Barium‐induced automatic activity in isolated ventricular myocytes from guinea‐pig hearts.

1. A suction‐pipette whole‐cell clamp technique was applied to single ventricular myocytes isolated from guinea‐pig hearts, in order to investigate the ionic mechanism underlying Ba2+‐induced automatic activity. 2. The application of 0.1 mM or less Ba2+ to the myocytes caused a depolarization of the resting membrane potential without inducing spontaneous activity. The stimulated action potential showed a prolonged repolarization phase followed by an after‐hyperpolarization. 3. Concentrations of Ba2+ of 0.2 mM or greater produced further depolarization of the resting membrane potential and induced spontaneous activity. Spontaneous activity developed from the slow diastolic depolarization preceded by after‐hyperpolarizations of spontaneous or stimulated action potentials. 4. Under voltage‐clamp conditions, a decaying outward or inward current in response to hyperpolarizing clamp steps from depolarized potentials appeared in the presence of Ba2+. The Ba2+‐induced current decay showed a faster time course with increasing hyperpolarizing clamp pulses and reversed its polarity at around ‐90 mV, the presumed equilibrium potential for K+ (EK). In the late current‐voltage (I‐V) relation, Ba2+ almost eliminated the inward‐rectifying property. These effects on the cardiac membrane are consistent with a time‐ and voltage‐dependent blocking action of Ba2+ on inward‐rectifying K+ currents as reported for other excitable tissues. 5. The concentration‐ and voltage‐dependence of the steady‐state block of the inward rectifying K+ current (IK1) was fitted by a simple model assuming 1:1 binding of Ba2+ to a site within the membrane. The apparent dissociation constant at the holding potential of 0 mV (K(0] was 0.3 mM, and the parameter for the membrane potential dependence of Ba2+ blockade (mu) was approximately 0.5. 6. A computer model of the ventricular action potential proposed by Beeler & Reuter (1977) was modified, based on the recent experiments using single cardiac myocytes. The modifications include (1) the current‐voltage relationship of IK1, (2) time courses of activation and inactivation of the Ca2+ current (ICa), (3) the activation voltage range for the delayed outward K+ current (IK). 7. The time‐ and voltage‐dependent blocking action of Ba2+ on IK1, including the experimentally determined values for K(0) and mu, were incorporated into the modified version of the action potential model. The computer model reproduced an after‐hyperpolarization at doses of Ba2+ lower than 0.1 mM and automatic activity at doses higher than 0.15 mM.(ABSTRACT TRUNCATED AT 400 WORDS)