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CARDIOVASCULAR

The Inducible Nitric-Oxide Synthase Modulates Endothelin-1-Dependent Release of Prostacyclin and Inhibition of Platelet Aggregation ex Vivo in the Mouse

Department of Pharmacology, Institut de Pharmacologie de Sherbrooke (E.C., I.B., P.D.-J.) and Division of Rheumatology (A.J.dB.-F.), School of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada

Nitric oxide and other reactive oxygen species generated by nitric-oxide synthases (NOS) modulate, among several other cellular responses, the production of eicosanoids and platelet aggregation. The roles of specific NOS in these two phenomena remain to be determined. Thus, the present study assessed whether inducible NOS (iNOS) and endothelial NOS (eNOS) modulate in a similar manner the production of eicosanoids and platelet aggregation. Mice knocked out for eNOS (eNOS–/–) or iNOS (iNOS–/–) and their wild-type (WT) congeners were used to analyze agonist-induced increases in plasma levels of eicosanoids as well as inhibition of platelet aggregation ex vivo. Systemically administered endothelin-1 (ET-1) triggered an increase in plasma levels of 6-keto prostaglandin F₁ (6-keto PGF₁) in WT and eNOS–/– but not in iNOS–/– mice. ET-1 (0.01–1 nmol/kg) also induced a dose-dependent inhibition of platelet aggregation in WT and eNOS–/– but not in iNOS–/– mice. Another agonist, bradykinin (10 nmol/kg), triggered the release of 6-keto PGF₁ and inhibited platelet aggregation in all strains of mice studied. In addition, ADP-induced platelet aggregation in vitro was similarly reduced by iloprost (100 nM) in iNOS–/– mice and WT congeners. In another series of experiments, ET-1 (0.1 nmol/kg) significantly increased 8-isoprostane plasma levels in WT but not in iNOS–/– mice. Finally, a 3-week treatment with anti-oxidants inhibited the capacity of ET-1 to significantly increase plasma 6-keto PGF₁ in WT mice. We show for the first time that iNOS is involved in the control of ET-1-induced prostacyclin release and related inhibition of platelet aggregation in the murine model.

Address correspondence to: Dr. Pedro D'Orléans-Juste, Department of Pharmacology, School of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, QC J1H 5N4, Canada. E-mail: labpdj{at}usherbrooke.ca