Digoxin's Minimal Inotropic Effect Is Not Limited by Sodium—Calcium Exchange in the Intact Immature Rabbit Heart

Abstract

BACKGROUND: In the intact immature heart, how much digoxin can drive sodium-calcium exchange has not been studied in the context of sodium-calcium exchanger abundance. METHODS AND RESULTS: The effects of digoxin and low potassium on contractility in the intact, paced and isovolumically contracting immature rabbit heart were studied in both the absence and presence of L-type calcium channel blockade. Without calcium channel blockade, digoxin increased contractility minimally and only at 10(_6) M/L. In contrast, low potassium (2.2 mM/L) substantially increased contractility in all experiments, a result indicating abundant sodium-calcium exchanger activity. During nifedipine-induced calcium channel blockade, digoxin (10(_6) M/L) allowed modest recovery of contractility, whereas digoxin and low potassium together allowed complete recovery as assessed by dP/dt(max); however, all hearts so perfused subsequently developed ventricular fibrillation, presumably because of calcium overload. CONCLUSIONS: In intact immature rabbit heart, digoxin can drive sodium-calcium exchange and thus increase contractility to only a minimal extent. This effect does not appear to be limited by intrinsic exchanger activity, which appears abundant in this preparation. Rather, digoxin's inability to drive the sodium-calcium exchanger may be due to developmental differences in binding to the sodium pump. The sodium-calcium exchanger itself seems capable not only of providing enough intracellular calcium for normal contraction, but also of overloading the myocardium with calcium, despite L-type calcium channel blockade.