Title

Characterization of the Rate-Dependent Effects of Ethmozine on Conduction, in Vivo, and on the Sodium Current, in Vitro, in the Newborn Heart

Document Type

Article

Publication Date

12-9-1992

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Abstract

We evaluated the effects of ethmozine on resting conduction intervals, myocardial refractory periods and His-Purkinje and intraventricular conduction in vivo in 11 neonatal dogs aged 7 to 16 days. Ethmozine produced significant prolongation in resting sinus cycle length (P < .05), in the atrioventricular nodal (P < .001) and His-Purkinje conduction time (P < .01) intervals and in the QRS duration (P < .01). Ventricular, but not atrial refractory periods were significantly prolonged (P < .05). Rate-dependent changes in His-Purkinje and intraventricular conduction were demonstrated after ethmozine by direct pacing of the bundle of His and right ventricular pacing. The development of steady-state conduction delay at a paced cycle length of 200 msec was characterized by a time constant (τ(on)) of 23.5 beats. The time constant of diastolic recovery (τ(off)) from rate-dependent conduction delay, determined during His bundle extrastimulation, was 171 msec. Ethmozine was highly proarrhythmic. A total of 7 arrhythmias were induced in 6 out of 12 neonates after administration of ethmozine. We also characterized ethmozine block of cardiac sodium channels in isolated neonatal canine ventricular myocytes using the whole cell variation of the patch clamp technique. Ethmozine (1.3-40 μM) produced a use-dependent block of cardiac Na channels that was dependent upon both drug concentration and pulse duration. Drug binding to inactivated channel states accounted for the observed use-dependent block. The time constant of recovery from use- dependent block ranged between 10 and 30 sec at 16°C. Ethmozine is a sodium channel blocker which in the neonatal heart has selective affinity for inactivated sodium channels, results in rate-dependent conduction slowing in vivo and is potentially very proarrhythmic.

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