Nonlinear Changes of Transmembrane Potential During Defibrillation Shocks

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Abstract
—Defibrillation shocks induce complex nonlinear changes of transmembrane potential (ΔVm). To elucidate the ionic mechanisms of nonlinear ΔVm, we studied the effects of ionic channel blockers on ΔVm in geometrically defined myocyte cultures. Experiments were carried out in cell strands with widths of 0.2 mm (narrow strands) and 0.8 mm (wide strands) produced using a technique of directed cell growth. Uniform-field shocks were applied across strands during the action potential (AP) plateau, and the distribution of shock-induced ΔVm was measured using an optical mapping technique. Nifedipine and 4-aminopyridine were applied to inhibit the L-type calcium current (ICa) and the transient outward current (Ito), respectively. In control conditions, the distribution of ΔVm across cell strands was highly asymmetrical with a large ratio of negative to positive ΔVm (ΔV−m/ΔV+m) measured at the opposite strand borders. Application of nifedipine caused a large increase of ΔV+m and a decrease of ΔV−m/ΔV+m, indicating involvement of ICa in the asymmetrical ΔVm, likely as a result of the outward flow of ICa when Vm exceeded the ICa reversal potential. ΔV−m decreased in the narrow strands but remained unchanged in the wide strands, indicating that the changes of ΔV−m were caused by electrotonic interaction with an area of depolarization. 4-Aminopyridine did not change ΔV−m/ΔV+m. These results provide evidence that (1) the asymmetry of shock-induced ΔVm during the AP plateau is due to outward flow of ICa in the depolarized portions of the strands, (2) Ito is not involved in the mechanism of ΔVm asymmetry, and (3) the effects of drugs on ΔVm are modulated by the tissue geometry.