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CARDIOVASCULAR

Up-Regulation of Angiotensin II Type 2 Receptor in Rat Thoracic Aorta by Pressure-Overload

Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Kobe, Japan (K.Y., M.H., H.H., M.T., H.O.); and Department of Pharmacology, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Nisinomiya, Japan (S.K., M.K.)

We have examined whether expression of angiotensin II (Ang II) type 1 (AT₁) and/or type 2 (AT₂) receptors are changed in thoracic aorta under pressure-overload by abdominal aortic banding in rats and determined whether their changes are accompanied by alteration in contractile response of thoracic aorta to Ang II. AT₂ receptor mRNA levels determined by reverse transcription-polymerase chain reaction or quantitative real-time polymerase chain reaction were increased by about 300% in aortas 4, 7, 14, and 28 days after banding without changes in AT₁ receptor mRNA levels. Contractile response of aortic rings to Ang II was decreased in thoracic aortas 7 days after banding, and AT₂ receptor antagonist PD123319 (1-[[4-(dimethulamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) (10^–6 M) increased the Ang II responsiveness in pressure-loaded but not in sham rings. After removal of the endothelium or treatment with N^G-nitro-L-arginine methyl ester (L-NAME), no differences were observed in Ang II responsiveness between sham and pressure-loaded rings. Either losartan (1 mg/kg/day i.p.) or candesartan (2 mg/kg/day p.o.) for 7 days after banding not only abolished the up-regulation of AT₂ receptor mRNA in aortas but also recovered their Ang II responsiveness. Basal cGMP levels were 2 times higher in pressure-loaded than in sham rings; both levels were not affected by Ang II (10^–7 M; 5 min), but greatly decreased by L-NAME (10^–4 M, 30 min). These results suggest that pressure-overload induces the up-regulation of AT₂ receptor expression in aortas via AT₁ receptor and thereby negatively modulates the vasoconstrictor sensitivity to Ang II, probably mediated by the mechanisms independent of the nitric oxide-cGMP system.

Address correspondence to: Dr. Hiroshi Okamoto, Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Ikawadanicho, Nishi-ku, Kobe 651-2180, Japan. E-mail: p-okamoto{at}kobegakuin.ac.jp

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