THERAPEUTIC AND REFLEXOGENIC EFFECTS OF DIGITALIS

氨基糖洋地黄类化合物是极性的， 脂质屏障或生物膜。 他们的行为不同 来自中性糖洋地黄，因为氨基腰果内酯具有 更强的心脏变力效力，是更有效的抑制剂， Na+，K +-ATP酶使房室结延长更明显 不应期（AVRP），具有较高的治疗指数和 不同的心脏毒性模式，并与 反射系统改变自主神经系统活动 在心脏，显然只会导致同情心的撤回， 紧张的语气。 我们假设氨基腰果内酯， 由于高极性，无法与某些 被膜脂质屏障覆盖的细胞位点。 与此相反， 中性强心内酯能够到达这些位点。 的 因此，氨基腰果酚会产生不同的光谱 心血管和神经系统事件比中性糖 洋地黄制剂。 为了验证这一假设，我们提出了四个调查领域：1） 对心脏自主神经活动的影响。 氨基腰果内酯与传统的洋地黄类药物不同， 延长AVRP的能力;我们从间接证据得出结论 仅仅是因为他们的交感神经 语气，而不是地高辛和哇巴因， 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 迷走神经活动，由输注一种 在整个过程中， 治疗和毒性剂量范围。 2)关于Reflexogenic 受体区。 因为一种氨基腺苷酸 单纯撤心延长房室不应期 交感神经紧张，而不是额外增加 迷走神经张力，我们将确定反射受体的部位 与这些位点相比，氨基腺苷的相互作用 与地高辛和哇巴因有关 这将是 通过系统地排除所有， 这些网站。 局部、离散给予强心苷 也会被制作成这些特定的网站。 此外，传入 将检查来自特定站点的神经流量。 以来 不同器官的交感神经张力可能不同， 受这些糖苷的影响，我们将监测神经活动， 几个地区。 3)对AV传输的影响。 既然我们有 有证据表明，一种氨基腺苷酸，ASI-222产生 治疗重要性和更大的增加AVRP比 地高辛的剂量分数，我们将研究 其作用的性质以及两种密切相关的同系物的作用的性质 以及心脏传导系统的位置。 的 药物降低心房颤动模型中心室率的能力 还将确定原纤化。 4)治疗和毒性 长期治疗清醒犬的作用。 心脏收缩 以及长期给予这些药物的房室结效应 清醒狗体内的强心内酯可能与急性观察到的不同， 在麻醉的狗中，并且可能在不同剂量下发生。 他们的 对清醒狗的毒性作用也可能不同。 对这些极性试剂的作用的进一步研究将建立一个 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， 氨基腰果酚类化合物具有明显而直接的临床意义 因为它们可能被证明比 目前可用的强心苷。

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.