Comparison of the effects of nitric oxide and peroxynitrite on the 12-lipoxygenase and cyclooxygenase metabolism of arachidonic acid in rabbit platelets.
The effects of a new type of nitric oxide (NO)-releasing compound, 1-hydroxyl-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC7), and peroxynitrite (ONOO-) on the formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), thromboxane (TX) B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) from exogenous arachidonic acid in washed rabbit platelets have been compared. At concentrations of 5 microM and below, NOC7 inhibited 12-HETE formation (56.5-98.8% inhibition). Moreover, NOC7 inhibited TXB2 and HHT formation at concentrations ranging from 5 to 20 microM (TXB2, 62.2-88.1% inhibition; HHT, 11.6-62.2% inhibition). ONOO- had little or no effect on the production of these three metabolites at concentrations of up to 50 microM. Experiments utilizing a new class of NO antidote, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, revealed that the observed effects of NOC7 are caused by NO. The effects of NO were reversed by addition of the superoxide generating system (xanthine plus xanthine oxidase and catalase), indicating that superoxide is a vital modulator of the action of NO. These results suggest that NO, but not ONOO- (up to 50 microM), can be a potent dual inhibitor of the 12-lipoxygenase and cyclooxygenase activities in platelets and that superoxide is an important regulator of the action of NO.
Department of Hygienic Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
Y
Y
Fujimoto
S
S
Tagano
K
K
Ogawa
S
S
Sakuma
T
T
Fujita
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D014226:Triazenes / Q000494:pharmacology*; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
C100973:(1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-3-aminopropyl)-3-methyl-1-triazene; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D016859:Lipoxygenase Inhibitors; D009566:Nitrates; D014226:Triazenes; D013481:Superoxides; D019820:Xanthine; C039642:peroxynitric acid; D016718:Arachidonic Acid; D009569:Nitric Oxide; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D013929:Thromboxane B2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002374:Catalase; D001092:Arachidonate 12-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D014969:Xanthine Oxidase