title: Vascular effects of COX inhibition and AT1 receptor blockade in transgenic rats harboring mouse renin-2 gene.
abstract: 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.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Cheng
authors.forename: I
authors.initials: I
authors.lastname: Tikkanen
authors.forename: H
authors.initials: H
authors.lastname: Vapaatalo
authors.forename: E M A
authors.initials: EM
authors.lastname: Mervaala
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D020033:Protein Isoforms / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D012083:Renin / Q000235:genetics / Q000494:pharmacology*; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D057911:Angiotensin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D009566:Nitrates; D009573:Nitrites; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012083:Renin