THERAPEUTIC AND TOXIC ACTIONS OF DIGITALIS

洋地黄通常用于治疗充血性心力衰竭。 然而，它的临床应用受到其毒性的影响。 我们将 检查洋地黄如何产生其正性肌力作用，在隔离 羊心脏浦肯野纤维。 我们将要检验的假设是， 洋地黄通过抑制钠泵起作用， 细胞内钠离子活性（aiNa）的增加是导致 增加的钙离子可用于收缩。 我们会研究 洋地黄收缩力的需求增加aiNa通过阻断 药物和生理干预的钠积累。 这将通过使用两个微电极电压来实现 钳方案，其中将使用低保持电位和河豚毒素 以限制Na流入。 抽搐张力和aiNa也将被监测， 后者用Na敏感的细胞内微电极。 以这种方式 我们将能够确定是否在aiNa的上升实际上是必不可少的 强心类固醇的正性肌力作用。 Na、K抑制 洋地黄的反向转运也是已知的 数字感应电压、电流和张力振荡的发生。 这些振荡最近备受关注，因为它们可能 导致了洋地黄中毒引起的心律失常 我们将 使用电压钳方法和离子敏感细胞内微电极 以测量与事件发生相关的Na和Ca活性的变化， 的振荡。 通过这种方式，我们将量化离子的变化 组合物，其1）由Na泵抑制产生，和2）进而可 影响洋地黄毒性的机械和电表达。 我们还将研究保持电位对离子组成的影响， 由于洋地黄的去极化作用， 以及跨膜电位对细胞内离子的影响。 这 研究将提供新的信息1）洋地黄如何产生其 治疗作用; 2）是否治疗和毒性作用 洋地黄可以分离，以便更安全的代理可以制造; 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细胞内 糖苷毒性的表达（通过振荡和心律失常）; 5）Na和Ca如何影响心脏收缩力 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.