Vascular effects of COX inhibition and AT1 receptor blockade in transgenic rats harboring mouse renin-2 gene

Ang II-induced endothelial dysfunction is associated with perivascular inflammation and increased superoxide production in the vascular wall. The present study examined the role of cyclo-oxygenase (COX)-synthetized eicosanoids in the pathogenesis of Ang II-induced endothelial dysfunction in transgen...

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Bibliographic Details
Published in:Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 2002-12, Vol.53 (4 Pt 1), p.597-613
Main Authors: Cheng, Z J, Tikkanen, I, Vapaatalo, H, Mervaala, E M A
Format: Article
Language:English
Subjects:
Angiotensin Receptor Antagonists
Animals
Animals, Genetically Modified - genetics
Aorta - drug effects
Aorta - physiology
Autoradiography
Blood Pressure - drug effects
Cyclooxygenase Inhibitors - pharmacology
Male
Mice
Nitrates - urine
Nitrites - urine
Protein Isoforms - genetics
Protein Isoforms - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1
Receptor, Endothelin A
Receptor, Endothelin B
Receptors, Endothelin - metabolism
Renal Artery - drug effects
Renal Artery - physiology
Renin - genetics
Renin - pharmacology
Vasoconstriction
Vasodilation
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Summary:Ang II-induced endothelial dysfunction is associated with perivascular inflammation and increased superoxide production in the vascular wall. The present study examined the role of cyclo-oxygenase (COX)-synthetized eicosanoids in the pathogenesis of Ang II-induced endothelial dysfunction 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) vehicle, 2) cyclo-oxygenase-2 (COX-2) inhibitor (MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2(5H)-furanone], 14 mg/kg p.o.), 3) COX-1/COX-2 inhibitor (sulindac, 14 mg/kg p.o.), 4) angiotensin II receptor antagonist (losartan 40 mg/kg p.o.). Normotensive Sprague Dawley (SD) rats served as controls. In vitro vascular responses of the descending aorta and renal artery were studied using organ bath system. mREN2 rats developed pronounced hypertension which was associated with impaired endothelium-dependent and endothelium-independent vascular relaxations in the aorta. In contrast, the relaxation responses of the renal arteries remained largely unchanged in mREN2 rats. Urinary NO, excretion, a marker of total body NO generation, was also decreased in mREN2 rats. Neither non-selective COX inhibitor sulindac nor COX-2 selective MF-tricyclic were capable of preventing Ang II-induced hypertension or endothelial dysfunction in mREN2 rats, whereas ATi receptor antagonist losartan completely normalized blood pressure, vascular relaxation responses as well as urinary NOx excretion. Our findings indicate that NO synthesis and/or bioavailability as well as the sensitivity of arterial smooth muscle cells to NO are decreased in mREN2 rats. The present study also demonstrated that COX does not play a central role in the pathogenesis of Ang II-induced endothelial dysfunction in mREN2 rats.
ISSN:0867-5910