Kim D H, Akera T, Kennedy R H
J Pharmacol Exp Ther. 1983 Aug;226(2):335-42.
Digitalis sensitivity of the heart is increased in patients with ischemic heart disease. Whether this elevation of digitalis sensitivity occurs as the result of ischemia-induced changes in the cardiac tissue and whether changes in the sarcolemmal Na,K-adenosine triphosphatase (ATPase) or reserve capacity of the sodium pump are responsible for the increased digitalis sensitivity were examined using isolated heart preparations obtained from guinea pigs. Ligation of the left anterior descending coronary artery (LAD) in Langendorff preparations 40 min before perfusion with a toxic concentration (either 1.8 or 2.5 microM) of digoxin decreased the time to the onset of arrhythmias. LAD-ligation by itself did not cause arrhythmias. The time to the onset of arrhythmias during digoxin perfusion was slightly longer in preparations obtained from reserpine-treated animals; however, the reserpine pretreatment failed to alter the effect of LAD ligation on digitalis sensitivity, indicating that the release of catecholamines is not involved in the sensitization. The effects of ischemia on Na,K-ATPase and sodium pump activities, glycoside binding to the enzyme and reserve capacity of the sodium pump were examined in globally ischemic Langendorff preparations. The preparations were perfused with a Krebs-Henseleit bicarbonate buffer solution (pH 7.4) saturated with a 95% O2-5% CO2 gas mixture at a control flow rate of 2.5 ml/g of tissue per min or at 5 or 0% of the control flow rate. After 6 hr of zero perfusion, Na,K-ATPase activity and the number of specific ouabain binding sites were reduced in ventricular muscle homogenates. However, the remaining Na,K-ATPase was not altered in its sensitivity to dihydrodigoxin-induced inhibition or affinity of binding sites for ouabain, sodium or potassium. Similar results were observed after reperfusion following 2 or 5 hr of zero perfusion. A 5% perfusion for 2 or 6 hr, or zero perfusion for 2 hr failed to affect Na,K-ATPase activity in muscle homogenates. Sodium pump activity in ventricular slices, estimated from the ouabain-sensitive 86Rb+ uptake, was unchanged after 5% perfusion or zero perfusion for 2 hr, but was significantly reduced after a 20-min reperfusion following 2 hr of zero perfusion. Reserve capacity of the sodium pump, as estimated from the differences in 42K+ uptake by right ventricular strips under 1.5 and 7 Hz stimulation, was unaffected by 2 hr of 5% perfusion. These results indicate that coronary artery occlusion enhances the arrhythmogenic action of digitalis in isolated heart preparations. This change in digitalis sensitivity produced by 40 min of occlusion cannot be explained by reductions in Na,K-ATPase activity or sodium pump reserve capacity as 2 hr of zero perfusion does not alter Na,K-ATPase or sodium pump activity in ventricular tissue.
缺血性心脏病患者心脏对洋地黄的敏感性增加。这种洋地黄敏感性的升高是否是由于缺血引起的心脏组织变化所致，以及肌膜钠钾 - 三磷酸腺苷酶（ATP酶）的变化或钠泵储备能力是否是洋地黄敏感性增加的原因，我们使用从豚鼠获得的离体心脏标本进行了研究。在以中毒浓度（1.8或2.5微摩尔）的地高辛灌注前40分钟，在Langendorff标本中结扎左冠状动脉前降支（LAD），可缩短心律失常发作的时间。单独结扎LAD不会引起心律失常。在从利血平处理的动物获得的标本中，地高辛灌注期间心律失常发作的时间稍长；然而，利血平预处理未能改变LAD结扎对洋地黄敏感性的影响，表明儿茶酚胺的释放与敏感性增加无关。在全心缺血的Langendorff标本中，研究了缺血对钠钾ATP酶和钠泵活性、糖苷与该酶的结合以及钠泵储备能力的影响。标本用含有95% O₂ - 5% CO₂气体混合物饱和的Krebs - Henseleit碳酸氢盐缓冲溶液（pH 7.4）灌注，对照流速为每分钟2.5毫升/克组织，或为对照流速的5%或0%。零灌注6小时后，心室肌匀浆中的钠钾ATP酶活性和特异性哇巴因结合位点数量减少。然而，剩余的钠钾ATP酶对二氢地高辛诱导的抑制的敏感性或对哇巴因、钠或钾结合位点的亲和力未改变。在零灌注2或5小时后再灌注也观察到类似结果。5%灌注2或6小时，或零灌注2小时均未影响肌匀浆中的钠钾ATP酶活性。根据哇巴因敏感的⁸⁶Rb⁺摄取量估计的心室切片中的钠泵活性，在5%灌注或零灌注2小时后未改变，但在零灌注2小时后20分钟再灌注后显著降低。根据右心室条带在1.5和7赫兹刺激下⁴²K⁺摄取量的差异估计的钠泵储备能力，不受5%灌注2小时的影响。这些结果表明，冠状动脉闭塞增强了离体心脏标本中洋地黄的致心律失常作用。40分钟闭塞所产生的这种洋地黄敏感性变化不能用钠钾ATP酶活性或钠泵储备能力的降低来解释，因为零灌注2小时不会改变心室组织中的钠钾ATP酶或钠泵活性。
