Modulation by mexiletine of action potentials, L-type Ca current and delayed rectifier K current recorded from isolated rabbit atrioventricular nodal myocytes

Using whole-cell patch clamp recordings at 37 degrees C, we have examined the effects of externally applied mexiletine (a class Ib antiarrhythmic agent) on action potentials, L-type Ca current (I-Ca,I-L) and delayed rectifier K current (I-K) in Single isolated rabbit atrioventricular nodal (AVN) myocytes. In spontaneously active AVN cells, 30-100 mu M mexiletine depolarised the maximum diastolic potential and slowed both action potential upstroke and repolarisation. Under selective recording conditions for I-Ca,I-L, mexiletine reduced peak I-Ca,I-L (at +10 mV) amplitude in a dose-dependent fashion (41.8 +/- 3.0% inhibition by 100 mu M and 16.4 +/- 1.8% at 30 mu M). The voltage dependence of I-Ca,I-L, activation was unaffected by both concentrations of the drug. Under selective recording conditions, I-K amplitude was measured as the peak of the deactivating tail current following a depolarising voltage pulse to +20 mV. 30 mu M mexiletine inhibited I-K by 34.3 +/- 5.8%, whilst 100 mu M mexiletine reduced the current by 52.7 +/- 6.1%. The effects of mexiletine on I-Ca,I-L, and I-K are likely to contribute significantly to the changes in action potentials observed in spontaneously active cells. These findings are also suggestive of key roles for I-Ca,I-L and I-K in determining the shape and rate of action potentials in this region of the heart.