Nonaka Miki, Morimoto Sachio, Murayama Takashi, Kurebayashi Nagomi, Li Lei, Wang Yuan-Yuan, Arioka Masaki, Yoshihara Tatsuya, Takahashi-Yanaga Fumi, Sasaguri Toshiyuki
Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Br J Pharmacol. 2015 May;172(9):2369-82. doi: 10.1111/bph.13062. Epub 2015 Mar 17.
The Ca(2+) sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in patients with heart failure (HF). We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF.
A knock-in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end-stage HF at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms.
Pimobendan prevented myocardial remodelling in compensated HF and significantly extended life span in both compensated and end-stage HF, but dose-dependently increased sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably because of early or delayed afterdepolarizations. The L-type Ca(2+) channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from over-elevated cytoplasmic Ca(2+) through increased Ca(2+) entry by PDE3 inhibition under diminished sarcoplasmic reticulum Ca(2+) reuptake and increased Ca(2+) leakage from sarcoplasmic reticulum in end-stage HF.
Pimobendan was beneficial regardless of HF stage, but increased sudden cardiac death in end-stage HF with extensive remodelling of Ca(2+) handling. Reduction of cytoplasmic Ca(2+) elevated by PDE3 inhibition might decrease this risk of sudden cardiac death.
与传统的强心剂相比，钙离子增敏剂匹莫苯丹是一种独特的强心药物，它能增强心肌收缩力，同时较少增加耗氧量，并且对心肌重塑和心律失常的潜在不良影响可能更小。然而，临床试验报道了匹莫苯丹在心力衰竭（HF）患者中的矛盾作用。我们使用一种新型的进行性HF小鼠模型提供了匹莫苯丹疗效的机制性实验证据。
使用一种人类遗传性扩张型心肌病的基因敲入小鼠模型，该模型在生长过程中的固定时间显示出从代偿性HF到终末期HF的明显转变，以评估匹莫苯丹的疗效并探索潜在的分子和细胞机制。
匹莫苯丹可预防代偿性HF中的心肌重塑，并显著延长代偿性和终末期HF小鼠的寿命，但在终末期HF中剂量依赖性地增加猝死率。在从终末期HF小鼠分离的心肌细胞中，匹莫苯丹可能由于早期或延迟后去极化而诱导触发活动。L型钙离子通道阻滞剂维拉帕米降低了触发活动的发生率，这表明这是由于在终末期HF中肌浆网钙离子再摄取减少和肌浆网钙离子泄漏增加的情况下，通过抑制磷酸二酯酶3增加钙离子内流导致细胞质钙离子过度升高所致。
无论HF处于何种阶段，匹莫苯丹都是有益的，但在终末期HF且钙离子处理广泛重塑的情况下会增加心源性猝死。减少因磷酸二酯酶3抑制而升高的细胞质钙离子可能会降低这种心源性猝死的风险。
