 1-one (ODQ) inhibits the elevation of cGMP induced by the NO donor S-n itroso-DL-penicillamine in human platelets and rat vascular smooth mus cle (IC50 = 10-60 nM and <10 nM, respectively) and that this is accomp anied by prevention of the platelet inhibitory and vasodiIator actions of NO donors, ODQ also inhibited the antiaggregatory action of NO gen erated by the platelets but did not affect the action of prostacyclin or that of a cGMP mimetic, In addition, ODQ inhibited the vasodilator actions of endogenously released NO and of NO generated after inductio n of NO synthase in vascular preparations, It did not, however, affect the increase in vascular smooth muscle cGMP or the dilatation induced by atrial natriuretic factor, ODQ had no effect on NO synthase activi ty, nor did it react with NO, It did, however, potently (IC50 approxim ate to 10 nM) inhibit the activity of the SGC in cytosol obtained from crude extract of rat aortic smooth muscle. Thus ODQ prevents the acti ons of NO on platelets and vascular smooth muscle through its potent i nhibitory effect on the SGC.