内皮素-1参与体内去甲肾上腺素诱导的心室肥大。波生坦（一种口服活性的内皮素ETA和ETB受体混合拮抗剂）的急性效应。

Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo. Acute effects of bosentan, an orally active, mixed endothelin ETA and ETB receptor antagonist.

作者信息

Kaddoura S, Firth J D, Boheler K R, Sugden P H, Poole-Wilson P A

机构信息

National Heart and Lung Institute, Imperial College, London, England.

出版信息

Circulation. 1996 Jun 1;93(11):2068-79. doi: 10.1161/01.cir.93.11.2068.

DOI:10.1161/01.cir.93.11.2068

PMID:8640984

Abstract

BACKGROUND

Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ETA and ETB receptor antagonist.

METHODS AND RESULTS

Seventy male Sprague-Dawley rats (175 to 200 g) were divided into four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600 micrograms.kg-1.h-1 by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan. Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1 day before operation. Norepinephrine caused increases in absolute ventricular weight and ratios of ventricular weight to body weight and ventricular RNA to protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal alpha-actin, and beta-myosin heavy chain, which in adult rat ventricle are indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine did not significantly increase expression of ET-1 mRNA. Bosentan attenuated norepinephrine-induced increases in ventricular weight, ratio of RNA to protein, and expression of skeletal alpha-actin mRNA and beta-myosin heavy chain mRNA at 5 days, but it did not attenuate increased ventricular expression of atrial natriuretic factor mRNA.

CONCLUSIONS

These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.

摘要

背景

内皮素 -1（ET-1）对细胞生长具有强大作用，并可诱导培养的心室肌细胞肥大。儿茶酚胺可增加培养的心肌细胞中ET-1 mRNA的表达。我们通过研究持续输注去甲肾上腺素对心室肥大的生理和分子标志物、ET-1 mRNA在心室及非心脏组织中的表达，以及口服活性ETA和ETB受体拮抗剂波生坦的急性效应，来探讨内源性ET-1在体内儿茶酚胺诱导的肥大中的作用。

方法与结果

70只雄性Sprague-Dawley大鼠（175至200克）分为四组：（1）假手术大鼠；（2）输注去甲肾上腺素的大鼠（通过皮下渗透泵以600微克·千克-1·小时-1的速度输注，持续7天）；（3）给予波生坦的假手术大鼠；（4）给予波生坦的输注去甲肾上腺素的大鼠。波生坦（100毫克/千克，每日一次）在手术前1天开始通过灌胃给药6天。去甲肾上腺素导致心室绝对重量、心室重量与体重之比以及心室RNA与蛋白质之比增加。心房利钠因子、骨骼肌α-肌动蛋白和β-肌球蛋白重链的mRNA在心室中的表达增加，在成年大鼠心室中这些是肥大的指标。去甲肾上腺素组在第1、2和3天时心室ET-1 mRNA的表达升高。到第5天时，其已降至对照水平。在肺、肾和骨骼肌中，去甲肾上腺素未显著增加ET-1 mRNA的表达。波生坦在第5天时减轻了去甲肾上腺素诱导的心室重量增加、RNA与蛋白质之比增加以及骨骼肌α-肌动蛋白mRNA和β-肌球蛋白重链mRNA的表达增加，但未减轻心房利钠因子mRNA在心室中的表达增加。