Role of oscillatory potential and pacemaker shifts in digitalis intoxication of the sinoatrial node

Background. Digitalis intoxication causes tachycardia, pacemaker shifts, and conduction disturbances in the sinoatrial (SA) node, but the mechanisms underlying these changes have not been clarified. We studied the role played by oscillatory potentials, electrical inhomogeneity, and calcium overload in cardiac steroid intoxication of the SA node. Methods and Results. Guinea pig SA nodes (isolated from atrial tissue) were perfused in vitro. Transmembrane potentials and force were recorded. Strophanthidin (1 μmol/L) induced minor changes, although it was perfused for more than 30 minutes. In contrast, ouabain (0.5 μmol/L) and digoxin (1 μmol/L) intoxicated the SA node in 10-20 minutes. Ouabain and digoxin increased spontaneous rate and slope of diastolic depolarization, shifted the plateau to more negative values, and decreased the maximum diastolic potential. These cardiac steroids increased and then decreased contractile force and eventually caused the action potential and twitch to become irregular in amplitude and rhythm. In the presence of acetylcholine (ACh, 0.01-1 μmol/L), cardiac steroids decreased the resting potential, caused spontaneous activity, and increased force and, eventually, oscillatory potentials (V_os) and aftercontractions as well as overdrive excitation. To make the SA node electrically homogeneous (only slow responses), the SA node was perfused with high extracellular potassium concentration (with and without norepinephrine), tetrodotoxin (2.61 μmol/L), or lidocaine (50 μmol/L). Adding ouabain or digoxin to these solutions increased the rate but far less than in Tyrode's solution. Recovery in Tyrode's solution initially caused fast and irregular rhythms, which then subsided. Low extracellular calcium concentration ([Ca]_o) (0.54 mmol/L) decreased force; adding ouabain markedly increased force and induced V_os. High [Ca]_o (8.1 mmol/L) increased force; adding ouabain decreased force and made action potentials as well as contractions quite irregular. Conclusions. Ouabain and digoxin quickly intoxicate the SA node by inducing calcium overload and its manifestations (V_os, decrease in contractile force and aftercontractions), whereas strophanthidin does not, possibly because of the lack of a sugar moiety. The intoxication is less pronounced when sodium influx is decreased (slow responses), and this accounts for the shifts from dominant to subsidiary pacemakers. Marked conduction disturbances result from calcium overload, leading to the fractionation of SA node activity.