THERAPEUTIC AND REFLEXOGENIC EFFECT OF DIGITALIS

氨基糖洋地黄化合物是极性的，不会穿越 脂质屏障或生物膜。他们在行动上有所不同 从中性糖洋地黄中分离出来的氨基卡宾内酯具有 更强的心脏变力作用，是更有效的抑制 Na+，K+-ATPase使房室结延长更明显 不应期(AVRP)，有较高的治疗指数和 心脏毒性的不同模式，并与 改变自主神经系统活动的反射系统 在心脏，显然只会引起交感神经的消失 紧张的语气。我们假设氨基卡宾内酯， 因为高极性，无法与某些物质相互作用 被膜脂屏障覆盖的细胞部位。相比之下， 中性的卡登内酯能够到达这些部位。这个 因此，氨基卡宾内酯会产生不同的光谱 心血管和神经事件比中性糖记录的更多 洋地黄药剂。 为了验证这一假设，我们提出了四个方面的调查：1) 对心脏自主神经活动的影响。 氨基卡宾内酯与传统洋地黄类药物的区别在于 延长AVRP的能力；我们从间接证据得出结论 他们做到这一点完全是通过撤销交感神经 语气，而不是影响地高辛和哇巴因的 交感神经张力和迷走神经活动。我们寻求确认我们的 结论：通过直接测量和比较交感神经和交感神经 血管紧张素转换酶引起的迷走神经活动 氨基肉豆内酯或中性肉豆内酯 治疗性和毒性剂量范围。2)对反射的作用 感受区。因为氨基卡豆内酯似乎 单纯心脏停搏延长房室不应期 交感神经音调，而不是额外增强 迷走神经张力，我们将确定反射受体的位置(S) 氨基卡宾内酯与这些位点的相互作用比较 参与地高辛和哇巴因的活动。这将是 通过实验系统地排除除 这些网站。卡登内酯的局部、离散给药 也会被做成这些特定的网站。此外，传入 来自特定站点的神经流量将被检查。自.以来 不同器官的交感神经张力可能不同 在这些糖苷的影响下，我们将监测神经活动以 几个地区。3)对房室感染传播的影响。因为我们有 有证据表明，一种名为ASI-222的氨基卡菌内酯能产生 具有重要的治疗意义，AVRP的增加幅度大于 地高辛在心律失常剂量的分数，我们将研究 其行为的性质以及两个密切相关的同系物的行为 以及心脏传导系统受累的部位。这个 药物在心房模型中降低心室率的能力 纤颤也将被确定。4)治疗性和毒性 长期治疗的清醒狗的行为。心脏变力作用 长期服用这些药物对房室结的影响 清醒狗体内的卡登内酯可能与那些敏锐地注意到的不同。 在麻醉的狗身上，并可能在不同的剂量下发生。他们的 清醒狗的毒性效应也可能有所不同。 进一步研究这些极性试剂的作用将创造一个 更好地理解自动神经反射和 选择性反射所必需的洋地黄类似物的性质 受体相互作用。除了基本的机制考虑之外， 氨基卡宾内酯具有明显而直接的临床意义。 因为它们可能会被证明比 目前已有的强心苷。

Aminosugar digitalis compounds are polar and do not traverse lipid barriers or biological membranes. They differ in actions from neutral sugar digitalis in that aminocardenolides have a greater cardiac inotropic potency, are more potent inhibitors of Na+, K+-ATPase, produce more marked lengthening of A-V nodal refractory period (AVRP), have a higher therapeutic index and a different pattern of cardiac toxicity, and interact differently with reflexogenic systems to alter autonomic nervous system activity at the heart, apparently causing only withdrawal of sympathetic nervous tone. We hypothesize that the aminocardenolides, because of high polarity, are incapable of interacting with certain cellular sites covered by membrane lipid barriers. In contrast, neutral cardenolides are able to reach these sites. The aminocardenolides therefore produce a different spectrum of cardiovascular and neural events than noted with neutral sugar digitalis agents. To test this hypothesis, we propose four areas of investigation: 1) Effects on Cardiac Autonomic Nerve Activity. Aminocardenolides differ from traditional digitalis agents in their ability to lengthen AVRP; we conclude from indirect evidence that they do solely by the withdrawal of sympathetic nervous tone, as opposed to digoxin and ouabain which influence sympathetic tone and vagal activity. We seek to confirm our conclusion by directly measuring and comparing sympathetic and vagal nervous activity produced by infusion of an aminocardenolide or neutral cardenolide throughout the therapeutic and toxic dose range. 2) Actions on Reflexogenic Receptor Areas. Because an aminocardenolide appears to lengthen A-V refractory period solely by withdrawal of cardiac sympathetic nervous tone rather than additionally augmenting vagal tone, we will identify the site(s) of reflex receptor interaction of an aminocardenolide compared to those sites involved in the actions of digoxin and ouabain. This will be examined by experiments which systematically exclude all but these sites. Local, discrete administration of the cardenolides will also be made into these specific sites. Additionally, afferent neural traffic from specific sites will be examined. Since sympathetic nervous tone to various organs may be differentially affected by these glycosides, we shall monitor nerve activity to several regions. 3) Effects on A-V Transmission. Since we have evidence that an aminocardenolide, ASI-222 produces therapeutically important and greater increases in AVRP than digoxin at fractions of the arrhythmic dose, we shall study the nature of its actions and those of two closely related congeners and the site of the cardiac conduction system involved. the ability of agents to reduce ventricular rate in a model of atrial fibrillation will also be determined. 4) Therapeutic and Toxic Actions in Chronically Treated Conscious Dogs. Cardiac inotropic and A-V nodal effects of chronic administration of these cardenolides in conscious dogs may be unlike those noted acutely in anesthetized dogs and may occur at different doses. Their toxic effects in conscious dogs may also be different. Further study of the actions of these polar agents will create a better understanding of automatic nervous reflexes and the properties of digitalis analogs necessary for selective reflex receptor interactions. Beyond basic mechanism considerations, aminocardenolides are of obvious and direct clinical significance since they may prove to be safer and more effective than presently available cardiac glycosides.