Physiological Modulations of Cardiac K^+ Currents by Ca^<2+> and their Roles for Arrhythmogenesis

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In this research project, we studied two types of K+ currents in isolated vetricular myocytes from guinea-pig and rabbit hearts using the patch-clamp technique of the whole-cell configurations. The one type was the transient outward current (I_<to>) recorded from rabbit myocytes and the other was the delayed outward K^+ current (I_k) from guinea-pig myocytes. I_<to> was activated by step depolarizations positive to -20 mV I_<to> was found to be composed of two components, the Ca^<2+>-insensitive and Ca^<2+>-sensitive components. The Ca^<2+>-insensitive I_<to> was easily blocked by 4-aminopyridine and the Ca^<2+>-sensitive one was inhibited by caffeine. The latter component was also abolished by removing extracellular Ca^<2+> or application of Ca^<2+> blocking agents. It was inhibited by application of ryanidine. All of these results suggest that the Ca^<2+>-sensitive I_<to> was activated by Ca^<2+>-influx via the Ca^<2+> channel and/or increased internal Ca^<2+> through the Ca^<2+> rel … More ease from SR. The Ca^<2+>-sensitive I_<to> was increased during rapid stimulation and, therefore, it contributed the formation of the notch on action potential repolarization and its shortening during tachycardia.I_K was activated by depolarization positive to -50 mV and it contributed to the final repolarization phase. From the kinetic analysis of the tail current, I_k was separated by two components with a rapid and slow activation. The fast activating I_k was sensitive to Ca^<2+>-influx. Therefore, the inhibition of the Ca^<2+>-influx either by Ca^<2+> free solution or application of the Ca^<2+> antagonists produced a paradoxical prolongation of action potential duration, which was attributed to suppression of the fast activating I_k. The behaviors of I_k and action potential repolarizations were well simulated by the modulation of I_k by changes in internal Ca^<2+>. Co^<2+> was often used as a blocker of the Ca^<2+> channel but it also inhibited I_k at comparable concentrations. The mechanisms of the I_k block by Co^<2+> were shown to be screening the negative surface charges, decreasing the functional channel and additional voltage-dependent process. Therefore, Co^<2+> blocked I_k by multiple mechanisms. Less