title: Barium-induced automatic activity in isolated ventricular myocytes from guinea-pig hearts.
abstract: 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)
authors: Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors: Y
authors: Y
authors: Hirano
authors: M
authors: M
authors: Hiraoka
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001464:Barium / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology; D003198:Computer Simulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D013779:Tetrodotoxin / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D007473:Ion Channels; D001464:Barium; D003035:Cobalt; D013779:Tetrodotoxin