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1 Certain heterocyclic N-oxides are vasodilators and inhibitors of platelet aggregation. The pharmacological activity of the furoxan derivative condensed with pyridazine di-N-oxide 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide (FPTO) and the corresponding furazan (FPDO) was studied. 2 FPTO reacted with thiols generating nitrite (NO), S-nitrosoglutathione and hydroxylamine (nitroxyl) and converted oxyHb to metHb. FPDO did not generate detectable amounts of NO-like species but reacted with thiols and oxyHb. 3 FPTO and FPDO haem-dependently stimulated the activity of soluble guanylate cyclase (sGC) and this stimulation was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and by 0.1 mM dithiothreitol. 4 FPTO relaxed noradrenaline-precontracted aortic rings and its concentration-response curve was biphasic (pIC 50 =9.03+0.13 and 5.85+0.06). FPDO was signi®cantly less potent vasodilator (pIC 50 =5.19+0.14). The vasorelaxant activity of FPTO and FPDO was inhibited by ODQ. oxyHb signi®cantly inhibited only FPTO-dependent relaxation. 5 FPTO and FPDO were equipotent inhibitors of ADP-induced platelet aggregation (IC 50 =0.63+0.15 and 0.49+0.05 mM, respectively). The antiplatelet activity of FPTO (but not FPDO) was partially suppressed by oxyHb. The antiaggregatory eects of FPTO and FPDO were only partially blocked by sGC inhibitors. 6 FPTO and FPDO (10 ± 20 mM) signi®cantly increased cyclic GMP levels in aortic rings and platelets and this increase was blocked by ODQ. 7 Thus, FPTO can generate NO and, like FPDO, reacts with thiols and haem. The vasorelaxant activity of FPTO and FPDO is sGC-dependent and a predominant role is played by NO at FPTO concentrations below 1 mM. On the contrary, inhibition of platelet aggregation is only partially related to sGC activation.

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Preincubation of bovine caudate nucleus membranes with the 2',3'-dialdehyde of GTP (oGTP) reduces adenylate cyclase activation by guanylyl imidodiphosphate (GppNHp) in a time-dependent fashion. A slower rate of inhibition is observed if membranes are treated with both GTP and oGTP. The efficacy of oGTP action is enhanced by raising the Mg*+ concentration. Reduction of adenylate cyclase sensitivity to GppNHp is followed by an irreversible decrease of enzyme stimulation by forskolin. Addition of a Lubrol soluble preparation from guinea pig lung membranes to oGTP-treated caudate nucleus membranes causes restoration of the adenylate cyclase sensitivity to GppNHp. These data suggest that oGTP blocks the GTPbinding site of the adenylate cyclase system localized on the N, protein. Such modification leads to the elimination of the N,-mediated regulation of the enzyme. GTP 2'.3'-dialdehyde Adenylate cyclase N, protein