Effects of Mexiletine on Steady-State Characteristics an Recovery Kinetics of &OV0312;max and Conduction Velocity in Guinea Pig Myocardium

Abstract

Summary We studied the effects of the antiarrhythmic compound mexiletine on the maximal rate of rise (JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max) of the action potential and on conduction velocity in isolated papillary muscles of guinea pigs. Action potentials and JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max were measured by means of conventional microelectrodes. The conduction velocity was determined from extracellular recordings. Mexiletine (concentrations, 4.6 × 10⁻⁵ and 1.15 × 10⁻⁴ mol/L) caused a depression of JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max that depended on the condition examined. The h_x curve relating JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max of the action potential to the resting membrane potential was shifted along the voltage axis to more negative membrane potentials. Qualitatively equal effects were observed on the curve of membrane responsiveness relating JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max to the membrane potential during the phase of repolarization of the preceding action potential. Eventually, marked prolongation of the recovery kinetics of JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max by mexiletine, as well as frequency-dependent reduction of JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max, could be demonstrated. The action of mexiletine on conduction velocity was very similar to its influence on JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max. Thus, a prolongation of the recovery kinetics was found of about the same magnitude as that measured in JOURNAL/jcph/04.03/00005344-198203000-00011/OV0312/v/2021-02-06T190229Z/r/image-png_max. Similarly, in experiments with K⁺-induced depolarizations, a dependence on the membrane potential of the action of mexiletine on the conduction velocity could be demonstrated. The results suggest that mexiletine may exert antiarrhythmic effects mainly in damaged cardiac cells exhibiting a moderately reduced resting potential.