Cardiovascular and renal effects of cyclooxygenase inhibition in transgenic rats harboring mouse renin-2 gene (TGR[mREN2]27).

Zhong Jian Cheng, Piet Finckenberg, Marjut Louhelainen, Saara Merasto, Ilkka Tikkanen, Heikki Vapaatalo, Eero M A Mervaala

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland.

European journal of pharmacology 2003 Feb 14

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The present study examined the role of cyclooxygenase-synthetized prostanoids in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in transgenic rats harboring mouse renin-2 gene (mREN2 rats). Five- to six-week-old, heterozygous mREN2 rats received the following drug regimens for 8 weeks: (1) controls; (2) cyclooxygenase-2 inhibitor (MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2(5H)-furanone], 14 mg kg(-1) p.o.); (3) cyclooxygenase-1/cyclooxygenase-2 inhibitor (sulindac, 14 mg kg(-1) p.o.); (4) angiotensin II receptor antagonist (losartan 40 mg kg(-1) p.o.); (5) MF-tricyclic + losartan; (6) sulindac + losartan. Normotensive Sprague-Dawley rats served as controls. mREN2 rats developed pronounced hypertension, cardiac hypertrophy, and albuminuria as compared to normotensive Sprague-Dawley controls. mREN2 rats showed pronounced perivascular inflammation and morphological damage in the kidneys and the heart. Both MF-tricyclic and sulindac further increased blood pressure and albuminuria in mREN2 rats. Neither MF-tricyclic nor sulindac were able to prevent angiotensin-II-induced perivascular inflammation and morphological changes in the heart or in the kidneys. Myocardial and renal cyclooxygenase-2 mRNA expressions were decreased in mREN2 rats, whereas no difference was found in cyclooxygenase-1 mRNA expressions. Sulindac increased both cyclooxygenase-1 and cyclooxygenase-2 gene expressions, whereas MF-tricyclic increased only cyclooxygenase-2 gene expressions. Losartan normalized blood pressure, cardiac hypertrophy, albuminuria, inflammatory response and morphological changes in mREN2 rats, both in the presence and absence of cyclooxygenase inhibitors. Our findings indicate that cyclooxygenase does not play a central role in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in mREN2 rats. Copyright 2003 Published by Elsevier Science B.V.

Citation

Zhong Jian Cheng, Piet Finckenberg, Marjut Louhelainen, Saara Merasto, Ilkka Tikkanen, Heikki Vapaatalo, Eero M A Mervaala. Cardiovascular and renal effects of cyclooxygenase inhibition in transgenic rats harboring mouse renin-2 gene (TGR[mREN2]27). European journal of pharmacology. 2003 Feb 14;461(2-3):159-69