MODELS OF DRUG BINDING TO CARDIAC SODIUM CHANNELS

这项提议的长期目标是建立一个量化的基础 用于抗心律失常药物在心肌的作用。这一增长 作用的数量和方式(钠通道、钙通道阻滞剂) 药物为药物管理创造了更多的机会 心律失常的数量。在这方面进展甚微。 描述一个定量准确地描述药物通道的过程 相互作用及其对心脏传导系统的相关影响。 心脏组织的调节性受体假说假设了一个变量 亲和力受体与通道门与药物的相互作用 频道。我们已经建议了一个相当简单的基于GATED的过程 控制药物池和通道结合部位之间的扩散路径。 一种“明显的”可变亲和力受体作为一种自然结果出现 这种方法。此外，还出现了对浇口动力学的“明显”修正 当然。这项工作将集中在扩展这种渠道的描述 阻断剂对传播系统的影响；评估 阻断剂对电流、电压和电导关系的影响 传播和电压钳位设置；并调查潜在的作用 阻断剂引起传播速度的变化。我们期待我们的 通道阻断时传播性动作电位的研究 用于阐明离子电流、电压和电流之间关系的试剂 电导，从而有助于设计适当的实验 协议的重点是将混淆影响降至最低。

The long term objective of this proposal is to develop a quantitative basis for action of antiarrhythmic drugs in cardiac muscle. The increase in number and modes of action (sodium channel, calcium channel blockers) of drugs has created expanded opportunities for pharmacologic management of a number of cardiac arrhythmias. There has been little progress in describing a quantitatively accurate process depicting drug-channel interaction and the associated effect on the cardiac conduction system. The modulated receptor hypothesis for cardiac tissue postulates a variable affinity receptor and interaction between channel gates and drug complexed channels. We have suggested a considerably simpler process based on gated control of the diffusion path between drug pool and channel binding site. An "apparent" variable affinity receptor arises as a natural consequence of this approach. Further, an "apparent" modification of gate kinetics arises naturally. This work will focus on extending this description of channel blocking agents to a propagating system; evaluate the potential effect of blocking agents on current, voltage and conductance relationships in a propagating and voltage clamped setting; and investigate the potential role of blocking agent mediated changes in propagation velocity. We expect our studies of propagated action potentials in the presence of channel blocking agents to illuminate the relationship between ionic currents, voltage and conductance, and thus aid in the design of appropriate experimental protocols focused on minimizing confounding effects.