Kost C K, Jackson E K
Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pa. 15261.
Hypertension. 1993 Apr;21(4):420-31. doi: 10.1161/01.hyp.21.4.420.
Results from renal transplantation experiments demonstrate that a renal defect is responsible for the development of hypertension in the spontaneously hypertensive rat (SHR). In addition, studies with inhibitors of the renin-angiotensin system have shown that angiotensin II (Ang II) is required for the development and maintenance of hypertension in the SHR. These observations prompted us to propose the hypothesis that hypertension in these rats is due to an enhanced renal responsiveness to Ang II. The purpose of the present study was to determine whether an enhanced renal responsiveness to Ang II exists in adult (12- to 14-week-old) SHR relative to Wistar-Kyoto control rats. To prevent hypertension-induced changes in renal function in SHR, we maintained both strains in the normotensive state from 4 weeks of age with long-term captopril treatment (100 mg/kg per day). Intrarenal Ang II infusions induced a significantly greater decrease in renal blood flow and glomerular filtration rate and a significantly greater increase in renal vascular resistance in SHR compared with Wistar-Kyoto rats. DuP 753 (Ang II subtype 1 [AT1] receptor antagonist), but not PD 123177 (Ang II subtype 2 receptor antagonist), blocked the renal responses to Ang II in SHR, suggesting that the enhanced renal responsiveness to Ang II was mediated solely by the AT1 receptor subtype. Unlike renal responses to Ang II, renal responses to periarterial renal nerve stimulation were similar in both strains, suggesting a selective renal hyperresponsiveness to Ang II in the SHR rather than a general hyperresponsiveness toward all vasoconstrictors. From these studies in chronically captopril-treated rats, we conclude that 1) SHR have a genetically determined, enhanced renal responsiveness to Ang II; 2) the enhanced renal responsiveness to Ang II is mediated by the AT1 receptor; and 3) renal responses to periarterial nerve stimulation are not significantly enhanced, suggesting a selective hyperresponsiveness to Ang II in the kidneys of SHR.
肾移植实验结果表明，肾脏缺陷是自发性高血压大鼠（SHR）发生高血压的原因。此外，肾素 - 血管紧张素系统抑制剂的研究表明，血管紧张素II（Ang II）是SHR高血压发生和维持所必需的。这些观察结果促使我们提出假说，即这些大鼠的高血压是由于肾脏对Ang II的反应性增强所致。本研究的目的是确定成年（12至14周龄）SHR相对于Wistar - Kyoto对照大鼠是否存在对Ang II增强的肾脏反应性。为了防止高血压引起的SHR肾功能变化，我们从4周龄开始用长期卡托普利治疗（每天100mg/kg）使两种品系都维持在正常血压状态。与Wistar - Kyoto大鼠相比，肾内注射Ang II在SHR中引起肾血流量和肾小球滤过率的显著更大降低以及肾血管阻力的显著更大增加。DuP 753（血管紧张素II 1型[AT1]受体拮抗剂）而非PD 123177（血管紧张素II 2型受体拮抗剂）阻断了SHR对Ang II的肾脏反应，表明对Ang II增强的肾脏反应性仅由AT1受体亚型介导。与对Ang II的肾脏反应不同，两种品系对肾动脉周围神经刺激的肾脏反应相似，表明SHR对Ang II具有选择性肾脏高反应性而非对所有血管收缩剂的普遍高反应性。从这些对长期卡托普利治疗大鼠的研究中，我们得出结论：1）SHR具有遗传决定的对Ang II增强的肾脏反应性；2）对Ang II增强的肾脏反应性由AT1受体介导；3）对肾动脉周围神经刺激的肾脏反应没有显著增强，表明SHR肾脏对Ang II具有选择性高反应性。
