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

Abstract

Although cisapride is widely used to treat gastrointestinal motility disorders, it has been associated with QT prolongation, torsades de pointes, and cardiac arrest. Only in children, however, has atrioventricular (AV) block after cisapride been reported. This study used Langendorff perfusion to determine the direct effects of cisapride (0.03, 0.1, 0.3, and 1 M) on the conduction properties of neonatal (Ͻ7 d) and adult (Ͼ3 mo) rabbit hearts. At a clinically relevant dose (0.03 M), cisapride slowed the recovery of the His-Purkinje system. At 0.1 M, the refractoriness of the His-Purkinje system and conduction through this system were prolonged. Corrected QT intervals and the ventricular refractory period were also lengthened. These parameters were significantly more prolonged in neonates than in adults. The level of AV block at rapid atrial pacing shifted from the AV node to the His-Purkinje system, with an ED 50 of 0.06 and 0.52 M in the neonate and the adult, respectively. In the neonate, cisapride even resulted in infranodal AV block rhythm (ED50 ϭ 0.12 M), but this was not the case in the adult. Polymorphic ventricular tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1 M) and in one in seven adults (14%; 0.03 M). It is concluded that cisapride may affect the refractoriness of cardiac tissue and that the His-Purkinje system seems to be the most sensitive. In neonatal hearts, this modification may, in fact, progress to infranodal AV block. Such susceptibility to cisapride strongly indicates that the therapeutic safety range used for the young heart should be narrowed. Cisapride, a widely used gastrointestinal prokinetic agent, has been associated with the development of prolonged QT interval, malignant ventricular arrhythmias, and sudden death (1, 2). Cisapride is a gastrointestinal prokinetic agent that facilitates gastrointestinal motility by increasing lower esophageal sphincter pressure and improving gastric emptying (3). The mechanism of such gastrointestinal action is attributable to an enhanced release of acetylcholine at the mesenteric plexus as well as a direct suppression of human ether-a-go-go-related gene (HERG)-like K ϩ currents in the esophageal smooth muscle (4, 5). 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).In the immature heart, the presence of age-related differences in the K ϩ repolarizing currents has been well documented (8, 9), but whether these differences make immature hearts ...