Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo acute effects of Bosentan, an orally active, mixed endothelin ET(A) and ET(B) receptor antagonist
Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo acute effects of Bosentan, an orally active, mixed endothelin ET(A) and ET(B) receptor antagonist
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DOI：
10.1161/01.cir.93.11.2068
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发表时间：
1996-06-01
期刊：
影响因子：
37.8
通讯作者：
PooleWilson, PA
中科院分区：
文献类型：
--
作者：
Kaddoura, S;Firth, JD;PooleWilson, PA
背景内皮素-1（ET-1）对培养的心室肌细胞具有明显的生长抑制作用，并可诱导心室肌细胞肥大。儿茶酚胺增加培养心肌细胞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物理和分子标志物、心室和非心脏ET-1 mRNA表达的影响以及波生坦的急性作用，一种口服活性ET（A）和ET（B）受体拮抗剂。方法和结果（175 - 200 μ g）分为4组：（1）假手术组，（2）去甲肾上腺素灌注组（600 μ g . kg（-1）。h（-1）皮下渗透泵，长达7天），（3）给予波生坦的假手术大鼠，和（4）给予波生坦的去甲肾上腺素输注大鼠。波生坦（100 mg/kg，每日一次）从手术前1天开始灌胃给药6天。去甲肾上腺素引起绝对心室重量和心室重量与体重的比值以及心室RNA与蛋白质的比值增加。心室的心房利钠因子、骨骼α-肌动蛋白和β-肌球蛋白重链的mRNA表达也增加，这些在成年大鼠心室中是肥大的指标。去甲肾上腺素组1、2、3d时心室ET-1 mRNA表达增加。到第5天，这已经下降到控制水平。在肺、肾和骨骼肌中，去甲肾上腺素没有显著增加ET-1 mRNA的表达。波生坦衰减去甲肾上腺素诱导的心室重量增加，RNA与蛋白质的比例，骨骼肌钙蛋白mRNA和P-肌球蛋白重链mRNA的表达在5天，但它没有衰减增加心室心房利钠因子mRNA.Conclusions这些数据表明，内源性ET-1在体内介导去甲肾上腺素诱导的心室肥大中起着直接的作用。
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 ET(A) and ET(B) 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 mu g . 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 cu-actin mRNA and P-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.