Age-related differences in the direct cardiac effects of cisapride: narrower safety range in the hearts of young rabbits.
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 microM) on the conduction properties of neonatal (<7 d) and adult (>3 mo) rabbit hearts. At a clinically relevant dose (0.03 microM), cisapride slowed the recovery of the His-Purkinje system. At 0.1 microM, 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 microM in the neonate and the adult, respectively. In the neonate, cisapride even resulted in infranodal AV block rhythm (ED50 = 0.12 microM), but this was not the case in the adult. Polymorphic ventricular tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1 microM) and in one in seven adults (14%; 0.03 microM). 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.
Wu
Mei-Hwan
MH
Department of Pediatrics, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan. mhwu@ha.mc.ntu.edu.tw
Su
Ming-Jai
MJ
Sun
Selma Siu-Man
SS
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001283:Atrioventricular Node / Q000187:drug effects; D002036:Bundle of His / Q000187:drug effects; D020117:Cisapride / Q000009:adverse effects*; D004562:Electrocardiography / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000009:adverse effects*; D006325:Heart Atria / Q000187:drug effects; D006327:Heart Block / Q000139:chemically induced*; D006329:Heart Conduction System / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits
D005765:Gastrointestinal Agents; D020117:Cisapride