Wong P C, Hart S D, Zaspel A M, Chiu A T, Ardecky R J, Smith R D, Timmermans P B
Medical Products Department, E.I. du Pont de Nemours & Company, Wilmington, Delaware.
J Pharmacol Exp Ther. 1990 Nov;255(2):584-92.
DuP 753 and PD123177 are two nonpeptide angiotensin II (AII)-specific ligands, which show high affinities for two respective and distinct subtypes of AII binding sites, i.e., AII-1 and AII-2 sites, respectively, in the rat adrenal gland, brain and uterus. The objective of this study is to identify the functions of these subtype binding sites in the adrenal, sympathetic ganglia, brain and vascular smooth muscle. In conscious rats, DuP 753 at 1, 3 and 10 mg/kg i.v. but not PD123177 at 30 and 100 mg/kg i.v. inhibited the AII-induced aldosterone increase. In the isolated perfused rat adrenal gland, DuP 753 at 10(-6) and 10(-4) M but not PD123177 at 10(-3) M blocked the AII-induced epinephrine secretion. In control and chemically sympathectomized pithed rats, the pressor and tachycardiac responses to AII were blocked by DuP 753 at 10 mg/kg i.v. but not by PD123177 at 100 mg/kg i.v. In conscious rats, DuP 753 at 10 mg/kg s.c. but not PD123177 at 100 mg/kg s.c. inhibited the AII-induced water drinking. In the rabbit aorta, DuP 753 at 10(-6) M but not PD123177 at 10(-4) M inhibited the contractile effect of AII. In conscious renal artery-ligated hypertensive rats, DuP 753 but not PD123177 at 0.1 to 10 mg/kg i.v. lowered blood pressure. In summary, a function of the PD123177-sensitive AII binding site (AII-2) has not yet been identified. However, the DuP 753-sensitive site (AII-1) appears to mediate the AII-induced responses such as adrenal aldosterone and catecholamine secretion, release of catecholamine from sympathetic ganglia, drinking and vasoconstriction.
DuP 753和PD123177是两种非肽类血管紧张素II（AII）特异性配体，它们分别对大鼠肾上腺、脑和子宫中两种各自不同且独特的AII结合位点亚型，即AII-1和AII-2位点，表现出高亲和力。本研究的目的是确定这些亚型结合位点在肾上腺、交感神经节、脑和血管平滑肌中的功能。在清醒大鼠中，静脉注射1、3和10 mg/kg的DuP 753可抑制AII诱导的醛固酮增加，而静脉注射30和100 mg/kg的PD123177则无此作用。在离体灌注的大鼠肾上腺中，10^(-6)和10^(-4) M的DuP 753可阻断AII诱导的肾上腺素分泌，而10^(-3) M的PD123177则无此作用。在对照和化学去交感神经的脊髓麻醉大鼠中，静脉注射10 mg/kg的DuP 753可阻断对AII的升压和心动过速反应，而静脉注射100 mg/kg的PD123177则无此作用。在清醒大鼠中，皮下注射10 mg/kg的DuP 753可抑制AII诱导的饮水，而皮下注射100 mg/kg的PD123177则无此作用。在兔主动脉中，10^(-6) M的DuP 753可抑制AII的收缩作用，而l0^(-4) M的PD123177则无此作用。在清醒肾动脉结扎的高血压大鼠中，静脉注射0.1至10 mg/kg的DuP 753可降低血压，而PD123177则无此作用。总之，尚未确定PD123177敏感的AII结合位点（AII-2）的功能。然而，DuP 753敏感位点（AII-1）似乎介导了AII诱导的反应，如肾上腺醛固酮和儿茶酚胺分泌、交感神经节释放儿茶酚胺、饮水和血管收缩。
