Li Q, Pfaffendorf M, van Zwieten P A
Department of Pharmacotherapy, AMC, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Fundam Clin Pharmacol. 2001 Apr;15(2):143-50. doi: 10.1046/j.1472-8206.2001.00018.x.
A previous study by our group has demonstrated that the selective AT1-receptor antagonist losartan behaves as a noncompetitive antagonist in rabbit isolated renal artery (RA). In the present investigation, the influence of losartan and irbesartan on the contractile effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) was determined in the rabbit isolated RA and femoral artery (FA). The arteries were set up in organ chambers and changes in isometric force were recorded. In both rabbit isolated RA and FA preparations, AII, AIII and AIV elicited significant contractile responses with a similar efficacy. These effects were impaired by the presence of functional endothelium in RA preparations but not in FA preparations. In both preparations studied, the effects of AII, AIII and AIV were influenced neither by the aminopeptidase-A and -M inhibitor amastatin (10 microM), nor by the aminopeptidase-B and -M inhibitor bestatin (10 microM). In endothelium-denuded FA preparations, preincubation with losartan (3-300 nM) antagonized AII-, AIII- and AIV-induced contractions in a competitive manner. However, in endothelium-denuded RA preparations, losartan depressed the maximal contractile responses induced by AII but not those induced by AIII and AIV. In the same preparations, preincubation of another selective AT1-receptor antagonist irbesartan (3-30 nM) concentration-dependently shifted AII and AIII curves to the right in an insurmountable manner. The reduction of the maximal response of AII is more potent when compared to that of AIII (47.7 +/- 1.51% vs. 66.7 +/- 1.88%, percentage of the initial maximal response; P < 0.05; n=5). The selective AT2-receptor antagonist PD123177 (1 microM) did not influence the responses to all three peptides in both RA and FA preparations. These heterogeneous antagonistic effects of the two AT1-receptor antagonists studied with respect to the contractile actions of AII, AIII and AIV suggest the possible existence of multiple, functionally relevant AT1-receptor subtypes in rabbit RA preparations.
我们团队之前的一项研究表明，选择性AT1受体拮抗剂氯沙坦在兔离体肾动脉（RA）中表现为非竞争性拮抗剂。在本研究中，在兔离体肾动脉和股动脉（FA）中测定了氯沙坦和厄贝沙坦对血管紧张素II（AII）及其降解产物血管紧张素III（AIII）和血管紧张素IV（AIV）收缩作用的影响。将动脉置于器官浴槽中，记录等长力的变化。在兔离体肾动脉和股动脉标本中，AII、AIII和AIV均引起显著的收缩反应，且效力相似。在肾动脉标本中，功能性内皮的存在会削弱这些效应，但在股动脉标本中则不会。在所研究的两种标本中，AII、AIII和AIV的效应既不受氨肽酶-A和-M抑制剂抑氨肽酶（10μM）的影响，也不受氨肽酶-B和-M抑制剂苯丁抑制素（10μM）的影响。在去内皮的股动脉标本中，预先用氯沙坦（3 - 300 nM）孵育以竞争性方式拮抗AII、AIII和AIV诱导的收缩。然而，在去内皮的肾动脉标本中，氯沙坦抑制AII诱导的最大收缩反应，但不抑制AIII和AIV诱导的反应。在相同标本中，另一种选择性AT1受体拮抗剂厄贝沙坦（3 - 30 nM）预先孵育以不可逾越的方式使AII和AIII曲线浓度依赖性地右移。与AIII相比，AII最大反应的降低更显著（初始最大反应的百分比分别为47.7±1.51%和66.7±1.88%；P<0.05；n = 5）。选择性AT2受体拮抗剂PD123177（1μM）在肾动脉和股动脉标本中均不影响对所有三种肽的反应。所研究的两种AT1受体拮抗剂对AII、AIII和AIV收缩作用的这些异质性拮抗作用表明，兔肾动脉标本中可能存在多种功能相关的AT1受体亚型。
