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

Abstract
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.
AuthorsZhong Jian Cheng, Piet Finckenberg, Marjut Louhelainen, Saara Merasto, Ilkka Tikkanen, Heikki Vapaatalo, Eero M A Mervaala
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 461 Issue 2-3 Pg. 159-69 (Feb 14 2003) ISSN: 0014-2999 [Print] Netherlands
PMID12586211 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2003 Published by Elsevier Science B.V.
Chemical References
  • Antihypertensive Agents
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Furans
  • Isoenzymes
  • Membrane Proteins
  • RNA, Messenger
  • Angiotensin II
  • 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone
  • Sulindac
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Ptgs1 protein, rat
  • Renin
  • Losartan
Topics
  • Albuminuria (chemically induced, prevention & control)
  • Angiotensin II (pharmacology)
  • Animals
  • Animals, Genetically Modified
  • Antihypertensive Agents (pharmacology)
  • Blood Pressure (drug effects)
  • Body Weight (drug effects)
  • Cardiomegaly (chemically induced, prevention & control)
  • Cardiovascular System (drug effects, enzymology, pathology)
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors (pharmacology)
  • Eating (drug effects)
  • Furans (pharmacology)
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Isoenzymes (drug effects, genetics, metabolism)
  • Kidney (drug effects, enzymology, pathology)
  • Losartan (pharmacology)
  • Male
  • Membrane Proteins
  • Mice
  • Prostaglandin-Endoperoxide Synthases (drug effects, genetics, metabolism)
  • RNA, Messenger (drug effects, genetics, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Renin (genetics, physiology)
  • Sulindac (pharmacology)
  • Urination (drug effects)

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