We tested the hypothesis that a selective increase in membrane current, as contrasted with the decreases in currents caused by most antiarrhythmic agents, would be an effective antiarrhythmic intervention. We studied models of early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and abnormal automaticity in single canine ventricular myocytes using intracellular microelectrodes or patch electrodes. EADs were induced by injected current, Bay K 8644 (0.5-1 microM), or ketanserin (1.0 microM); DADs were induced by ouabain intoxication (2 x 10(-7) M); and abnormal automaticity was induced by exposure to barium (0.25 mM). To increase outward K+ current, we used pinacidil and the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate (PDBu). Under control conditions, 10-100 microM pinacidil caused a concentration-dependent and reversible decrease in action potential duration and an increase in steady-state outward current; both effects were blocked by glibenclamide and thus presumably reflected changes in the ATP-regulated potassium current. Pinacidil increased the current required to induce EADs and abolished EADs caused by Bay K 8644 or ketanserin. After exposure of myocytes to ouabain, pinacidil caused a decrease in action potential duration and diminished or abolished DADs. Finally, pinacidil arrested abnormal automaticity caused by Ba2+. PDBu (30 nM) shortened action potential duration without altering plateau amplitude in some of the myocytes. In these cells the depolarizing current needed to produce an EAD was increased by over 70%; outward potassium current tails were also increased, an effect consistent with an increase of the repolarizing potassium current (IK). These findings show that each of the mechanisms for abnormal impulse generation can be effectively antagonized by an increase in outward current and suggest to us that selective augmentation of a repolarizing current, possibly IK, might be a reasonable antiarrhythmic intervention.

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1. Bursts of triggered activity can be induced in atrial fibres of the canine coronary sinus exposed to catecholamines. During a triggered burst there is an initial acceleration of rate accompanied by depolarization of the maximum diastolic potential (m.d.p.) followed by slowing of the rate and termination accompanied by hyperpolarization. 2. We have used extracellular K+-sensitive micro-electrodes (potassium ISE) to monitor extracellular K+ concentration ([K+]o) during and following triggered activity, while simultaneously measuring membrane potential with conventional intracellular micro-electrodes. 3. We found that the initial increase in rate during triggered activity is accompanied by increased [K+]o and depolarization. Later rate slowing and m.d.p. hyperpolarization is accompanied by decline of extracellular K+ accumulation. Following termination of triggered activity, extracellular K+ depletion occurred. 4. The decline of [K+]o and slowing of rate are known responses to enhanced Na+-K+ pump activation, as is the post-triggering depletion of extracellular K+. 5. Strophanthidin, which blocks the Na+-K+ pump, also blocks the [K+]o decline, the slowing of rate seen towards the end of the triggered episode, and the post-triggering depletion of extracellular K+. 6. Separate experiments studying the effects of elevated bath K+ and depolarizing current on triggering rate and delayed after-depolarization amplitude support our hypothesis that the rate profile of the triggered episode is to a large extent controlled by variations in m.d.p. subsequent to extracellular K+ accumulation and Na+-K+ pump activation.

SUMMARY We used intracellular microelectrodes to study the effect of changes in extracellular calcium ion concentration [Ca 2+ ] o on the transmembrane potentials of canine cardiac Purkinje fibers in control Tyrode's solution and in the presence of agents thought to modify membrane permeability to potassium. In Tyrode's solution, decreasing [Ca 2+ ] o from 2.7 to 0.9 mM increased action potential duration measured at -60 mv (APD «,) and at full repolarization (APDioo) but did not significantly modify the normal linear relationship between cycle length and APD between cycle lengths of 500 to 4000 msec. We used 9-aminoacridine (9-AA) to decrease potassium permeability. At concentrations between 0.01 and 1.5 x 10" 5 M, 9-AA caused a concentration-dependent increase in APD-M and APD 1O o and a significant increase in the slope of the line relating APD to cycle length. (Schiitz, 1936;Cranefield and Hoffman, 1958;Surawicz et al., 1959) and that substitution of other divalent cations such as Sr 2+ for Ca 2+ delays repolarization (Brooks et al., 1955;Garb, 1951). After intracellular microelectrodes were introduced to the study of cardiac electrophysiology, it was shown in most studies that a decrease in [Ca 2+ ] o prolonged and an increase in [Ca 2+ ] o shortened the transmembrane action potential of both ventricular muscle fibers (Hoffman and Suckling, 1956) and Purkinje fibers (Hoffman and Suckling, 1956; Weidmann, 1955). Somewhat similar relationships between [Ca 2+ ] o and action potential duration were found for atrial muscle fibers (Hoffman and Suckling, 1956;Hoffman and Cranefield, 1960 field, 1960). Finally, a number of studies have shown for fibers from sheep and calf hearts that an increase in [Ca 2+ ] o shifts the plateau to more positive potentials and a decrease has the opposite effect (Reuter and Scholz, 1976;Beeler and Reuter, 1970).These effects of [Ca 2+ ] o on action potential duration and on the voltage level of the plateau were difficult to explain in terms of the finding for both Purkinje fibers and ventricular muscle that a significant inward current is carried by Ca 2+ through the secondary or slow inward channels (g si ) and that this current is responsible in large part for maintaining the membrane potential at depolarized levels after the initial action potential upstroke. In terms of these findings one would expect an increase in [Ca 2+ ] o to delay repolarization by increasing inward current and a decrease to have the opposite effect because of the change in driving force for Ca 2+ . An increase in action potential duration in the presence of high [Ca 2+ ] o has been seen only at quite low rates of stimulation (Niedergerke and Orkand, 1972); at usual rates of activation the opposite effect is observed. This apparently anomalous effect of Ca 2+ on action potential duration has been explained by assuming that changes in [Ca 2+ ] o result in changes in [Ca 2+ ]i and that the latter influences the conductance of the membrane by guest on