DRUG EFFECTS ON THE NA-TENSION RELATIONSHIP IN HEART

Na-Ca平衡交换过程是挤压 因此，它是心肌细胞中的一个关键调节过程， 确定可用于收缩的Ca 1的量。 我们将研究 改变Na 1活性的试剂（a-Na-1）对 α-Na-1（如使用Na敏感微电极直接测量的， Na-ISE）和张力。 我们将研究河豚毒素的影响， 通过钠通道阻断钠内流，强心苷可防止钠 通过Na，K泵和几种阻断Na通道的药物外排 失活，如藜芦定。 研究这些不同的 药物是检查的性质Na紧张关系下的各种 增加a-Na-1的条件 我们还将使用Ca-1 SE， 更充分地描述了钠钙张力关系， 影响心脏的收缩状态。 这些实验将 联合收割机电压下分离犬心室肌细胞技术 钳夹对照，直接测量a-Na-1和a-Ca-1， 伊势，同时监测电池长度的变化。 我们所知的大部分 钠钙交换来自浦肯野纤维，但本研究将 直接检测心肌细胞的这些生理特性。 这项研究将量化的钠钙张力关系，这是至关重要的 我们对生理因素的理解 兴奋-收缩偶联在心脏和药理学 对收缩强度的影响 这些实验不仅 帮助我们理解一些生理过程 收缩力，可能会受到不利影响的疾病状态，如 心力衰竭和心肌病，但也将帮助我们设计一个更 开发新的正性肌力药物的合理方法 这些疾病的治疗。

The Na-Ca equilibrium exchange process is responsible for the extrusion of Ca1 from cardiac cells and is therefore a critical regulatory process in determining the amount of Ca1 available for contraction. We will examine the effects of agents which alter Na1 activity (a-Na-1 on the relation between a-Na-1 (as measured directly using Na-sensitive microelectrodes, Na-ISE) and tension. We will study the effects of tetrodotoxin which blocks Na influx through Na channels, cardiac glycosides which prevent Na efflux via the Na,K pump and several agents which block Na channel inactivation such as veratridine. The purpose for studying these different drugs is to examine the nature of the Na-tension relation under a variety of conditions of increasing a-Na-1. We will also use Ca-1SE in order to more fully characterize the Na-Ca-tension relationships which so strongly influence the contractile state of the heart. These experiments will combine the techniques of isolated dog ventricular cells under voltage clamp control with measurements of a-Na-1 and a-Ca-1 obtained directly with ISE while changes in cell length are monitored. Most of our knowledge of Na-Ca exchange is derived from Purkinje fibers but the present study will directly examine these physiological characteristics in myocardial cells. This study will quantify the Na-Ca-tension relationships which are critical to our understanding of physiological factors that determine excitation-contraction coupling in the heart and of the pharmacological influences on contraction strength. Thus these experiments will not only help us understand some of the physiological processes determining contractile force that may be adversely affected in disease states like heart failure and cardiomyopathy, but will also help us to devise a more rational approach in the development of new positive inotropic agents for the treatment of these diseases.