title: The comparative antiarrhythmic and proarrhythmic activity of a 3,7-diheterobicyclo[3.3.1]nonane, BRB-I-28, and lidocaine in the 1-4-day-old infarcted dog heart.
abstract: We compared the electrophysiological effects and quantified the antiarrhythmic/proarrhythmic potential of the 3,7-diheterobicyclo[3.3.1]nonane-derivative, BRB-I-28 and lidocaine in 15 consecutive postinfarction dogs. Electrophysiologic studies were performed in anesthetized animals, 1-4 days (mean +/- SE = 2.47 +/- 0.36) after the two-stage ligation of the left anterior descending coronary artery. Inducibility of sustained monomorphic ventricular tachycardia (SMVT) was compared in the pre-drug state, and after i.v. lidocaine (3 and 6 mg/kg) and BRB-I-28 (3 and 6 mg/kg) administration. During the control state, SMVT was inducible in 6/15 dogs (40%). After the administration of lidocaine, the rate of the inducible SMVT slowed (353 +/- 91 to 272 +/- 96 beat/min; p < 0.01), but due to the proarrhythmic action of the drug, SMVT became inducible in 13/15 dogs (87%). Sustained reentry was induced after 3 mg/kg lidocaine in 3 dogs and after 6 mg/kg in 4. The mean aortic blood pressure in these SMVTs was 36 +/- 8 mm Hg. After administration of BRB-I-28 (6 mg/kg) SMVT was not inducible in 2/6 and in 4 the SMVT rate was slowed (380 +/- 104 to 208 +/- 105 beat/min; p < 0.005) before termination in 3. In 2 dogs SMVT was induced after BRB-I-28 was given whereas they were non-inducible in the control state (proarrhythmic effect: 13%). Furthermore the hemodynamic state during the SMVTs was more stable after BRB-I-28 (mean aortic blood pressure = 65 +/- 7 mm Hg; post-BRB-I-28 vs post-lidocaine, p < 0.001). During sinus rhythm, lidocaine caused a transient lowering of the MBP (105 +/- 17 to 84 +/- 18 mm Hg; p < 0.001), whereas, BRB-I-28, induced a consistent but short-lasting pressor response (98 +/- 18 to 120 +/- 29 mm Hg; p < 0.001) after its bolus injection. The low proarrhythmic activity and the lack of a cardiodepressant action makes this new chemical class of antiarrhythmics worthy of further development.
authors.affiliation: Department of Medicine, Oklahoma University Health Sciences Center, Oklahoma City.
authors.forename: T
authors.initials: T
authors.lastname: Fazekas
authors.forename: B J
authors.initials: BJ
authors.lastname: Scherlag
authors.forename: P
authors.initials: P
authors.lastname: Mabo
authors.forename: K D
authors.initials: KD
authors.lastname: Berlin
authors.forename: G L
authors.initials: GL
authors.lastname: Garrison
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Sangiah
authors.forename: E
authors.initials: E
authors.lastname: Patterson
authors.forename: R
authors.initials: R
authors.lastname: Lazzara
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004285:Dogs; D004558:Electric Stimulation; D004594:Electrophysiology; D006439:Hemodynamics / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D009203:Myocardial Infarction; D017180:Tachycardia, Ventricular / Q000188:drug therapy
chemical_list: D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C041492:7-benzyl 3-thia-7-azabicyclo(3.3.1)nonane; D008012:Lidocaine