Tazawa S, Nakane T, Chiba S
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
J Pharmacol Exp Ther. 1999 Feb;288(2):898-904.
We investigated the effects of the angiotensin II (Ang II) type 1 receptor (AT1) antagonist KRH-594 on levels of the mRNAs for AT1A, AT1B, platelet-derived growth factor-receptor beta (PDGF-Rbeta), and extracellular matrix (ECM)-related genes using the competitive reverse transcription-polymerase chain reaction (RT-PCR) method and on neointimal formation in the balloon-injured rat carotid artery. The mRNA levels for AT1A and PDGF-Rbeta, but not for AT1B, increased from day 3 after injury to day 14. KRH-594 administered orally at 3 and 10 mg/kg/day significantly suppressed these increases. KRH-594 (10 mg/kg/day) also suppressed the injury-induced gene expressions for transforming growth factor-beta1 and fibronectin and reduced collagen alpha1(I) and alpha1(III) mRNA levels for the first 7 days after injury. KRH-594 (10 and 30 mg/kg/day) significantly and dose-dependently reduced the neointimal area in cross sections of the artery 14 days after injury. Another AT1 antagonist, TCV-116 (candesartan cilexetil; 1 and 3 mg/kg/day p.o.), had similar effects on the morphological change and AT1A mRNA level, whereas a smooth muscle relaxant, hydralazine (10 mg/kg/day p.o.), did not. These results indicate that up-regulation of AT1A, PDGF-Rbeta, and ECM-related genes in the balloon-injured carotid artery is in part an AT1-mediated phenomenon and that prevention of receptor up-regulation may contribute to the attenuating effects of AT1 antagonists on neointimal formation after injury.
我们使用竞争性逆转录-聚合酶链反应（RT-PCR）方法研究了血管紧张素II（Ang II）1型受体（AT1）拮抗剂KRH-594对AT1A、AT1B、血小板衍生生长因子受体β（PDGF-Rβ）以及细胞外基质（ECM）相关基因的mRNA水平的影响，以及对球囊损伤大鼠颈动脉新生内膜形成的影响。损伤后第3天至第14天，AT1A和PDGF-Rβ的mRNA水平升高，但AT1B的mRNA水平未升高。以3和10 mg/kg/天的剂量口服KRH-594可显著抑制这些升高。KRH-594（10 mg/kg/天）还抑制了损伤诱导的转化生长因子-β1和纤连蛋白的基因表达，并在损伤后的前7天降低了胶原蛋白α1（I）和α1（III）的mRNA水平。KRH-594（10和30 mg/kg/天）在损伤后14天显著且剂量依赖性地减少了动脉横截面积的新生内膜面积。另一种AT1拮抗剂TCV-116（坎地沙坦酯；1和3 mg/kg/天，口服）对形态变化和AT1A mRNA水平有类似作用，而平滑肌松弛剂肼屈嗪（口服，10 mg/kg/天）则没有。这些结果表明，球囊损伤的颈动脉中AT1A、PDGF-Rβ和ECM相关基因的上调部分是由AT1介导的现象，并且预防受体上调可能有助于AT拮抗剂对损伤后新生内膜形成的减轻作用。
