Use of a failing rabbit heart as a model to predict torsadogenicity.
Humans with underlying cardiovascular disease are at greater risk than humans with normal hearts for developing torsade de pointes (TdP) following exposure to some drugs that prolong ventricular repolarization. This study was designed to test the hypothesis that rabbits with ischemic myocardial failure are at similarly increased risk of developing QTc prolongation and TdP following exposure to escalating doses of drugs, which is known to have a capacity to induce TdP in humans. Coronary artery ligation was performed in 28 rabbits, causing significant (p < 0.05) reduction in left ventricular shortening fraction and systolic myocardial dysfunction 4 weeks after ligation in all operated animals compared to 38 normal, nonoperated controls. All studies were performed on rabbits anesthetized with ketamine (35 mg/kg) and xylazine (5 mg/kg). Rabbits were exposed to escalating doses of amiodarone (3, 10, 30 mg/kg/10 min), cisapride (0.10, 0.25, 0.50 mg/kg/10 min), clofilium (0.1, 0.2, 0.4 mg/kg/10 min), dofetilide (0.005, 0.01, 0.02, 0.04 mg/kg/10 min), quinidine (3, 10, 30 mg/kg/10 min), and verapamil (0.25, 0.5, 1.0 mg/kg/10 min). A greater percentage of rabbits with failing hearts developed TdP following intravenous infusion of escalating doses of dofetilide (85%), clofilium (100%), or cisapride (50%) than did normal rabbits exposed to the same drug protocol (20, 33, and 0%, respectively). None of the rabbits in either group developed TdP when exposed to escalating doses of amiodarone, verapamil, or quinidine. Two out of four test articles lengthened QTc more in rabbits with myocardial failure than in normals, and TdP occurred in 13 out of 28 rabbits with myocardial failure as opposed to only four out of 38 rabbits with normal myocardial function.
Kijtawornrat
Anusak
A
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA.
Nishijima
Yoshinori
Y
Roche
Brian M
BM
Keene
Bruce W
BW
Hamlin
Robert L
RL
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D002303:Cardiac Output, Low / Q000503:physiopathology*; D020117:Cisapride / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D023421:Models, Animal; D010627:Phenethylamines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology*; D014700:Verapamil / Q000494:pharmacology
D010627:Phenethylamines; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C022799:clofilium; D014700:Verapamil; D011802:Quinidine; D000638:Amiodarone; C063533:dofetilide; D020117:Cisapride