THERAPEUTIC AND TOXIC ACTIONS OF DIGITALIS

洋地黄是治疗充血性心力衰竭的常用药物。 然而，它的毒性破坏了它的临床用途。我们会 研究洋地黄是如何产生正性肌力作用的 羊心蒲肯野纤维。我们要检验的假设是 洋地黄通过抑制钠泵起作用，由此产生的 细胞内钠离子活性(AINA)的增加是导致 增加了可供收缩的钙离子。我们将研究 洋地黄的正性肌力对阻断AINA增加的要求 药理和生理干预下钠的积累。 这将通过使用两个微电极电压来实现 将使用低保持电位和河豚毒素的钳制方案 以限制钠的流入。抽搐张力和艾娜也会被监控， 后者具有钠敏感的细胞内微电极。以这种方式 我们将能够确定Aina的上涨是否真的对 心脏类固醇的正性变力作用。钠、钾的抑制作用 洋地黄的反转运也是已知的原因 发生洋地黄诱发的电压、电流和张力振荡。 这些振荡最近受到了极大的关注，因为它们可能 与洋地黄中毒相关的心律失常是其基础。我们会 使用电压钳方法和离子敏感的细胞内微电极 以测量与发生相关的钠和钙活动的变化 震荡的影响。通过这种方式，我们将量化离子的变化 1)由钠泵抑制而产生的组合物以及2)依次可 影响洋地黄毒性的机械和电学表达。 我们还将研究保持电位对离子组成的影响，以及 洋地黄的去极化效应引起的洋地黄振荡 以及跨膜电位对细胞内离子的影响。这 研究将提供关于1)洋地黄是如何产生其 治疗作用；2)是否具有治疗作用和毒性作用 洋地黄可以分离，以便制造更安全的药剂；3)如何 洋地黄中毒影响细胞内离子组成；4)如何 细胞内离子和膜电位的变化影响 表现出糖苷毒性(通过振荡和心律失常)； 5)钠和钙是如何影响心脏收缩的 将军。

Digitalis is commonly used in the treatment of congestive heart failure. However, its clinical usefulness is marred by its toxicity. We will examine how digitalis produces its positive inotropic effect in isolated sheep heart Purkinje fibers. The hypothesis that we will test is that digitalis acts by inhibiting the sodium pump and that the resulting increase in intracellular sodium ion activity (aiNa) is responsible for the increased calcium ion available for contraction. We will examine the requirement of digitalis inotropy for increased aiNa by blocking the accumulation of Na with pharmacological and physiological interventions. This will be accomplished through the use of a two microelectrode voltage clamp protocol in which low holding potential and tetrodotoxin will be used to limit Na influx. Both twitch tension and aiNa will also be monitored, the latter with a Na-sensitive intracellular microelectrode. In this way we will be able to determine if a rise in aiNa is in fact essential to the positive inotropic action of cardiac steroids. Inhibition of Na, K countertransport by digitalis is also known to be responsible for the occurrence of digitalis-induced voltage, current and tension oscillations. These oscillations have received much attention recently because they may underlie the arrhythmias associated with digitalis intoxication. We will use voltage clamp methods and ion sensitive intracellular microelectrodes to measure changes in Na and Ca activities associated with the occurrence of the oscillations. In this way we will quantify changes in ionic composition which 1) result from Na pump inhibition and 2) in turn may influence the mechanical and electrical expression of digitalis toxicity. We will also examine effects of holding potential on ionic composition and the digitalis oscillations because of the depolarizing effect of digitalis and of the effect of transmembrane potential on intracellular ions. This study will provide new information about 1) how digitalis produces its therapeutic action; 2) whether or not the therapeutic and toxic actions of digitalis can be separated so that safer agents can be manufactured; 3) how digitalis intoxication affects intracellular ionic composition; 4) how changes in intracellular ions and membrane potential influence the expression of glycoside toxicity (through oscillations and arrhythmias); and 5) how Na and Ca influence the force of contraction of the heartbeat in general.