P108Two sides of the same coin: integrative role of the calcium-activated chloride channels in the ventricular myocardium

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Abstract

As a part of the transient outward current, the calcium-activated chloride current (ICl(Ca)) is involved in the action potential (AP) repolarization, however, its possible contribution to formation of delayed afterdepolarizations and thus life threatening arrhythmias was also suggested, especially in cardiac pathologies e.g. cardiac failure and myocardial hypertrophy, where intracellular Ca2+ concentration increases.

The aim of this work was to study the profile of ICl(Ca) during AP in various regions of ventricular muscle.

Experiments were performed using conventional microelectrode, whole-cell patch-clamp and AP-clamp techniques at 37 C degrees on isolated canine ventricular myocytes. ICl(Ca) was studied by an inhibitor, anthracene-9-carboxylic acid (9-AC, 0.5 mM).

Under voltage-clamp conditions ICl(Ca) started to activate at -20 mV and peaked at +60 mV (2.11±0.35 pA/pF, n=8), while in the presence of BAPTA (10 mM), a calcium chelating agent, the current was abolished indicating its calcium-activated feature. ICl(Ca) amplitude increased progressively with higher stimulatory frequencies. AP measurements with sharp microelectrodes confirmed this property as 9-AC reduced the size of the AP notch and elevated the mid-plateau potential in a direct rate-dependent manner. However, these changes resulted in a reverse rate-dependent AP lengthening in midmyocardial and subendocardial cells (+24.34±3.26 ms and +15.85±2.14 ms at 1 Hz, n=15 and n=7, respectively). On the contrary, under 2 Hz stimulatory frequencies a progressive AP shortening was observed in subepicardial myocytes (−13.18±7.50 ms at 1 Hz, n=7). AP-clamp experiments revealed an early narrow outward and a late inward current peak after the application of 9-AC (+1.15±0.11 pA/pF and -0.18±0.04 pA/pF, respectively, n=13). Similar peak current amplitudes were measured in every transmural heart regions. Beta-adrenergic activation (by isoproterenol, 10 nM) nearly doubled the amplitudes of both part of ICl(Ca) (2.43±0.11 pA/pF and -0.31±0.10 pA/pF, n=4). Furthermore, early afterdepolarizations appeared following ICl(Ca) blockade at low heart rates, especially during beta-adrenergic stimulation.

These findings suggest that the different contribution of ICl(Ca) to the AP generation in different cardiac regions is a consequence of the characteristic shape of the given AP. A selective ICl(Ca) blocking agent could be beneficial in Ca2+-overloaded cells by decreasing the development of delayed afterdepolarizations, but it could be harmful by increasing the transmural dispersion of repolarization and provoking early afterdepolarizations.

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