Contraction-excitation feedback in heart failure and cardiac hypertrophy

据报道，机械应力会影响心脏的电兴奋过程。这种现象被称为“收缩-兴奋反馈”。虽然一直认为拉伸激活离子通道参与了其机制，但其确切机制尚不清楚。我们测量了qt间期作为各种条件下电兴奋的指标，如左心室压力过载、左心室容量过载、valsalva刺激、心肌功能失调。此外，我们还研究了心肌内皮素-1和收缩-兴奋反馈。心肌细胞和血管内皮产生内皮素(ET)-1。在心脏中，ET-1诱导心肌肥大，引起心肌细胞损伤。在这项研究中，我们探讨了ET-1在慢性心力衰竭（CHF）和心脏肥厚等心脏疾病中的作用。我们采用冠状动脉结扎大鼠模型作为CHF模型动物（CHF大鼠）。结果表明，CHF大鼠患病心脏中ET-1的产生（肽和mRNA水平）均增加。我们还获得的数据表明，心肌ET-1系统的上调可能在CHF的进展中起加重作用，因为长期（12周）使用ET受体拮抗剂BQ-123治疗可以大大提高CHF大鼠的存活率。应用BQ-123 12周后，BQ-123处理的GHF大鼠（CHF- bq大鼠）的存活率显著高于单独用生理盐水处理的CHF大鼠（CHF-生理盐水大鼠）（85% vs 43%， P< 0.01）。慢性BQ-123治疗可改善存活大鼠血流动力学参数。BQ-123治疗可有效预防CHF大鼠的不利心室重构。主动脉束带大鼠肥大左心室ET-1 mRNA表达明显升高。BQ-123治疗7天可显著减轻主动脉束带大鼠心肌肥厚。BQ-123可改变心肌离子通道mRNA的表达。这些结果提示，心衰和心脏肥厚性心律失常可能与收缩-兴奋反馈机制有关。少

The mechanical stress has been reported to affect the process of electrical excitation in the heart. This phenomenon is called to be "contraction-excitation feedback". Although it has been considered that the stretch activated ion channel is involved in its mechanisms, the precise mechanism is unclear.We measured QT-interval as an indicator of electrical excitation in various conditions such as pressure-overload to the left ventricic, volume-overload to the left ventricle, valsalva stimulation, dysopyramide application. Furthermore, we also studied myocardial endothelin-1 and contraction- excitation feedback.Cardiac myocytes as well as vascular endothelium produce endothelin (ET)-1. In the heart, ET-1 induces myocardial hypertrophy and causes cellular injury of cardiac myocytes. In this study, we investigated roles of ET-1 in heart diseases such as chronic heart failure (CHF) and cardiac hypertrophy. We used coronary artery-ligated rat model as a CHF model animal (CHF rats). It was rev … More ealed that production of ET-1 (both peptide and mRNA levels) is increased in the ailing heart of the CHF rats. We also obtained the data that the upregulated myocardial ET-1 system may play an aggravating role in the progression of CHF, because long-term (12 weeks) treatment with the ET receptor antagonist BQ-123 greatly improved survival rate of CHF rats. Twelve weeks after BQ-123 application, survival rate of the GHF rats treated with BQ-123 (CHF-BQ rats) was markedly higher than that of the CHF rats treated with saline alone (CHF-saline rats) (85% vs 43%, P< 0.01).Hemodynamic parameters of surviving rats were ameliorated by chronic BQ-123 treatment. BQ-123 treatment effectively prevented unfavorable ventricular remodeling of the CHF rats. In the hypertrophied left ventricle of the aorta-banded rats, the expression of ET-1 mRNA was significantly increased. Treatment with BQ-123 for 7 days significantly reduced cardiac hypertrophy of the aorta- banded rats. In these rats treated with BQ-123, the expression of mRNA of myocardial ion channels was altered.These findings suggest that contraction-excitation feedback mechanism is involved in arrhythmias in heart failure and cardiac hypertrophy. Less