Calcium-dependent modulation of the cardiac repolarization

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Normal heart function and optimal repolarization of the cardiac action potential (AP) is to high extent subject to synchronized activity of sarcolemmal K+ channels, expressed in both ventricular and atrial myocardium, largely contributing to regulation of the resting potential, the pacemaker activity, and the shape and duration of the AP (APD). Clinical observations and experimental studies in both isolated cardiomyocytes and multicellular preparations provided firm evidence for the sensitivity of several major K+ currents and the corresponding ion channels to shifts in intracellular Ca2+ concentration ([Ca2+]i). Direct regulation via interaction between [Ca2+]i and the channel protein or indirect modulation via Ca2+ signaling pathways of these currents may have implications to mechanical and electrical performance of the heart, and its physiological adaptation to altered load. Nonetheless, it may also lead to severe cardiac dysfunction, if [Ca2+]i handling is significantly disturbed, as is the case in a variety of pathological conditions. The primary aims of our studies, summarized in this thesis were 1) to attempt to clarify the apparently unsolved question of the physiological role of the cardiac small conductance Ca2+-activated K+ (SK) channels and, since data in literature, regarding the direction and nature of this modulation are also highly controversial: 2) to investigate in detail the possible Ca2+-dependence of the inward rectifier K+ current (IK1). Our results demonstrate that in rat, dog and human ventricular cells - though present - SK2 channels seem to be inactive and do not contribute to AP repolarization, at least under normal physiological conditions. We also provide evidence that in canine myocardium theAPD shortening effect of [Ca2+]i riseis at least partially mediated by [Ca2+]i-dependent augmentation of IK1.

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