Cisapride‐induced prolongation of cardiac action potential and early afterdepolarizations in rabbit Purkinje fibres

Abstract

Cisapride, a gastrointestinal prokinetic agent, has been associated with cases of Torsades de Pointes but its effects on the cardiac action potential have not been described. We investigated its electrophysiological effects on rabbit isolated Purkinje fibres. The results demonstrated that cisapride (0.01-10 tM) lengthened concentration-dependently the action potential duration without modifying other parameters and induced early after depolarizations and subsequent triggered activity. This typical class III antiarrhythmic effect, that showed 'reverse' rate-dependence and was reduced by increasing external K concentration, can account for clinical arrhythmogenesis.

Lack of Action Potential-Prolonging Effect of Terfenadine on Rabbit Myocardial Tissue Preparations

“…[9][10][11][12][13][14] The maximum concentration of terfenadine examined (20 mM) was higher than the maximum clinically approachable plasma concentration of the drug in hepatic compromise or coadministration with drugs affecting its metabolism. [20][21][22] A lack of APD prolongation by terfenadine in tissue has also been reported in guinea pig ventricle, 15) and canine, 23,24) and porcine Purkinje fiber.…”

“…Purkinje fibers are known to be highly sensitive to the APD-prolonging effect of drugs, [9][10][11][12][13][14] and some researchers have recommended the use of rabbit Purkinje fiber 134 Vol. 27, No.…”

Age-Related Differences in the Direct Cardiac Effects of Cisapride: Narrower Safety Range in the Hearts of Young Rabbits

“…The changes persisted even after washing with normal Tyrode's solution for 2 h. On the basis of these controls, the changes after cisapride in adult rabbits were deemed as partially irreversible effects caused by cisapride. No previous studies have documented the reversibility of changes as a result of cisapride in mature animals (4,6,7,14).…”

“…As for the mechanisms underlying the adverse cardiac effects, a direct inhibition of the repolarizing K ϩ current and the subsequent prolongation of action potential have previously been suggested. In rabbit Purkinje fibers, cisapride (0.1-10 M) lengthened the action potential duration in a concentration-dependent and reverse rate-dependent manner, and early after-depolarizations with the succeeding triggered activity were observed at abruptly decelerating pacing rates (6). Apart from this, in isolated rabbit myocytes, the rapid component of the delayed rectifying K ϩ current (I Kr ) was blocked by cisapride with an IC 50 of 9 nM (7).…”

“…Among the cardiac tissues, the action potential duration of the His-Purkinje system was the longest. An earlier study in isolated Purkinje fibers showed a stronger effect of cisapride in fibers with action potential duration longer than 300 ms (6). In isolated rabbit cardiac tissues, the action potential (at 90% repolarization) was increased by 22 Ϯ 1.5% and 48 Ϯ 5.6% in the ventricular muscle and the Purkinje fibers, respectively (7).…”