MS-551 PROTECTS AGAINST VENTRICULAR-FIBRILLATION IN A CHRONIC CANINE MODEL OF SUDDEN CARDIAC DEATH

We studied the electrophysiologic and antifibrillatory properties of M S-551 dimethyl-6-{(2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino} 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious c anine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI:2-h occlusion of the left anterior d escending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden card iac death. MS-551 was administered (2.0, 3.0, or 4 x 2.0 mg/kg intrave nously, i.v.). Vehicle-treated animals received 0.9% sodium chloride s olution for injection. MS-551 (multiple-dose regimen) increased ventri cular effective refractory period (VERP) from 112 +/- 4 to 137 +/- 4 m s (p < 0.05) as compared with vehicle treatment, which did not alter V ERP (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 surg ically induced MI did not differ among groups: 2.0 mg/kg, 23 +/- 4%; 3 .0 mg/kg, 28 +/- 2%; 4 x 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 ca rdiac death. However, repeated administration of MS-551 protected agai nst sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in t he vehicle-treated group (p < 0.05). The data indicate that a multiple -dose regimen of MS-551 provides protection against ischemia-induced v entricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depe nds on its ability to prolong VERP of myocardium without altering vent ricular conduction velocity.