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(Hypertension. 2002;40:521.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Angiotensin II AT₁ Receptor Antagonists Inhibit Platelet Adhesion and Aggregation by Nitric Oxide Release

Leszek Kalinowski; Tomasz Matys; Ewa Chabielska; Wodzimierz Buczko; Tadeusz Malinski

From the Department of Chemistry and Biochemistry, Ohio University (L.K., T. Malinski), Athens, Ohio; Department of Laboratory Medicine, Medical University of Gdansk, and the Laboratory of Cellular and Molecular Nephrology, Medical Research Center of the Polish Academy of Science (L.K.), Gdansk; and the Department of Pharmacodynamics, Medical Academy of Bialystok (T. Matys, E.C., W.B.), Poland.

Correspondence to Tadeusz Malinski, Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701. E-mail malinski{at}ohio.edu

This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT₁)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT₁-receptor antagonist–stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT₁-receptor antagonists on platelet adhesion to collagen and thromboxane A₂ analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 µmol/L, which was attenuated by NO synthase inhibitor N^G-nitro-L-arginine methyl ester. The angiotensin II AT₁-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT₁-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N^G-nitro-L-arginine methyl ester. Neither the AT₂ receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A₂/prostaglandin H₂ receptor antagonist SQ29,548 had any effect on angiotensin II AT₁-receptor antagonist–stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT₁-receptor antagonists.

Key Words: platelets • nitric oxide • endothelium • angiotensin II • angiotensin antagonist

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