[Ca2+](i)-induced augmentation of the inward rectifier potassium current (I-K1) in canine and human ventricular myocardium

The inward rectifier K+ current (I-K1) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although I-K1 was shown to be sensitive to changes in intracellular Ca2+ concentration ([Ca2+](i)), the nature of this Ca2+ sensitivity-in spite of its deep influence on action potential morphology-is controversial. Therefore, we aimed to investigate the effects of a nonadrenergic rise in [Ca2+](i) on the amplitude of I-K1 in canine and human ventricular myocardium and its consequences on cardiac repolarization. I-K1, defined as the current inhibited by 10 mu M Ba2+, was significantly increased in isolated canine myocytes following a steady rise in [Ca2+](i). Enhanced I-K1 was also observed when [Ca2+](i) was not buffered by ethylene glycol tetraacetic acid, and [Ca2+](I) transients were generated. This [Ca2+](i)-dependent augmentation of I-K1 was largely attenuated after inhibition of CaMKII by 1 mu M KN-93. Elevation of [Ca2+](o) in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca2+](o) enhanced the action potential lengthening effect of the Ba2+-induced I-K1 blockade and attenuated the prolongation of action potentials following a 0.3-mu M dofetilide-induced I-Kr blockade. Blockade of I-Ks by 0.5 mu M HMR-1556 had no significant effect on APD(90) in either 2 mM or 4 mM [Ca2+](o). It is concluded that high [Ca2+](i) leads to augmentation of the Ba2+-sensitive current in dogs and humans, regardless of the mechanism of the increase. This effect seems to be at least partially mediated by a CaMKII-dependent pathway and may provide an effective endogenous defense against cardiac arrhythmias induced by Ca2+ overload.