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Vasorelaxant and antiplatelet activity of 4,7‐dimethyl‐1,2,5‐oxadiazolo[3,4‐ d ]pyridazine 1,5,6‐trioxide: role of soluble guanylate cyclase, nitric oxide and thiols
Author(s) -
Kots Alexander Ya,
Grafov Mikhail A,
Khropov Yuri V,
Betin Vasily L,
Belushkitalya N,
Busygina Olga G,
Yazykova Marina Yu,
Ovchinnikov Igor V,
Kulikov Alexander S,
Makhova Ni,
Medvedeva Natalya A,
Bulargina Tamara V,
Severina Irina S
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703156
Subject(s) - chemistry , pyridazine , soluble guanylyl cyclase , nitric oxide , dithiothreitol , nitroxyl , hydroxylamine , furoxan , peroxynitrite , pharmacology , stereochemistry , biochemistry , guanylate cyclase , enzyme , superoxide , organic chemistry , medicine
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. 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. FPTO and FPDO haem‐dependently stimulated the activity of soluble guanylate cyclase (sGC) and this stimulation was inhibited by 1 H ‐[1,2,4]oxadiazolo[4,3‐ a ]quinoxalin‐1‐one (ODQ) and by 0.1 m M dithiothreitol. 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 significantly less potent vasodilator (pIC 50 =5.19±0.14). The vasorelaxant activity of FPTO and FPDO was inhibited by ODQ. oxyHb significantly inhibited only FPTO‐dependent relaxation. FPTO and FPDO were equipotent inhibitors of ADP‐induced platelet aggregation (IC 50 =0.63±0.15 and 0.49±0.05 μ M , respectively). The antiplatelet activity of FPTO (but not FPDO) was partially suppressed by oxyHb. The antiaggregatory effects of FPTO and FPDO were only partially blocked by sGC inhibitors. FPTO and FPDO (10–20 μ M ) significantly increased cyclic GMP levels in aortic rings and platelets and this increase was blocked by ODQ. 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 μ M . On the contrary, inhibition of platelet aggregation is only partially related to sGC activation.British Journal of Pharmacology (2000) 129 , 1163–1177; doi: 10.1038/sj.bjp.0703156