DRUG EFFECTS ON CA2+I TRANSIENTS & CONTRACTION IN HEART

大多数药物的变力作用取决于 它们影响肌浆网（SR）的Ca 2+释放。使用 荧光指示剂indo-1提供了以前无法获得的 细胞内离子测量的分辨率和良好的 检测药物对Ca 2 =1代谢的作用。拟议的研究 将检查几类正性肌力药物的作用，所有 这也改变了Na+1。对SR和力的Ca 2+释放的影响。的 膜电流和光学特性的这些钳测量的影响 在分离的狗心室肌细胞中测量细胞收缩。 这些实验的总体目标是定义1）直接 这些药物对SR Ca ~（2+）释放的作用; 通过Na+1的改变，并因此通过Na-Ca交换的Ca 2 +1的改变来施加力; 3） SR功能的改变在多大程度上有助于药物 正性肌力和/或毒性，以及4）Na+ i-Ca 2 + i-张力关系， 心室肌将讨论以下具体问题： 1)毒性：治疗比例之间差异的基础是什么 不同的心脏类固醇吗2)做一些或所有的心脏类固醇 对SR具有直接作用以促进肌力和/或毒性？第三章 临床上有用的局部麻醉药是否产生 负性肌力的直接干扰SR释放的Ca 2+？4)并 钠通道毒素Anthopleurin-A具有一种新正性肌力作用 涉及SR Ca 2+释放改变的作用？5)丹曲洛林 像ryanodine一样通过直接机制抑制SR的Ca 2+释放？ 6)Na+i、Ca 2 +i-和Ca ~（2+）之间的定量关系是什么？ 心室肌中的心力？这些的意义 实验是三重的：首先区分（直接）Ca 2 +i- 和（间接Na+1依赖性正性肌力药物的影响将改善我们的 了解这些临床治疗和毒性作用 重要药物：第二，定义参与的正常过程 收缩的决定因素这将为确定 异常（例如心肌病和心力衰竭）。三、界定毒品 对亚细胞机制的研究将有助于我们设计出更具体的 开发新的正性肌力药物的方法 这些疾病的治疗。

The inotropic effect of most agents is determined by the extent to which they influence Ca2+ release from the sarcoplasmic reticulum (SR). The use of the fluorescent indicator indo-1 provides a previously unobtainable degree of resolution of intracellular ionic measurements and an excellent means to examine drug actions on Ca2=1 metabolism. The proposed studies will examine the effects of several classes of inotropic agents, all of which also change Na+1. on Ca2+ release from the SR and force. The effects of these clamp measurements of membrane current and optical measurements of cell contraction in isolated dog ventricular myocytes. The overall goals of these experiments are to define 1) the direct actions of these agents on SR Ca2+ release; 2) indirect drug actions on force via alteration in Na+i and, therefore Ca2+1 via Na-Ca exchange; 3) the extent to which alterations in SR function contribute to drug inotropy and/or toxicity, and 4) the Na+i-Ca2+i-tension relation in ventricular muscle. The following specific questions will be addressed: 1) What is the basis for the disparity between toxic: therapeutic ratios for different cardiac steroids? 2) Do some or all cardiac steroids possess a direct action on the SR to promote inotropy and/or toxicity? 3) Do clinically useful local anesthetic antiarrhythmic agents produce negative inotropy by direct interference with SR release of Ca2+? 4) Does the Na+ channel toxin Anthopleurin-A possess a novel positive inotropic action that involves alterations in SR Ca2+ release? 5) Does dantrolene act like ryanodine to inhibit Ca2+ release from SR by a direct mechanism? 6) What are the quantitative relationships between Na+i, Ca2+i- and cardias force in ventricular muscle? The significance of these experiments is three-fold: first distinguishing between (direct) Ca2+i- and (indirect Na+1- dependent inotropic drug influences will improve our understanding of therapeutic and toxic actions of these clinically important drugs: second, defining the normal processes involved in determinants of contraction. This will provide some basis for defining abnormal (e.g. cardiomyopathy and heart failure). Third, defining drug actions on subcellular mechanisms will help us to devise more specific approaches to the development of new positive inotropic agents for the treatment of these diseases.