Gibson R E, Thorpe H H, Cartwright M E, Frank J D, Schorn T W, Bunting P B, Siegl P K
Department of Radiopharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Am J Physiol. 1991 Sep;261(3 Pt 2):F512-8. doi: 10.1152/ajprenal.1991.261.3.F512.
The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.
最近研究表明，血管紧张素II（ANG II）受体在拮抗剂结合方面存在亚型。特别值得关注的是强效非肽类拮抗剂DUP 753和PD 121981，它们分别对1型（AT1）和2型（AT2）受体具有选择性。我们使用这些高亲和力拮抗剂与125I-[Sar1，Ile8]ANG II竞争，通过放射自显影法确定这些ANG II受体亚型在大鼠和恒河猴肾皮质中的分布。DUP 753可抑制放射性配体与大鼠肾皮质切片中受体的结合；未检测到PD 121981的抑制作用。相比之下，AT1和AT2受体在恒河猴肾皮质中存在于区域不同的结构中。DUP 753抑制肾小球中ANG II受体的结合。PD 121981抑制动脉平滑肌和肾小球旁器（JG）的结合。JG装置也表现出放射性配体结合，可被DUP 753抑制。研究了DUP 753和PD 123177（PD 121981的一种水溶性更高的类似物）对血浆肾素活性变化的影响，以确定这些亚型中的一种或两种是否参与ANG II介导的肾素释放控制的负反馈。尽管在大鼠和恒河猴中，DUP 753使血浆肾素活性升高的程度与血管紧张素转换酶抑制剂依那普利拉相同，但AT2拮抗剂对这两个物种的肾素释放均无影响。因此，ANG II受体的两种亚型均存在于恒河猴皮质中，但仅证明了AT1亚型的功能。
