Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart
Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart
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DOI：
10.1093/cvr/cvn057
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发表时间：
2008-07-01
影响因子：
10.8
通讯作者：
Mackiewicz, Urszula
中科院分区：
文献类型：
--
作者：
Maczewski, Michal;Mackiewicz, Urszula
β受体阻滞剂可降低心力衰竭的死亡率和发病率。其诸多益处仅通过心率降低（HRR）就能解释。我们旨在验证β受体阻滞剂美托洛尔和单纯的心率降低药物伊伐布雷定在大鼠心肌梗死后（MI）心力衰竭中对血流动力学功能、心室重构以及钙离子处理是否具有相同作用。
在大鼠诱导心肌梗死或假手术后24小时，开始给予美托洛尔（250毫克/千克/天）或伊伐布雷定（10毫克/千克/天），二者具有相似的心率降低作用，或不进行治疗。心肌梗死后8周，美托洛尔和伊伐布雷定同样部分阻止了左心室（LV）射血分数的恶化，并降低了心肌梗死后左心室壁应力。然而，美托洛尔部分阻止了左心室扩张，而伊伐布雷定则加重了左心室肥厚。美托洛尔而非伊伐布雷定部分阻止了心肌梗死后的变时性功能不全。美托洛尔显著地，而伊伐布雷定轻度地，增加了心肌梗死后心肌细胞中钙离子瞬变的幅度。伊伐布雷定而非美托洛尔部分阻止了心肌梗死诱导的肌浆网钙离子 - ATP酶（SERCA）活性降低，而美托洛尔而非伊伐布雷定抑制了钠/钙交换体（NCX）过度活跃，并使兰尼碱受体的钙离子敏感性恢复正常。
尽管美托洛尔和伊伐布雷定都能相当程度地阻止大鼠心肌梗死后血流动力学功能的恶化，但美托洛尔还有其他潜在的有益作用；它阻止了左心室扩张和肥厚、变时性功能不全，强烈增加了分离的心肌细胞的收缩力，并阻止了钠/钙交换体活性可能导致心律失常的增加。这表明单纯的心率降低并不能解释心肌梗死后β受体阻滞剂的作用。美托洛尔和伊伐布雷定同样改善左心室功能，尽管在心肌梗死后的大鼠心脏中对左心室形态和细胞内钙离子处理有不同影响。
beta-Blockers reduce mortality and morbidity in heart failure. Many of their benefits can be explained solely by heart rate reduction (HRR). We aimed to verify whether the beta-blocker, metoprolol, and the pure heart-rate-reducing agent, ivabradine, have the same effects on haemodynamic function, ventricular remodeling, and Ca2+ handling in post-myocardial infarction (MI) heart failure in rat.Metoprolol (250 mg/kg/day) or ivabradine (10 mg/kg/day), offering similar HRR, or no treatment, was started 24 h after an induction of MI or sham surgery in rat. Eight weeks post-MI metoprolol and ivabradine similarly partially prevented deterioration of left ventricular (LV) ejection fraction and reduced post-MI LV wall stress. However, metoprolol partially prevented LV dilation, whereas ivabradine potentiated LV hypertrophy. Metoprolol, but not ivabradine, partially prevented post-MI chronotropic incompetence. Metoprolol markedly, whereas ivabradine mildly, increased the amplitude of the Ca2+ transient in post-MI cardiomyocytes. Ivabradine, but not metoprolol, partially prevented the MI-induced depression of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity, while metoprolol, but not ivabradine, suppressed Na+/Ca2+ exchanger (NCX) overactivity and normalized Ca2+ sensitivity of ryanodine receptors.Although both metoprolol and ivabradine comparably prevented post-MI deterioration of haemodynamic function in the rat, metoprolol had additional potentially beneficial effects; it prevented LV dilation and hypertrophy, chronotropic incompetence, strongly increased contractility of isolated cardiomyocytes, and prevented the potentially proarrhythmic increase in NCX activity. This indicates that pure HRR does not account for effects of beta-blockade in the post-MI setting. Metoprolol and ivabradine similarly improve LV function, although differently affect LV morphology and cellular Ca2+ handling in the post-infarction rat heart.