Yayama Katsutoshi, Horii Miyuki, Hiyoshi Hiromi, Takano Masaoki, Okamoto Hiroshi, Kagota Satomi, Kunitomo Masaru
Department of Pharmacology, Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Japan.
J Pharmacol Exp Ther. 2004 Feb;308(2):736-43. doi: 10.1124/jpet.103.058420. Epub 2003 Nov 10.
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.
我们研究了在大鼠腹主动脉缩窄造成压力负荷增加时，胸主动脉中血管紧张素II（Ang II）1型（AT(1)）和/或2型（AT(2)）受体的表达是否发生变化，并确定其变化是否伴随着胸主动脉对Ang II收缩反应的改变。通过逆转录-聚合酶链反应或定量实时聚合酶链反应测定，缩窄后4、7、14和28天，主动脉中AT(2)受体mRNA水平增加了约300%，而AT(1)受体mRNA水平无变化。缩窄7天后，胸主动脉环对Ang II的收缩反应降低，AT(2)受体拮抗剂PD123319（1-[[4-(二甲氨基)-3-甲基苯基]甲基]-5-(二苯乙酰基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-羧酸二氟乙酸盐）（10(-6) M）增加了压力负荷环而非假手术环对Ang II的反应性。去除内皮或用N(G)-硝基-L-精氨酸甲酯（L-NAME）处理后，假手术环和压力负荷环对Ang II的反应性无差异。缩窄后7天，每天腹腔注射氯沙坦（1 mg/kg）或口服坎地沙坦（2 mg/kg），不仅消除了主动脉中AT(2)受体mRNA的上调，还恢复了它们对Ang II的反应性。压力负荷环中的基础环磷酸鸟苷（cGMP）水平比假手术环高2倍；两种水平均不受Ang II（10(-7) M；5分钟）影响，但L-NAME（10(-4) M，30分钟）使其大幅降低。这些结果表明，压力负荷通过AT(1)受体诱导主动脉中AT(2)受体表达上调，从而对Ang II的血管收缩敏感性产生负调节作用，可能是通过独立于一氧化氮-cGMP系统的机制介导的。
