Published Online
on September 16, 2002

A more recent version of this article appeared on October 1, 2002

This Article Full Text (PDF) All Versions of this Article: 40/4/521    most recent 01.HYP.0000034745.98129.ECv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalinowski, L. Articles by Malinski, T. Search for Related Content PubMed PubMed Citation Articles by Kalinowski, L. Articles by Malinski, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Cardiovascular Pharmacology ACE/Angiotension receptors Aggregation Signal transduction Platelet function inhibitors Antiplatelets Platelets Endothelium/vascular type/nitric oxide

Submitted on April 16, 2002
Revised on May 28, 2002

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

Leszek Kalinowski; Tomasz Matys; Ewa Chabielska; Wodzimierz Buczko; and 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.

^* To whom correspondence should be addressed. E-mail: malinski{at}ohio.edu.

Abstract—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

This article has been cited by other articles:

				K.-H. Su, J.-Y. Tsai, Y. R. Kou, A.-N. Chiang, S.-H. Hsiao, Y.-L. Wu, H.-H. Hou, C.-C. Pan, S.-K. Shyue, and T.-S. Lee Valsartan regulates the interaction of angiotensin II type 1 receptor and endothelial nitric oxide synthase via Src/PI3K/Akt signalling Cardiovasc Res, June 1, 2009; 82(3): 468 - 475. [Abstract] [Full Text] [PDF]

				C. Grothusen, S. Umbreen, I. Konrad, K. Stellos, C. Schulz, B. Schmidt, E. Kremmer, O. Teebken, S. Massberg, M. Luchtefeld, et al. EXP3179 Inhibits Collagen-Dependent Platelet Activation via Glycoprotein Receptor-VI Independent of AT1-Receptor Antagonism: Potential Impact on Atherothrombosis Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1184 - 1190. [Abstract] [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

				I. Chung and G. Y.H. Lip Platelets and heart failure Eur. Heart J., November 2, 2006; 27(22): 2623 - 2631. [Abstract] [Full Text] [PDF]

				I. L Williams, P. J Chowienczyk, S. B Wheatcroft, A. G Patel, R. A Sherwood, A. M Shah, and M. T Kearney Divergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans Diabetes and Vascular Disease Research, May 1, 2006; 3(1): 34 - 38. [Abstract] [PDF]

				A. W.J.H. Dielis, M. Smid, H. M.H. Spronk, K. Hamulyak, A. A. Kroon, H. ten Cate, and P. W. de Leeuw The Prothrombotic Paradox of Hypertension: Role of the Renin-Angiotensin and Kallikrein-Kinin Systems Hypertension, December 1, 2005; 46(6): 1236 - 1242. [Abstract] [Full Text] [PDF]

				S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]

				T. Petnehazy, K. Y. Stokes, J. M. Russell, and D. N. Granger Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules Hypertension, February 1, 2005; 45(2): 209 - 215. [Abstract] [Full Text] [PDF]

				T. Shokoji, Y. Fujisawa, S. Kimura, M. Rahman, H. Kiyomoto, K. Matsubara, K. Moriwaki, Y. Aki, A. Miyatake, M. Kohno, et al. Effects of Local Administrations of Tempol and Diethyldithio-Carbamic on Peripheral Nerve Activity Hypertension, August 1, 2004; 44(2): 236 - 243. [Abstract] [Full Text] [PDF]

				D. N. Granger, T. Vowinkel, and T. Petnehazy Modulation of the Inflammatory Response in Cardiovascular Disease Hypertension, May 1, 2004; 43(5): 924 - 931. [Abstract] [Full Text] [PDF]

				S. Tsiara, M. Elisaf, I. A. Jagroop, and D. P. Mikhailidis Platelets as Predictors of Vascular Risk: Is There a Practical Index of Platelet Activity? Clinical and Applied Thrombosis/Hemostasis, July 1, 2003; 9(3): 177 - 190. [Abstract] [PDF]

				A. D. Blann, S. Nadar, and G. Y.H. Lip Pharmacological Modulation of Platelet Function in Hypertension Hypertension, July 1, 2003; 42(1): 1 - 7. [Abstract] [Full Text] [PDF]

				J. M. Proudfoot, K. D. Croft, I. B. Puddey, and L. J. Beilin Angiotensin II Type 1 Receptor Antagonists Inhibit Basal As Well As Low-Density Lipoprotein and Platelet-Activating Factor-Stimulated Human Monocyte Chemoattractant Protein-1 J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 846 - 853. [Abstract] [Full Text] [PDF]

				K. Konner, B. Nonnast-Daniel, and E. Ritz The Arteriovenous Fistula J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1669 - 1680. [Full Text] [PDF]