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 cyclase (SGC); however, the lack of a selective inhibitor of this enzyme has 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-nitroso-DL-penicillamine in human platelets and rat vascular smooth muscle (IC50 = 10-60 nM and <10 nM, respectively) and that this is accompanied by prevention of the platelet inhibitory and vasodilator actions of NO donors. ODQ also inhibited the antiaggregatory action of NO generated 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 induction 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 activity, nor did it react with NO. It did, however, potently (IC50 approximately 10 nM) inhibit the activity of the SGC in cytosol obtained from crude extract of rat aortic smooth muscle. Thus ODQ prevents the actions of NO on platelets and vascular smooth muscle through its potent inhibitory effect on the SGC.
Moro
M A
MA
Wellcome Research Laboratories, Beckenham, United Kingdom.
Russel
R J
RJ
Cellek
S
S
Lizasoain
I
I
Su
Y
Y
Darley-Usmar
V M
VM
Radomski
M W
MW
Moncada
S
S
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D006152:Cyclic GMP / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011464:Epoprostenol / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000378:metabolism; D010974:Platelet Aggregation / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D010108:Oxyhemoglobins; D011810:Quinoxalines; D009569:Nitric Oxide; C024942:S-nitrosopenicillamine; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP