RESUMO
The inward rectifier K⺠current (IK1) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although IK1 was shown to be sensitive to changes in intracellular Ca²âº concentration ([Ca²âº]i), the nature of this Ca²âº 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 [Ca²âº]i on the amplitude of IK1 in canine and human ventricular myocardium and its consequences on cardiac repolarization. IK1, defined as the current inhibited by 10 µM Ba²âº, was significantly increased in isolated canine myocytes following a steady rise in [Ca²âº]i. Enhanced IK1 was also observed when [Ca²âº]i was not buffered by ethylene glycol tetraacetic acid, and [Ca²âº]I transients were generated. This [Ca²âº]i-dependent augmentation of IK1 was largely attenuated after inhibition of CaMKII by 1 µM KN-93. Elevation of [Ca²âº]o in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca²âº]o enhanced the action potential lengthening effect of the Ba(2+)-induced IK1 blockade and attenuated the prolongation of action potentials following a 0.3-µM dofetilide-induced IKr blockade. Blockade of IKs by 0.5 µM HMR-1556 had no significant effect on APD90 in either 2 mM or 4 mM [Ca²âº]o. It is concluded that high [Ca²âº]i leads to augmentation of the Ba²âº-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 Ca²âº overload.