Ku D D, Akera T, Frank M, Brody T M, Iwasa J
J Pharmacol Exp Ther. 1977 Feb;200(2):363-72.
We have demonstrated recently that grayanotoxin I (GTX I) produces a positive inotropic effect in isolated guinea-pig atria. In order to determine whether this effect of GTX I is related to the reported action of this compound to increase the sodium permeability of cytoplasmic membranes, the effect of GTX I and alpha-dihydrograyanotoxin II (alpha-2H-GTX II) on electrical and mechanical properties and transmembrane cation movements were studied in guinea-pig myocardium. In electrically driven guinea-pig left atrial preparations, both grayanotoxins produced a slight depolarization and appear to decrease the upstroke velocity of the action potential, with a concomitant increase in isometric contractile force in the presence or absence of propranolol. Pretreatment with propranolol shifted the dose-response curves for the inotropic effect of both grayanotoxins slightly to the right. The magnitudes of changes in the electrical and mechanical properties induced by GTX I and alpha-2H-GTX II were similar. The rate of development and subsequent washout of the positive inotropic effects, however, was faster with alpha-2H-GTX II than with GTX I, consistent with a previous report that the action of alpha-2H-GTX II to increase membrane sodium permeability develops more rapidly than that of GTX I. At higher concentrations, both grayanotoxins produced arrhythmias. Arrhythmias induced by GTX I were characterized by extrasystoles whereas those induced by alpha-2H-GTX II were characterized by initial extrasystoles followed by a failure of the atria to follow electrical stimulation. Positive inotropic and arrhythmic effects of both grayanotoxins were reversible after the washout of the drug. Both types of arrhythmias produced by either GTX I or alpha-2H-GTX II were reversed by tetrodotoxin, an agent which has been demonstrated to antagonize the action of the grayanotoxins to increase membrane sodium permeability. Although both grayanotoxins had no marked effect on partially purified Na+, K+-adenosine triphosphatase, they produced dose-dependent increases in ouabain-sensitive 86Rb uptake of ventricular slices under conditions in which the intracellular sodium concentration determines the rate of active monovalent cation transport by the Na+, K+-adenosine triphosphatase system. These data suggest that the positive inotropic effects of grayanotoxins are due to an increased membrane sodium permeability and are consistent with a hypothesis that alterations in transmembrane sodium movements result in an altered myocardial contractility.
我们最近已证明，灰藓毒素I（GTX I）在离体豚鼠心房中可产生正性肌力作用。为了确定GTX I的这种作用是否与该化合物增加细胞质膜钠通透性的报道作用相关，我们研究了GTX I和α-二氢灰藓毒素II（α-2H-GTX II）对豚鼠心肌电和机械特性以及跨膜阳离子转运的影响。在电驱动的豚鼠左心房标本中，两种灰藓毒素均引起轻微去极化，且似乎降低了动作电位的上升速度，同时在有无普萘洛尔存在的情况下等长收缩力均增加。普萘洛尔预处理使两种灰藓毒素正性肌力作用的剂量反应曲线均稍有右移。GTX I和α-2H-GTX II引起的电和机械特性变化幅度相似。然而，α-2H-GTX II引起的正性肌力作用的发展速度和随后的洗脱速度比GTX I快，这与先前的报道一致，即α-2H-GTX II增加膜钠通透性的作用比GTX I发展得更快。在较高浓度时，两种灰藓毒素均引起心律失常。GTX I诱导的心律失常以早搏为特征，而α-2H-GTX II诱导的心律失常以最初的早搏随后心房对电刺激无反应为特征。两种灰藓毒素的正性肌力作用和心律失常作用在洗脱药物后均可逆转。GTX I或α-2H-GTX II产生的两种类型的心律失常均被河豚毒素逆转，河豚毒素已被证明可拮抗灰藓毒素增加膜钠通透性的作用。尽管两种灰藓毒素对部分纯化的Na +，K + -三磷酸腺苷酶均无明显影响，但在细胞内钠浓度决定Na +，K + -三磷酸腺苷酶系统主动单价阳离子转运速率的条件下，它们使心室切片哇巴因敏感的86Rb摄取呈剂量依赖性增加。这些数据表明，灰藓毒素的正性肌力作用是由于膜钠通透性增加，并且与跨膜钠转运改变导致心肌收缩力改变的假说一致。
