Ischemia-induced enhancement of digitalis sensitivity in isolated guinea-pig heart.

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.