Prostaglandin endoperoxide-dependent vasospasm in bovine coronary arteries after nitration of prostacyclin synthase.
In the present study we used a bioassay to study the effects of peroxynitrite (ONOO-) on angiotensin II (A-II)-triggered tension in isolated bovine coronary arteries in order to show the consequences of the previously reported PGI2-synthase inhibition by ONOO- in this model. The following results were obtained: 1. 1 micromol L(-1) ONOO- impaired A-II-induced vasorelaxation and caused a second long lasting constriction phase. Indomethacin (10(-5)M) prevented both effects. U51605, a dual blocker of PGI2-synthase and thromboxane (TX)A2-synthase mimicked the effects of ONOO-. 2. The selective TXA2/prostaglandin endoperoxide (PGH2) receptor antagonist SQ29548 antagonized the second vasoconstriction phase after ONOO- -treatment. Since a generation of TXA2 and 8-iso-prostaglandin F2alpha could be excluded a direct action of unmetabolized PGH2 on the TXA2/PGH2 receptor was postulated. 3. ONOO- dose-dependently inhibited the conversion of 14C-PGH2 into 6-keto-PGF1alpha in isolated bovine coronary arteries with an IC50-value of 100 nM. 4. Immunoprecipitation of 3-nitrotyrosine-containing proteins with a monoclonal antibody revealed PGI2-synthase as the only nitrated protein in bovine coronary arteries treated with 1 micromol 1(-1) ONOO-. 5. Using immunohistochemistry a co-localization of PGI2-synthase and nitrotyrosine-containing proteins was clearly visible in both endothelial and vascular smooth muscle cells. We concluded that ONOO- not only eliminated the vasodilatory, growth-inhibiting, antithrombotic and antiadhesive effects of PGI2 but also allowed and promoted an action of the potent vasoconstrictor, prothrombotic agent, growth promoter, and leukocyte adherer, PGH2.
Zou
M
M
Faculty of Biology, University of Konstanz, Germany.
Jendral
M
M
Ullrich
V
V
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002250:Carbon Radioisotopes; D002417:Cattle; D003329:Coronary Vasospasm / Q000503:physiopathology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D044262:Prostaglandin H2; D011453:Prostaglandins / Q000378:metabolism; D011463:Prostaglandins H / Q000494:pharmacology / Q000502:physiology*; D011506:Proteins / Q000032:analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D009566:Nitrates; D016877:Oxidants; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D011463:Prostaglandins H; D011506:Proteins; D000804:Angiotensin II; C039642:peroxynitric acid; C002744:3-nitrotyrosine; D044262:Prostaglandin H2; D014443:Tyrosine; C015014:azo analog I; D011189:Potassium Chloride; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone