Wong P C, Price W A, Chiu A T, Duncia J V, Carini D J, Wexler R R, Johnson A L, Timmermans P B
Medical Products Department, E. I. du Pont de Nemours & Company, Wilmington, Delaware.
J Pharmacol Exp Ther. 1990 Feb;252(2):719-25.
In the spinal pithed rat, DuP 753, 2-n-butyl-4-chloro-5-hydroxy-methyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl) methyl] imidazole potassium salt, inhibited competitively the pressor response to angiotensin II (AII), whereas saralasin showed a noncompetitive pattern of interaction. It did not alter the pressor responses to vasopressin and norepinephrine as well as the heart rate response to isoproterenol. In the anesthetized rat, DuP 753 did not affect the vasodepressor response to bradykinin. Given p.o. or i.v., DuP 753 did not lower blood pressure in conscious normotensive rats, but it inhibited the pressor response to AII but not to vasopressin. It lowered blood pressure in furosemide-treated normotensive rats. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure even at 100 mg/kg i.v. DuP 753 at 3.5 micrograms i.c.v. inhibited the pressor response to i.c.v. AII, whereas DuP 753 at 10 mg/kg p.o. did not, suggesting that a single p.o. administration of DuP 753 does not affect brain AII receptors which are accessible by i.c.v. injection. Our study indicates that DuP 753 is a p.o. active, nonpeptide, selective, competitive AII receptor antagonist.
在脊髓毁损大鼠中，杜普753（2-正丁基-4-氯-5-羟甲基-1-[(2'-(1H-四氮唑-5-基)联苯-4-基)甲基]咪唑钾盐）竞争性抑制血管紧张素II（AII）引起的升压反应，而沙拉新表现出非竞争性相互作用模式。它不改变对血管加压素和去甲肾上腺素的升压反应以及对异丙肾上腺素的心率反应。在麻醉大鼠中，杜普753不影响对缓激肽的血管减压反应。经口服或静脉给药，杜普753不会降低清醒正常血压大鼠的血压，但它抑制对AII的升压反应，而不抑制对血管加压素的升压反应。它能降低用速尿处理的正常血压大鼠的血压。与沙拉新不同，即使静脉注射100mg/kg，杜普753也不会引起血压短暂升高。脑室内注射3.5微克杜普753可抑制脑室内注射AII引起的升压反应，而口服10mg/kg杜普753则无此作用，这表明单次口服杜普753不影响可通过脑室内注射到达的脑AII受体。我们的研究表明，杜普753是一种口服有效的、非肽类、选择性、竞争性AII受体拮抗剂。
