title: MS-551 protects against ventricular fibrillation in a chronic canine model of sudden cardiac death.
abstract: 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 x 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 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 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.
authors.affiliation: University of Michigan Medical School, Department of Pharmacology, Ann Arbor 48109-0632, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Friedrichs
authors.forename: L
authors.initials: L
authors.lastname: Chi
authors.forename: M R
authors.initials: MR
authors.lastname: Gralinski
authors.forename: S C
authors.initials: SC
authors.lastname: Black
authors.forename: G C
authors.initials: GC
authors.lastname: Basler
authors.forename: D X
authors.initials: DX
authors.lastname: Mu
authors.forename: S R
authors.initials: SR
authors.lastname: Pewitt
authors.forename: C R
authors.initials: CR
authors.lastname: Johnson
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004562:Electrocardiography; D004594:Electrophysiology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D011744:Pyrimidinones; C076259:nifekalant