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: G S Friedrichs, L Chi, M R Gralinski, S C Black, G C Basler, D X Mu, S R Pewitt, C R Johnson, B R Lucchesi
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 25 Issue 2 Pg. 314-23 (Feb 1995) ISSN: 0160-2446 [Print] United States
• PMID: 7752658 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Arrhythmia Agents
• Pyrimidinones
• nifekalant

Topics

• Animals
• Anti-Arrhythmia Agents (administration & dosage, pharmacology, therapeutic use)
• Chromatography, High Pressure Liquid
• Death, Sudden, Cardiac (etiology, prevention & control)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Electric Stimulation
• Electrocardiography
• Electrophysiology
• Male
• Myocardial Infarction (complications)
• Pyrimidinones (administration & dosage, pharmacology, therapeutic use)
• Random Allocation
• Ventricular Fibrillation (etiology, prevention & control)