Prostaglandin endoperoxide-dependent vasospasm in bovine coronary arteries after nitration of prostacyclin synthase

Br J Pharmacol. 1999 Mar;126(6):1283-92. doi: 10.1038/sj.bjp.0702434.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / physiology
  • Animals
  • Carbon Radioisotopes
  • Cattle
  • Coronary Vasospasm / physiopathology*
  • Coronary Vessels / drug effects
  • Coronary Vessels / metabolism
  • Coronary Vessels / physiopathology*
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / analysis
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dinoprostone / metabolism
  • Epoprostenol / metabolism
  • Immunohistochemistry
  • In Vitro Techniques
  • Intramolecular Oxidoreductases / analysis
  • Intramolecular Oxidoreductases / antagonists & inhibitors
  • Intramolecular Oxidoreductases / metabolism*
  • Nitrates / metabolism
  • Nitrates / pharmacology
  • Oxidants / pharmacology
  • Potassium Chloride / pharmacology
  • Prostaglandin Antagonists / pharmacology
  • Prostaglandin H2
  • Prostaglandins / metabolism
  • Prostaglandins H / pharmacology
  • Prostaglandins H / physiology*
  • Proteins / analysis
  • Tyrosine / analogs & derivatives
  • Tyrosine / analysis
  • Vasoconstriction / physiology
  • Vasodilation / physiology

Substances

  • Carbon Radioisotopes
  • Cytochrome P-450 Enzyme Inhibitors
  • Nitrates
  • Oxidants
  • Prostaglandin Antagonists
  • Prostaglandins
  • Prostaglandins H
  • Proteins
  • Angiotensin II
  • peroxynitric acid
  • 3-nitrotyrosine
  • Prostaglandin H2
  • Tyrosine
  • azo analog I
  • Potassium Chloride
  • Cytochrome P-450 Enzyme System
  • Epoprostenol
  • Intramolecular Oxidoreductases
  • prostacyclin synthetase
  • Dinoprostone