Couette B, Marger L, Nargeot J, Mangoni M E
Institut de Génomique Fonctionnelle, CNRS UPR5203, 141, rue de la Cardonille, F-34094 Montpellier Cedex 5, France.
Cardiovasc Hematol Disord Drug Targets. 2006 Sep;6(3):169-90. doi: 10.2174/187152906778249572.
The generation of cardiac pacemaker activity is a complex phenomenon which requires the coordinated activity of different membrane ionic channels, as well as intracellular signalling factors including Ca(2+) and second messengers. The precise mechanism initiating automaticity in primary pacemaker cells is still matter of debate and certain aspects of how channels cooperate in the regulation of pacemaking by the autonomic nervous system have not been entirely elucidated. Research in the physiopathology of cardiac automaticity has also gained a considerable interest in the domain of cardiovascular pharmacology, since accumulating clinical and epidemiological evidence indicate a link between an increase in heart rate and the risk of cardiac mortality and morbidity. Lowering the heart rate by specific bradycardic agents in patients with heart disease constitutes a promising way to increase cardioprotection and improve survival. Thus, the elucidation of the mechanisms underlying the generation of pacemaker activity is necessary for the development of new therapeutic molecules for controlling the heart rate. Recent work on genetically modified mouse models provided new and intriguing evidence linking the activity of ionic channels genes to the generation and regulation of pacemaking. Importantly, results obtained on genetically engineered mouse strains have demonstrated that some channels are specifically involved in the generation of cardiac automaticity and conduction, but have no functional impact on the contractile activity of the heart. In this article, we will outline the current knowledge on the role of ionic channels in cardiac pacemaker activity and suggest new potential pharmacological targets for controlling the heart rate without concomitant negative inotropism.
心脏起搏器活动的产生是一个复杂的现象，它需要不同膜离子通道以及包括Ca(2+)和第二信使在内的细胞内信号因子的协同活动。启动初级起搏器细胞自律性的精确机制仍存在争议，并且自主神经系统如何通过通道协同调节起搏的某些方面尚未完全阐明。心脏自律性生理病理学的研究在心血管药理学领域也引起了相当大的兴趣，因为越来越多的临床和流行病学证据表明心率增加与心脏死亡率和发病率风险之间存在联系。在心脏病患者中使用特定的减慢心率药物降低心率是增强心脏保护作用和提高生存率的一种有前景的方法。因此，阐明起搏器活动产生的潜在机制对于开发控制心率的新治疗分子是必要的。最近对转基因小鼠模型的研究提供了新的有趣证据，将离子通道基因的活动与起搏的产生和调节联系起来。重要的是，在基因工程小鼠品系上获得的结果表明，一些通道特别参与心脏自律性和传导的产生，但对心脏的收缩活动没有功能影响。在本文中，我们将概述关于离子通道在心脏起搏器活动中作用的当前知识，并提出控制心率而不伴有负性肌力作用的新的潜在药理学靶点。
