The cellular electropharmacology of mexiletine in papillary muscles of guinea pigs chronically treated with amiodarone

Abstract

Objective: The combination of mexiletine and amiodarone has proved useful in the control of serious ventricular arrhythmias, but the electrophysiological basis for their effectiveness in combination is unknown. The objective of this study was to compare the effects of mexiletine on action potential parameters of papillary muscles taken from guinea pigs chronically treated with amiodarone, with tissue taken from a control group.

Design: The effects of 12.5 to 200 microM mexiletine on action potential parameters of papillary muscles taken from guinea pigs chronically treated with amiodarone were compared with tissue taken from a control group, at frequencies of 1.0, 1.5 and 3.0 Hz, using standard microelectrode techniques. Onset of use-dependent block was assessed by 30 beat trains, and recovery from block by extrastimuli at diastolic intervals ranging from 200 to 5000 ms at both 1.5 and 3.0 Hz.

Animals: Eighteen four-week-old guinea pigs were randomly divided into two groups. One group received amiodarone in a loading dose of 20 mg/kg/day by intraperitoneal injection for one week, followed by 10 mg/kg/day for 15 weeks. The control animals were given equivalent volumes of dextrose intraperitoneally for 16 weeks.

Main results: Mexiletine depressed the maximum rate of depolarization of phase 0 of the action potential (Vmax) in a concentration- and use-dependent fashion. Whereas chronic amiodarone treatment did not alter steady-state Vmax values, the extent of tonic Vmax depression induced by mexiletine was decreased, while use-dependent depression was increased. Mexiletine combined with amiodarone increased effective refractory period prolongation from 306.7 +/- 27.2 to 348.8 +/- 37.2 ms, while action potential duration shortening of mexiletine was moderated from 134.0 +/- 19.8 to 151.0 +/- 8.3 ms (to 90% repolarization at 3 Hz in the presence of 200 microM mexiletine).