Published online before print May 7, 2007, doi: 10.1161/HYPERTENSIONAHA.106.085035
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(Hypertension. 2007;50:96.)
© 2007 American Heart Association, Inc.
Original Articles |
Paradoxical Role of Angiotensin II Type 2 Receptors in Resistance Arteries of Old Rats
From the Centre National de la Recherche Scientifique Unité Mixte de Recherche (CNRS UMR) 6214 (A.B., O.D., K.R., R.A., L.L., D.H.), Institut National de la Santé Et de la Recherche Médicale UMR (INSERM UMR) 771 (A.B., O.D., K.R., R.A., L.L., D.H.), Université d’Angers; and Centre Hospitalier Universitaire d’Angers (F.P., C.B.), Department of Cardiac Surgery and Unité Propre de Recherche de l’Enseignement Supérieur-Equipe Associée 3860, Angers, France.
Correspondence to Daniel Henrion, Department of Neurovascular Integrated Biology, UMR CNRS 6214, INSERM 771, Faculté de Médecine, 49045 Angers, France. E-mail daniel.henrion{at}univ-angers.fr
The role of angiotensin II type 2 receptors (AT2Rs) remains a matter of controversy. Its vasodilatory and antitrophic properties are well accepted. Nevertheless, in hypertensive rats, AT2R stimulation induces a vasoconstriction counteracting flow-mediated dilation (FMD). This contraction is reversed by hydralazine. Because FMD is also decreased in aging, another risk factor for cardiovascular diseases, we hypothesized that AT2R function might be altered in old-rat resistance arteries. Mesenteric resistance arteries (250 µm in diameter) were isolated from old (24 months) and control (4 months) rats receiving hydralazine (16 mg/kg per day; 2 weeks) or water. FMD, NO-mediated dilation, and endothelial NO synthase expression were lower in old versus control rats. AT2R blockade improved FMD in old rats, suggesting that AT2R stimulation produced vasoconstriction. AT2R expression was higher in old rats and mainly located in the smooth muscle layer. In old rats, AT2R stimulation induced endothelium-independent contraction, which was suppressed by the antioxidant Tempol. Reactive oxygen species level was higher in old-rat arteries than in controls. Hydralazine improved FMD and NO-dependent dilation in old rats without change in AT2R expression and location. In old rats treated with hydralazine, reactive oxygen species level was reduced in endothelial and smooth muscle cells, and AT2R-dependent contraction was abolished. Thus, AT2R stimulation induced vasoconstriction through activation of reactive oxygen species production, contributing to decrease FMD in old-rat resistance arteries. Hydralazine suppressed AT2R-dependent reactive oxygen species production and AT2R-dependent contraction, improving FMD. Importantly, endothelial alterations in aging were reversible. These findings are important to consider in the choice of vasoactive drugs in aging.
Key Words: aging • endothelium • microcirculation • angiotensin II receptors • NO • oxidative stress • vasodilator agents
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