内皮素ETA受体拮抗剂可阻断血流动力学过载引发的心肌肥大。

Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload.

作者信息

Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto H, Ohta Y, Marumo F

机构信息

Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.

出版信息

Circulation. 1994 May;89(5):2198-203. doi: 10.1161/01.cir.89.5.2198.

DOI:10.1161/01.cir.89.5.2198

PMID:8181145

Abstract

BACKGROUND

We have recently shown that angiotensin II-induced hypertrophy of cultured rat cardiomyocytes was partially blocked by an endothelin (ET) receptor antagonist (BQ123) selective for the ETA subtype, suggesting the possible involvement of endogenous ET-1 in the mechanism of cardiac hypertrophy in vitro. In the present study, we studied the in vivo blockade effects of BQ123 on cardiac hypertrophy provoked by left ventricular overload with aortic banding in adult rats.

METHODS AND RESULTS

Forty rats were divided into four groups: (1) sham-operated rats without BQ123 administration, (2) rats with aortic banding without BQ123 administration, (3) sham-operated rats with BQ123 administration, and (4) rats with aortic banding with BQ123 administration. BQ123 (250 micrograms/h) was administered continuously by an osmotic pump starting 24 hours before operation. BQ123 blocked increases in the ratio of left ventricular weight to body weight and in the diameter of cardiomyocytes provoked by aortic banding at 1 week, but those blockade actions were no longer observed at 2 weeks. Skeletal alpha-actin and atrial natriuretic peptide (ANP) mRNA in the left ventricle, transcriptional markers for cardiac hypertrophy, significantly increased in the rats with aortic banding at 1 week and 2 weeks. In the rats with BQ123 administration, despite the hemodynamic overload, skeletal alpha-actin and ANP mRNA in the left ventricle remained at the control levels at 1 week; however, those blockade actions were abolished at 2 weeks. Plasma ET-1 levels increased after aortic banding, peaking at 24 hours, then returned to the basal level at 4 days. Prepro-ET-1 mRNA levels in the left ventricle also increased 24 hours after aortic banding, then declined to the basal level at 4 days.

CONCLUSIONS

These data suggest that endogenous ET-1 synthesized in the cardiovascular system plays a role in the mechanism of cardiac hypertrophy during the early phase of pressure overload in vivo.

摘要

背景

我们最近发现，血管紧张素II诱导的培养大鼠心肌细胞肥大被一种对ETA亚型具有选择性的内皮素（ET）受体拮抗剂（BQ123）部分阻断，这表明内源性ET-1可能参与了体外心肌肥大的机制。在本研究中，我们研究了BQ123对成年大鼠主动脉缩窄引起的左心室超负荷所致心肌肥大的体内阻断作用。

方法与结果

40只大鼠分为四组：（1）未给予BQ123的假手术大鼠；（2）未给予BQ123的主动脉缩窄大鼠；（3）给予BQ123的假手术大鼠；（4）给予BQ123的主动脉缩窄大鼠。在手术前24小时开始通过渗透泵持续给予BQ123（250微克/小时）。BQ123在1周时阻断了主动脉缩窄引起的左心室重量与体重比值增加和心肌细胞直径增加，但在2周时不再观察到这些阻断作用。左心室中的骨骼肌α-肌动蛋白和心房利钠肽（ANP）mRNA，作为心肌肥大的转录标志物，在主动脉缩窄大鼠的1周和2周时显著增加。在给予BQ123的大鼠中，尽管存在血流动力学超负荷，但左心室中的骨骼肌α-肌动蛋白和ANP mRNA在1周时仍保持在对照水平；然而，这些阻断作用在2周时消失。主动脉缩窄后血浆ET-1水平升高，在24小时达到峰值，然后在4天时恢复到基础水平。左心室中前ET-1 mRNA水平在主动脉缩窄后24小时也升高，然后在4天时降至基础水平。