Hong K W, Rhim B Y, Shin Y W, Yoo S E
Department of Pharmacology, College of Medicine, Pusan National University, Korea.
J Pharmacol Exp Ther. 1994 Dec;271(3):1591-6.
The unmasking of the low concentration effect of angiotensin II (AII) was identified within the concentration ranges of 10(-13) to 10(-11) M of AII by PD 121981 (5-diphenylacetyl-1-(4-methoxy-3-methylbenzyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid) and 10(-12) to 3 x 10(-10) M of AII by CGP 42112 (nicotinic acid-Tyr-(N alpha-benzyl-oxycarbonyl-Arg)Lys-His-Pro-IIe-OH), AT2 antagonists, in association with the ordinary contraction curve, i.e., high concentration effect (at 3 x 10(-10)-10(-6) M of AII), in the rabbit abdominal aorta. Thus, they showed clear biphasic features of AII-induced contraction curves. However, this was not the case for angiotensin I and angiotensin III. This PD 121981-evoked low concentration effect of AII was selectively inhibited by DuP 753 (0.01-1 nM), dithiothreitol (10 and 100 microM), pertussis toxin (50 and 300 ng/ml, for 2 hr), nifedipine (1 and 10 microM) and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (1 and 3 microM), which suggests the receptors were the AT1 subtype. However, the high concentration effect of AII was not affected by these drugs within the concentration ranges used in the present studies. These myographic results were almost consistent with the features of the intracellular Ca++ changes. Thus, it was concluded that the receptors that mediate the low concentration effect of AII belong to the AT1 subtype. However, the current study did not determine the mechanism by which PD 121981 and CGP 42112 evoked the up-regulation of the AT1 receptors.
在兔腹主动脉中，PD 121981（5-二苯乙酰基-1-(4-甲氧基-3-甲基苄基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-羧酸）在10(-13)至10(-11) M的血管紧张素II（AII）浓度范围内，以及CGP 42112（烟酸-Tyr-(Nα-苄氧羰基-Arg)Lys-His-Pro-IIe-OH），一种AT2拮抗剂，在10(-12)至3×10(-10) M的AII浓度范围内，揭示了AII的低浓度效应，这与普通收缩曲线，即高浓度效应（在3×10(-10)-10(-6) M的AII时）相关。因此，它们显示出AII诱导的收缩曲线明显的双相特征。然而，血管紧张素I和血管紧张素III并非如此。这种由PD 121981诱发的AII低浓度效应被DuP 753（0.01-1 nM）、二硫苏糖醇（10和100 microM）、百日咳毒素（50和300 ng/ml，作用2小时）、硝苯地平（1和10 microM）以及盐酸8-(二乙氨基)辛基3,4,5-三甲氧基苯甲酸酯（1和3 microM）选择性抑制，这表明该受体为AT1亚型。然而，在本研究使用的浓度范围内，这些药物对AII的高浓度效应没有影响。这些肌动描记结果几乎与细胞内Ca++变化的特征一致。因此，得出结论，介导AII低浓度效应的受体属于AT1亚型。然而，当前研究并未确定PD 121981和CGP 42112诱发AT1受体上调的机制。
