Otsuka S, Sugano M, Makino N, Sawada S, Hata T, Niho Y
From the First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, and the Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Oita, Japan.
Hypertension. 1998 Sep;32(3):467-72. doi: 10.1161/01.hyp.32.3.467.
We administered angiotensin II (Ang II) receptor type 1 (AT1) blockade (losartan, 40 mg x kg-1 x d-1), type II receptor (AT2) blockade (PD123319, 100 mg x kg-1 x d-1), or angiotensin-converting enzyme (ACE) inhibitor (enalapril, 30 mg x kg-1 x d-1) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. Control SHR and Wister-Kyoto rats (WKY) received a placebo for the same period. At the end of treatment, losartan and enalapril were both found to have significantly reduced the arterial systolic blood pressure and the collagen concentration to the level of WKY, whereas PD123319 had no effect. Enalapril and PD123319 significantly reduced the media cross-sectional area of the aorta in comparison to that of untreated SHR, which was still larger than that of the WKY; however, losartan did not change it. Using reverse transcription-polymerase chain reaction, we next examined the mRNA expressions for ACE, AT1 receptor, and AT2 receptor in experimental animals. We observed significantly enhanced mRNA expression for AT1 and AT2 receptors and ACE in untreated SHR compared with WKY. The AT1 mRNA level was also significantly decreased in the SHR treated with either losartan or enalapril, whereas the AT2 mRNA level was significantly decreased in the SHR treated with either PD123319 or enalapril in comparison to untreated SHR. The level of ACE mRNA was significantly decreased only in the SHR treated with enalapril. These results indicate that AT1 receptor, but not AT2 receptor, plays a crucial role in the remodeling of matrix tissue, while AT2 receptor may play a role in the development of hypertrophy of smooth muscle in aorta in SHR, and that the reduction of hypertrophy of smooth muscle does not fully account for the suppression of hypertension.
我们从10至20周龄开始，给自发性高血压大鼠（SHR）施用1型血管紧张素II（Ang II）受体（AT1）阻滞剂（氯沙坦，40毫克/千克/天）、2型受体（AT2）阻滞剂（PD123319，100毫克/千克/天）或血管紧张素转换酶（ACE）抑制剂（依那普利，30毫克/千克/天）。对照SHR和Wister-Kyoto大鼠（WKY）在同一时期接受安慰剂。治疗结束时，发现氯沙坦和依那普利均显著降低了动脉收缩压和胶原蛋白浓度，使其达到WKY的水平，而PD123319则无效果。与未治疗的SHR相比，依那普利和PD123319显著降低了主动脉中膜横截面积，该横截面积仍大于WKY；然而，氯沙坦未改变其大小。接下来，我们使用逆转录-聚合酶链反应检测了实验动物中ACE、AT1受体和AT2受体的mRNA表达。我们观察到，与WKY相比，未治疗的SHR中AT1和AT2受体以及ACE的mRNA表达显著增强。在用氯沙坦或依那普利治疗的SHR中，AT1 mRNA水平也显著降低，而与未治疗的SHR相比，在用PD123319或依那普利治疗的SHR中，AT2 mRNA水平显著降低。仅在用依那普利治疗的SHR中，ACE mRNA水平显著降低。这些结果表明，AT1受体而非AT2受体在基质组织重塑中起关键作用，而AT2受体可能在SHR主动脉平滑肌肥大的发展中起作用，并且平滑肌肥大的减轻并不能完全解释高血压的抑制。
