DRUG EFFECTS ON CA2+I TRANSIENTS & CONTRACTION IN HEART

大多数药物的肌力作用是由以下因素决定的 它们影响肌浆网(SR)的钙释放。它的用途 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出色的 检查药物对钙=1代谢作用的方法。建议进行的研究 将检查几类变力药物的效果，所有的 这也改变了Na+1。对Ca~(2+)从SR释放和作用力。这个 这些钳位测量对膜电流和光学性能的影响 离体犬心室肌细胞收缩的测量。 这些实验的总体目标是定义1)直接 这些药物对肌质网钙释放的作用；2)间接药物对肌质网钙释放的作用 通过Na+i的变化，从而通过Na-Ca交换而产生的钙离子的作用；3) SR功能改变在多大程度上与药物有关 变力和/或毒性；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：治疗比率差异的基础是什么 对于不同的心脏类固醇？2)使用部分或全部心脏类固醇 对SR有促进变力和/或毒性的直接作用？3) 临床上有用的局麻药抗心律失常药物 直接干扰肌浆网钙离子释放的负性肌力作用 钠离子通道毒素Anthopleurin-A具有一种新的正性变力作用 涉及肌质网钙释放变化的作用？丹曲林 像ryanodine一样通过直接机制抑制SR的钙释放？ 6)Na~+i、Ca~(2+)i~-与 心肌中的心肌力？这些因素的意义 实验有三个方面：第一，区分(直接)钙离子i- 和(间接的Na+1依赖的肌力药物的影响将改善我们的 对这些药物的临床治疗和毒性作用的认识 重要药物：第二，定义参与的正常过程 收缩的决定因素。这将为定义 异常(如心肌病和心力衰竭)。第三，界定毒品的定义 对亚细胞机制的行动将帮助我们设计出更具体的 新型正性肌力药的开发途径 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.