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):726-32.
In conscious renal artery-ligated rats, a high renin hypertensive rat model, DuP 753, a p.o. active nonpeptide angiotensin II (AII) receptor antagonist, decreased blood pressure at 0.1 to 3 mg/kg given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of given i.v. or at 0.3 to 10 mg/kg given p.o. with an i.v. ED30 of 0.78 mg/kg and a p.o. ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 was similar to that of captopril. Unlike the peptide AII antagonist saralasin, DuP 753 did not cause a transient increase in blood pressure, suggesting absence of agonistic activity. At 3 mg/kg p.o., DuP 753 lowered blood pressure for at least 24 hr and did not change heart rate, suggesting a long duration of antihypertensive effect. At 3 mg/kg i.v., DuP 753 inhibited the pressor response to AII but not to norepinephrine or vasopressin. Pretreatment of renal artery-ligated rats with captopril, saralasin or propranolol, but not with prazosin, hydralazine or indomethacin, abolished or reduced the antihypertensive effect of DuP 753. In the deoxycorticosterone acetate hypertensive rat, a low renin model, DuP 753 did not lower blood pressure. These results suggest that DuP 753 is a p.o. active, antihypertensive agent in renal artery-ligated rats with a similar antihypertensive efficacy as captopril. The antihypertensive effect of DuP 753 is most likely related to the blockade of the vasoconstrictor effect of AII. Unlike saralasin, DuP 753 does not have agonistic activity.
在清醒的肾动脉结扎大鼠（一种高肾素性高血压大鼠模型）中，口服活性非肽类血管紧张素II（AII）受体拮抗剂杜普753，静脉注射剂量为0.1至3mg/kg或口服剂量为0.3至10mg/kg时可降低血压，静脉注射的半数有效剂量（ED30）为0.78mg/kg，口服的ED30为0.59mg/kg。杜普753的降压效果与卡托普利相似。与肽类AII拮抗剂沙拉新不同，杜普753不会引起血压短暂升高，表明其无激动活性。口服3mg/kg时，杜普753可使血压降低至少24小时，且不改变心率，提示其降压作用持续时间长。静脉注射3mg/kg时，杜普753可抑制对AII的升压反应，但对去甲肾上腺素或血管加压素无此作用。用卡托普利、沙拉新或普萘洛尔而非哌唑嗪、肼屈嗪或吲哚美辛预处理肾动脉结扎大鼠，可消除或降低杜普753的降压作用。在醋酸脱氧皮质酮高血压大鼠（一种低肾素模型）中，杜普753不会降低血压。这些结果表明，杜普753在肾动脉结扎大鼠中是一种口服活性降压药，其降压效果与卡托普利相似。杜普753的降压作用很可能与阻断AII的血管收缩作用有关。与沙拉新不同，杜普753没有激动活性。
