Inhibition of L-type calcium current by propafenone in single myocytes isolated from the rabbit atrioventricular node

1. The atrioventricular node (AVN) is an important part of the conduction system in the heart and is a significant site of antiarrhythmic drug action. The class 1 antiarrhythmic propafenone is effective in treating a variety of arrhythmias, including those involving the AVN. In this study, we have investigated the effects of propafenone on ionic currents in single rabbit AVN cells, focusing in particular on those on L-type calcium current (I_Ca,L).
2. With a standard K-based internal dialysis solution, exposure to 5 μM propafenone reduced significantly the amplitude of I_Ca,L. In spontaneously active AVN myocytes, action potential upstroke velocity was decreased by propafenone exposure, consistent with the observed change in I_Ca,L.
3. By use of a Cs-based internal dialysis solution to record I_Ca,L selectively, voltage clamp test pulses were applied from a holding potential of −40 mV to +10 mV (stimulation frequency 0.33 Hz). Propafenone 5 μM reduced mean I_Ca,L density at +10 mV from −9.58±1.05 pA/pF to −4.19±0.60 pA/pF (P<0.002). A range of propafenone concentrations were applied which reduced I_Ca,L in a dose-dependent manner (IC₅₀ 1.7 μM). When test pulses were applied to a range of potentials, propafenone reduced I_Ca,L at each potential without significantly affecting the activation curve for this current. Thus, propafenone reduced I_Ca,L conductance, without affecting the voltage-dependent activation properties of the current.
4. I_Ca,L block by propafenone exhibited tonic-, use- and frequency-dependent characteristics.
5. In the presence of propafenone, the voltage-dependence of inactivation of I_Ca,L was shifted 8 mV in the hyperpolarizing direction. Also, the recovery of I_Ca,L from inactivation was slowed by propafenone.
6. The I_Ca,L blocking properties of propafenone may mediate some of the antiarrhythmic properties of this agent, particularly in regions of the heart such as the AVN in which I_Ca,L contributes significantly to the action potential upstroke.