Up-regulation of angiotensin II type 2 receptor in rat thoracic aorta by pressure-overload.
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-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 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.
Yayama
Katsutoshi
K
Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Japan.
Horii
Miyuki
M
Hiyoshi
Hiromi
H
Takano
Masaoki
M
Okamoto
Hiroshi
H
Kagota
Satomi
S
Kunitomo
Masaru
M
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000502:physiology; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014661:Vasoconstriction
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II