Cardioprotection by long-term ET_A receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy

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• 作者：Fraccarollo ; Daniela ; Bauersachs ; Johann ; Kellner ; Markus ; Galuppo ; Paolo ; Ertl ; Georg
• 关键词：Infarction ; Heart failure ; Endothelins ; Angiotensin ; Fibrosis
• 刊名：Cardiovascular Research
• 出版年：2002
• 期刊代码：48_00086363
• 类别：med
• 出版时间：April, 2002
• 卷：54
• 期：1
• 页码：85-94
• 文件大小：697 K

摘要

Objectives: We investigated the effects of long-term endothelin A (ET_A) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI). Methods: Rats were treated with placebo, the ET_A antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI. Results: Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET_A and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt_max (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac β-myosin heavy chain and skeletal α-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET_A and ACE inhibition. Conclusion: Long-term combined ET_A receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET_A receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.