Abstract

Ethmozin is a phenothiazine derivative that is effective against supraventricular and ventricular arrhythmias. Studies to date have examined ethmozin's effects on active cellular properties and automaticity, but nothing is known of its effects on passive properties or on the interrelationships among the several active and passive properties that are of particular relevance to cardiac excitability. The hypothesis tested in this study was that ethmozin, in concentrations equivalent to clinically effective antiarrhythmic levels, would simultaneously affect passive and active cellular properties so as to produce a net decrease in cardiac excitability. The multiple micro-electrode method of intracellular constant current application and trans-membrane voltage recording was used in sheep Purkinje fibers to determine strength-duration and constant current-voltage relationships as well as cable properties. A rapid, on-line computerized data analysis system tracked in time the alterations in the active and passive properties relevant to excitability. Ethmozin, at concentrations of 1.1 and 2.2 microM (0.5 and 1.0 mg/l), decreased cardiac excitability as manifested by an increase in the current required to attain threshold and/or an upward shift in strength- and charge-duration relationships, by depressing the sodium system (decreased maximal rate of rise of phase 0 of the action potential, voltage threshold and overshoot), by decreasing slope resistance and altering nonlinearities of the current-voltage relationships in the subthreshold potential range, by decreasing membrane resistance and by affecting other properties dependent on membrane resistance which would depress excitability. The data for ethmozin and other antiarrhythmic drugs are interpreted in terms of the recently proposed electrophysiologic matrix which we believe has important advantages over traditional hierarchical classifications.