Scott A L, Chang R S, Lotti V J, Siegl P K
Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania.
J Pharmacol Exp Ther. 1992 Jun;261(3):931-5.
Angiotensin II (AII) elicits a positive inotropic response in cardiac muscle preparations from several species including humans. The purpose of this study was to characterize the AII binding sites and inotropic responses in rabbit ventricle using the selective AII receptor antagonists/ligands, DuP 753 (AT1) and PD 121981 (AT2). Biphasic displacement of specific 125I-Sar1,Ile8-AII binding was observed with both DuP 753 and PD 121981, suggesting the presence of two AII binding sites. The high affinity site for DuP 753 (29 nM) was a low affinity site for PD 121981 (91 microM), and the high affinity site for PD 121981 (78 nM) was a low affinity site for DuP 753 (81 microM). Of the specific AII binding, 70% was DuP 753 (AT1)-sensitive sites. Positive inotropic responses to AII in isolated papillary muscles from rabbit heart were antagonized competitively by both DuP 753 and PD 121981. The potencies of DuP 753 (pA2 = 7.99) and PD 121981 (pA2 = 4.28) to antagonize AII inotropic responses were similar to their potencies to displace 125I-Sar1,Ile8-AII from AT1 sites. There was no apparent functional consequence of AII interaction with AT2 site. Inotropic responses to isoproterenol were unaffected by DuP 753 and PD 121981. Therefore, there are two binding sites for AII in rabbit ventricle; however, only one site, AT1, participates in the inotropic response to AII. The roles of these receptor subtypes in other cardiac responses to AII have yet to be determined. Also, DuP 753 and PD 121981 are useful tools to study these two AII binding sites in cardiac preparations.
血管紧张素II（AII）在包括人类在内的多个物种的心肌制备物中引发正性肌力反应。本研究的目的是使用选择性AII受体拮抗剂/配体DuP 753（AT1）和PD 121981（AT2）来表征兔心室中的AII结合位点和正性肌力反应。DuP 753和PD 121981均观察到特异性125I- Sar1，Ile8 - AII结合的双相置换，表明存在两个AII结合位点。DuP 753的高亲和力位点（29 nM）是PD 121981的低亲和力位点（91 microM），而PD 121981的高亲和力位点（78 nM）是DuP 753的低亲和力位点（81 microM）。在特异性AII结合中，70%是DuP 753（AT1）敏感位点。兔心脏分离乳头肌中对AII的正性肌力反应被DuP 753和PD 121981竞争性拮抗。DuP 753（pA2 = 7.99）和PD 121981（pA2 = 4.28）拮抗AII正性肌力反应的效力与其从AT1位点置换125I- Sar1，Ile8 - AII的效力相似。AII与AT2位点相互作用没有明显的功能后果。对异丙肾上腺素的正性肌力反应不受DuP 753和PD 121981影响。因此，兔心室中有两个AII结合位点；然而，只有一个位点，即AT1，参与对AII的正性肌力反应。这些受体亚型在心脏对AII的其他反应中的作用尚待确定。此外，DuP 753和PD 121981是研究心脏制备物中这两个AII结合位点的有用工具。
