[Ca^sup 2+^]^sub i^-induced augmentation of the inward rectifier potassium current (I^sub K1^) in canine and human ventricular myocardium

• Published in: Pflügers Archiv 2013-11, Vol.465 (11), p.1621
• Main Authors: Nagy, Norbert, Acsai, Károly, Kormos, Anita, Sebk, Zsuzsanna, Farkas, Attila S, Jost, Norbert, Nánási, Péter P, Papp, Julius Gy, Varró, András, Tóth, András
• Format: Article
• Language: English
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-013-1309-x

The inward rectifier K^sup +^ current (I^sub K1^) plays an important role in terminal repolarization and stabilization of the resting potential in cardiac cells. Although I^sub K1^ was shown to be sensitive to changes in intracellular Ca^sup 2+^ concentration ([Ca^sup 2+^]^sub i^), the nature of this Ca^sup 2+^ 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 [Ca^sup 2+^]^sub i^ on the amplitude of I^sub K1^ in canine and human ventricular myocardium and its consequences on cardiac repolarization. I^sub K1^, defined as the current inhibited by 10 [mu]M Ba^sup 2+^, was significantly increased in isolated canine myocytes following a steady rise in [Ca^sup 2+^]^sub i^. Enhanced I^sub K1^ was also observed when [Ca^sup 2+^]^sub i^ was not buffered by ethylene glycol tetraacetic acid, and [Ca^sup 2+^]^sub i^ transients were generated. This [Ca^sup 2+^]^sub i^-dependent augmentation of I^sub K1^ was largely attenuated after inhibition of CaMKII by 1 [mu]M KN-93. Elevation of [Ca^sup 2+^]^sub o^ in multicellular canine and human ventricular preparations resulted in shortening of action potentials and acceleration of terminal repolarization. High [Ca^sup 2+^]^sub o^ enhanced the action potential lengthening effect of the Ba^sup 2+^-induced I^sub K1^ blockade and attenuated the prolongation of action potentials following a 0.3-[mu]M dofetilide-induced I^sub Kr^ blockade. Blockade of I^sub Ks^ by 0.5 [mu]M HMR-1556 had no significant effect on APD^sub 90^ in either 2 mM or 4 mM [Ca^sup 2+^]^sub o^. It is concluded that high [Ca^sup 2+^]^sub i^ leads to augmentation of the Ba^sup 2+^-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 Ca^sup 2+^ overload.[PUBLICATION ABSTRACT]