A combination of inactivated sodium channel blockers causes competitive interaction on dV/dtmax of single ventricular myocytes

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Abstract
Study objective — The aim was to study an interaction between class I antiarrhythmic drugs on the cardiac sodium channels. Design — The single pipette, whole cell clamp method was employed to control and record membrane potential. The maximum upstroke velocity (dV/dtmax) was measured as an index of sodium channel availability during treatment of the preparations with aprindine (5 μM) in combination with mexiletine (40 μM), and lignocaine (40 μM). Experimental material — Single ventricular myocytes (n = 6-8 per experiment) isolated from guinea pig hearts were used. Measurements and main results — Trains of depolarisation to 0 mV (0.2-2.0 Hz) were applied from the resting membrane potential (−85 mV) following a long quiescent period to evaluate “tonic” and “use dependent” decrease (block) of dV/dtmax. Additional application of mexiletine or lignocaine to aprindine resulted in an increase of tonic block and a decrease of use dependent block. Because of such counteracting action, the steady state dV/dtmax during the train of depolarisation was unaffected for mexiletine, and even increased for lignocaine. Dual exponential components of dV/dtmax recovery following a 1 s conditioning depolarisation after admixture of mexiletine or lignocaine to aprindine suggest their competitive interaction on cardiac sodium channels. Conclusion — A combination of class I antiarrhythmic drugs having high affinity for the inactivated state of sodium channels may cause a reductive effect on dV/dtmax through competitive displacement from common receptors.

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