Efficacy of CI-1020, an endothelin-A receptor antagonist, in hypoxic pulmonary hypertension

被引：16

作者：

Haleen, S ^{[1
]}

Schroeder, R ^{[1
]}

Walker, D ^{[1
]}

Quenby-Brown, E ^{[1
]}

Welch, K ^{[1
]}

Hallak, H ^{[1
]}

Uprichard, A ^{[1
]}

Keiser, J ^{[1
]}

机构：

[1] Parke Davis Res Labs, Ann Arbor, MI 48105 USA

来源：

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY | 1998年 / 31卷

关键词：

ETA antagonist; CI-1020; hypoxia; pulmonary hypertension;

D O I：

10.1097/00005344-199800001-00092

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

We previously showed that CI-1020, an endothelin (ET)-A-selective receptor antagonist, dose-dependently blocked acute hypoxic pulmonary hypertension (PH) in rats. In this study we show that CI-1020 can reverse existing PH and prevent progression of right ventricular hypertrophy (RVH) in rats exposed to chronic hypoxia. Male Sprague-Dawley rats were exposed to 20 days of hypoxia (10% O-2) with CI-1020 treatment (20 or 40 mg/kg/day) starting on day 10. On day 20 of hypoxia, the rats were instrumented under anesthesia with a pulmonary artery cannula and allowed to recover to consciousness before measurement of mean pulmonary arterial pressure (MPAP). Blood samples were then collected for plasma ET-1 measurements, the rats killed, and their hearts dissected, dried, and weighed. RV/LV + septum ratio (g/g) was used as an index of RVH (RVH,.). Normoxic rats and rats exposed to hypoxia for only 10 days were also evaluated as controls. Normoxic rats had MPAPs of 13 +/- 1 mm. Hg, plasma ET-1 levels of 2.1 +/- 0.1 pg/ml, and an average RVH, of 0.29 +/- 0.03. Rats exposed to 10 or 20 days of hypoxia had MPAPs of 33 2 and 44 0 mm Hg, plasma ET-1 levels of 4.2 +/- 0.8 and 4.6 +/- 0.8 pg/ml, and average RVH(i)s of 0.47 +/- 0.05 and 0.52 +/- 0.03, respectively. In comparison, rats treated with CI-1020 had MPAPs that were 37% (20 mg/kg/day) and 44% (40 mg/kg/day) lower than untreated 20-day hypoxic rats. Furthermore, rats dosed with 40 mg/kg/day of CI-1020 had MPAPs that were significantly lower (24%) than control 10-day hypoxic rats, indicating a significant reversal of PH. Along with this reversal in PH, their average RVH, was 23% lower (p < 0.05) relative to untreated 20-day hypoxic rats.

引用

页码：S331 / S335

页数：5

共 8 条

[1] The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats [J].