哇巴因、地高辛和洋地黄毒苷在离体大鼠心脏中的变力作用、心肌摄取及亚细胞分布

Inotropic action, myocardial uptake and subcellular distribution of ouabain, digoxin and digitoxin in isolated rat hearts.

作者信息

Fricke U, Hollborn U, Klaus W

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 1975;288(2-3):195-214. doi: 10.1007/BF00500527.

Abstract

In experiments on isolated, electrically driven (240/min) rat hearts, perfused via the aorta at a constant flow (3.8 ml/min), the pharmacologically effective concentration range, the myocardial uptake and the subcellular distribution of three cardiac glycosides (digitoxin, digoxin, ouabain) were determined. The following results were obtained: 1. The effective range varied depending on the cardiac glycoside tested: With digoxin and ouabain very similar results were found- the positive inotropic concentration ranges being within 8x10(-6)M and 6x10(-5)M, the maximum positive inotropic effects attainable being about 100% and the concentration for half maximum effects (ED-50) being 2.4x10(-5)M and 2.3x10(-5)M, respectively. With digitoxin the inotropic concentration range was found to be within 3.6x10(-6)M and 2.4x10(-5)M with a maximum inotropic effect attainable of about 50% only and an ED-50 of 9.5x10(-6)M. The analysis of the time course of the inotropic action revealed extremely short half times for all cardiac glycosides studied (between 48 and 54 sec). 2. The myocardial uptake correlated with the physicochemical behaviour of the three cardiac glycosides studied and was found-depending on the perfusion time (5 to 60 min)-to be in the range of 23 and 36 (ouabain), 66 and 98 (digoxin) and 169 and 264 (digitoxin) nmoles/g wet weight. The respective computed half times for these uptake processes were 2.5 min (digoxin, ouabain) and 3.4 min )digitoxin). 3. Regarding the subcellular distribution an accumulation exceeding an "unspecific" binding (non-perfused hearts) was found mainly in the nuclear-membrane fraction. On the basis of these results (very short half times of either the pharmacological action and the cardiac uptake) the site of action of cardiac glycosides in the rat heart is supposed to be located at the surface membrane of the heart muscle cells. Furthermore, the above results are discussed with respect to those obtained in digitalis-sensitive species.

摘要

在对离体的、电驱动（每分钟240次）的大鼠心脏进行的实验中，通过主动脉以恒定流量（每分钟3.8毫升）进行灌注，测定了三种强心苷（洋地黄毒苷、地高辛、哇巴因）的药理有效浓度范围、心肌摄取量和亚细胞分布。得到了以下结果：1. 有效范围因所测试的强心苷而异：地高辛和哇巴因的结果非常相似——正性肌力浓度范围在8×10⁻⁶M和6×10⁻⁵M之间，可达到的最大正性肌力作用约为100%，半数最大效应浓度（ED-50）分别为2.4×10⁻⁵M和2.3×10⁻⁵M。对于洋地黄毒苷，正性肌力浓度范围在3.6×10⁻⁶M和2.4×10⁻⁵M之间，可达到的最大正性肌力作用仅约为50%，ED-50为9.5×10⁻⁶M。对正性肌力作用的时间进程分析显示，所有研究的强心苷的半衰期都极短（在48至54秒之间）。2. 心肌摄取与所研究的三种强心苷的物理化学行为相关，并且发现——取决于灌注时间（5至60分钟）——摄取量在23至36（哇巴因）、66至98（地高辛）和169至264（洋地黄毒苷）纳摩尔/克湿重范围内。这些摄取过程各自计算出的半衰期为2.5分钟（地高辛、哇巴因）和3.4分钟（洋地黄毒苷）。3. 关于亚细胞分布，发现超过“非特异性”结合（未灌注心脏）的积累主要在核膜部分。基于这些结果（药理作用和心脏摄取的半衰期都极短），推测强心苷在大鼠心脏中的作用部位位于心肌细胞的表面膜。此外，还根据在对洋地黄敏感的物种中获得的结果对上述结果进行了讨论。