Developmental changes in sensitivity of the heart to digitalis : possible involvement of Na channels

本研究的目的是确定Na~+通道在哇巴因正性变力作用的发育变化中是否起重要作用。这是一项从1990年到1991.1进行的为期两年的研究。正性肌力研究(1)哇巴因对胎龄(21天)和成年(4月龄)大鼠心脏的正性肌力作用，以及药物阻滞剂存在和不存在时的正性肌力作用。在胎鼠和成年大鼠心脏上，哇巴因引起双相正性肌力作用(低剂量和高剂量效应)。然而，低剂量效应在产前心脏中明显较低。肾上腺素能或组胺能受体拮抗剂不改变双相正性变力作用，但藜芦碱可显著增强正性变力作用。(2)几种神经毒素对胎鼠和成年大鼠心脏的变力作用。：在两个Pren…中河豚毒素对成年和成年心脏有负性变力作用，而藜芦碱、银莲花毒素或南雄龙胆毒素有正性变力作用。产前心脏需要所有这些神经毒素中更高的浓度才能产生类似的变力作用。结论：1.蛇床子虫毒素对成年大鼠心脏有正性变力作用，而对胎儿期心脏无正性变力作用。哇巴因结合研究对哇巴因特异性结合的Scatchard图分析表明，在胎鼠和成年大鼠的心肌匀浆中，均有高、低af结合位点。胎鼠和成年大鼠心脏高、低亲和力结合部位浓度之比分别为1：8和1：4。这些结果表明，心肌钠离子通道在发育过程中发生了显著的功能变化。由于在心脏周期的舒张期，细胞内Na~(++)浓度的轻微升高可能足以引起洋地黄的正性肌力作用；Na~+通道的发育增加可能在心脏对哇巴因敏感性的增加中起重要作用。此外，Na~(++)，K~(++)-ATPase生化特性的发育变化也可能是哇巴因敏感性随大鼠成熟而增强的原因之一。较少

A purpose of this study was to determine whether Na^+ channels play an important role in developmental changes in the positive inotropic action of ouabain in isolated rat hearts. This was a two year study conducted from 1990 through 1991.1. Inotropic studies(1) The positive inotropic effects of ouabain in isolate ventricular muscle preparations of prenatal (21 day gestation) and adult (4 month old) rat hearts, and the positive inotropic effects in the absence and presence of pharmacological blocking agents. : In both prenatal and adult rat hearts, ouabain caused biphasic positive inotropic effects (low dose and high dose effects). The low dose effect, however, was significantly lower in prenatal hearts. The biphasic positive inotropic effects were not altered by adrenergic or histaminergic receptor antagonists, but were signif icantly enhanced by veratridine.(2) The inotropic effects of several neurotoxins in isolated ventricular muscles of prenatal and adult rat hearts. : In both pren … More atal and adult hearts, tetrodotoxin caused negative inotropic effects, while veratridine, anemonia sulcata toxin or androctonus australis toxin caused positive inotropic effects. Prenatal hearts required higher concentrations in all of these neurotoxins to produce comparable inotropic effects. Centruroides sculpturatus toxin caused positive inotropic effects in adult hearts, however, this toxin failed to cause the positive inotropic effects in prenatal hearts.2. [ ^3H]ouabain binding studiesA scatchard plot analysis of the specific binding of[ ^3H]ouabain revealed high and low-af finity binding sites in both the homogenates obtained from the ventricular muscles of prenatal or adult rat heart. The ratio of the high and low affinity binding site concentrations observed in prenatal and adult rat hearts was 1 : 8 and 1 : 4, respectively.These results suggest that cardiac Na^+ channels undergo significant functional changes during development. Since a slight elevation of intracellular Na^+ concentration, during the diastolic phase of the cardiac cycle, may be sufficient to cause the positive inotropic effects of digitalis ; the developmental increase in Na^+ channels may play an important role in the increase in the sensitivity of the heart to ouabain. In addition, developmental changes in the biochemical characteristics of Na^+, K^+-ATPase may also contribute to the increase in the ouabain sensitivity with the maturity of the rat. Less