Modulation by mexiletine of action potentials, L-type Ca current and delayed rectifier K current recorded from...

Using whole-cell patch clamp recordings at 37 degrees C, we have examined the effects of externally applied mexiletine (a class 1b antiarrhythmic agent) on action potentials, L-type Ca current (ICa, L) and delayed rectifier K current (IK) in single isolated rabbit atrioventricular nodal (AVN) myocytes. In spontaneously active AVN cells, 30-100 micro;M mexiletine depolarised the maximum diastolic potential and slowed both action potential upstroke and repolarisation. Under selective recording conditions for ICa,L, mexiletine reduced peak ICa,L (at +10 mV) amplitude in a dose-dependent fashion (41.8 +/- 3.0% inhibition by 100 micro;M and 16.4 +/- 1.8% at 30 micro;M). The voltage dependence of ICa,L activation was unaffected by both concentrations of the drug. Under selective recording conditions, IK amplitude was measured as the peak of the deactivating tail current following a depolarising voltage pulse to +20 mV. 30 micro;M mexiletine inhibited IK by 34.3 +/- 5.8%, whilst 100 micro;M mexiletine reduced the current by 52.7 +/- 6.1%. The effects of mexiletine on ICa,L and IK 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 ICa,L and IK in determining the shape and rate of action potentials in this region of the heart.