Depressant effect of magnesium on early afterdepolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers

Abstract

Magnesium chloride has been shown to terminate torsades de pointes in some patients with the acquired long QT syndrome. The mechanism for this effect is unknown. Recently early afterdepolarizations (EADs) and triggered activity (TA) have been proposed as causes of torsades de pointes. The purpose of the present study was to examine whether magnesium suppressed EADs that were initiated in vitro by different agents and if so its mechanism of action. TA arising from EADs was induced by quinidine (1 to 4 μmol/L, n = 5) at high temperature (38.5 to 40° C), cesium chloride (5 to 12 mmol/L, n = 6), and 4-aminopyridine (1.5 to 5 mmol/L, n = 7) in canine cardiac Purkinje fibers superfused with modified Tyrode's solution (KCl = 2.7 mmol/L). MgCl 2 (2 to 7 mmol/L) reversibly ablished TA and suppressed EADs. Tetrodotoxin (TTX; 1 to 5 μmol/L) also abolished TA elicited by 4-aminopyridine (n = 6). We then examined the effects of MgCl 2, TTX, and verapamil on depolarization-induced automaticity by means of a single sucrose gap technique to gain insight into the mechanism of action of magnesium. MgCl 2 (5 mmol/L) abolished automaticity arising from membrane potentials more negative than −70 mV and prolonged the spontaneous cycle length at less negative membrane potentials. The effects of TTX (1 to 5 μmol/L) resembled those of MgCl 2. Verapamil (1 μmol/L) prolonged the cycle length of the initial automatic response at high levels of membrane potential and progressively reduced the amplitude of the subsequent automatic potentials. It abolished automaticity arising from less negative membrane potentials. Thus MgCl 2 suppressed EADs induced by three diverse agents that reduce potassium conductance. Similarities between the effects of MgCl 2 and TTX suggest that magnesium may suppress EADs and TA by reducing the TTX-sensitive sodium “window” current.