Experimental studies on the antiarrhythmic mechanism of mexiletine in guinea pig ventricular muscles using microelectrode techniques

Abstract

To clarify the pharmacologic action of a new antiarrhythmic agent, mexiletine (Mx), its electrophysiological properties were examined in guinea pig ventricular muscles at differing concentrations of extracellular potassium ([K⁺]o) and calcium ([Ca²⁺]o) using standard microelectrode techniques. The parameters measured were as follows :(1) the maximum rate of rise of phase O of the action potential (V_max), (2) the ratio of effective refractory period to action potential duration at 90% repolarization(ERP/APD₉₀) and (3) V_max recovery kinetics. The concentrations used were 2.7, 5.4 and 10.0 mM for [K⁺]o, 1.8 and 3.6 mM for [Ca²⁺]o, and 2μg/ml for Mx.
When the [Ca²⁺]o concentration was 1.8 mM, the rate of depression of V_max by Mx was 4.0±0.7% for [K⁺]o=2.7 mM, 4.2±1.6% for [K⁺]o=5.4 mM and 14.5±5.0% for [K⁺]o=10.0 mM, while the rate of increase in ERP/APD₉₀ ratios due to the action of Mx was 5.7±4.3%,
3.5±2.0% and 11.4±2.7% for the same concentrations of [K⁺]o. The changes in the V_max and ERP/APD₉₀ rate were not statistically significant for [K⁺]o concentrations between 2.7mM and 5.4 mM, but both rates were statistically significant with respect to the control [K⁺]p=5.4 mM values when [K⁺]o was 10.0 mM (p<0.01 in all cases).
On the other hand, the rate of depression of V_max by the action of Mx decreased to 2.8±0.8 when [K⁺]o=5.4 mM and to 5.7±1.6% when [K⁺]o=10.0mM and the [Ca²⁺]o concentration was increased from 1.8 to 3.6 mM. The rates of increase in the ERP/APD₉₀ ratio decreased when [K⁺]o was 5.4 or 10.0 mM (to 2.5±1.5% and 3.6±1.3%, respectively). The rate of change for V_max and ERP/APD₉₀ when [K⁺]o=10.0 mM (p<0.01) was statistically significant with respect to the control value [Ca²⁺]o=1.8 mM (p<0.001), but not significant when [K⁺]o=5.4 mM.
The recovery of V_max was markedly inhibited by Mx, but increasing the concentration of [Ca²⁺]o encouraged recovery and shortened its time constants.
In conclusion, the depression of V_max and increase of ERP/APD₉₀ induced by Mx were ascribed to its inhibitory action in the fast sodium channel. This depressant effect was regarded as the main antiarrhythmic action of this agent. Its electrophysiologic effects were pronounced at higher potassium concentrations. For this reason, Mx may be effective in the control of ventricular arrhythmias occurring in depolarized fibers of the acute myocardial ischemia. Additionally, increasing [Ca²⁺]o restored the "depressed fast sodium channel" induced by Mx.