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

• Published in: The Journal of pharmacology and experimental therapeutics 2004-02, Vol.308 (2), p.736-743
• Main Authors: Yayama, Katsutoshi, Horii, Miyuki, Hiyoshi, Hiromi, Takano, Masaoki, Okamoto, Hiroshi, Kagota, Satomi, Kunitomo, Masaru
• Format: Article
• Language: English
• Subjects: Angiotensin II - metabolism; Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - physiology; Blood Pressure; Endothelium, Vascular - physiology; Male; Pressure; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; RNA, Messenger - metabolism; Up-Regulation; Vasoconstriction
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.058420

We have examined whether expression of angiotensin II (Ang II) type 1 (AT 1 ) and/or type 2 (AT 2 ) 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. AT 2 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 AT 1 receptor mRNA levels. Contractile response of aortic rings to Ang II was decreased in thoracic aortas 7 days after banding, and AT 2 receptor antagonist PD123319 (1-[[4-(dimethulamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1 H -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 AT 2 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 AT 2 receptor expression in aortas via AT 1 receptor and thereby negatively modulates the vasoconstrictor sensitivity to Ang II, probably mediated by the mechanisms independent of the nitric oxide-cGMP system.