MS-551 protects against ventricular fibrillation in a chronic canine model of sudden cardiac death.

We studied the electrophysiologic and antifibrillatory properties of MS-551 (1,3-dimethyl-6-{(2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino} 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious canine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI: 2-h occlusion of the left anterior descending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden cardiac death. MS-551 was administered (2.0, 3.0, or 4×2.0 mg/kg intravenously, i.v.). Vehicle-treated animals received 0.9% sodium chloride solution for injection. MS-551 (multiple-dose regimen) increased ventricular effective refractory period (VERP) from 112±4 to 137±4 ms (p<0.05) as compared with vehicle treatment, which did not alter VERP (125±6 to 121±5 ms). MS-551 prolonged QTc interval from a predrug value of 293±8 to 333±18 ms postdrug. The size of surgically induced MI did not differ among groups: 2.0 mg/kg, 23±4%; 3.0 mg/kg, 28±2%; 4×2.0 mg/kg, 25±3%; and vehicle, 28±3% of the left ventricle. Single bolus administration of MS-551 (2.0 or 3.0 mg/kg i.v.) did not confer significant protection against sudden cardiac death. However, repeated administration of MS-551 protected against sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in the vehicle-treated group (p<0.05). The data indicate that a multiple-dose regimen of MS-551 provides protection against ischemia-induced ventricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depends on its ability to prolong VERP of myocardium without altering ventricular conduction velocity