Electrophysiologic actions of BRB-I-28 in ischemically injured canine myocardium.
We examined the electrophysiologic actions of BRB-I-28 using two in vivo and two in vitro models of myocardial ischemic injury. In intact canine heart studied 4 days after anterior descending coronary artery occlusion, BRB-I-28 (3 and 6 mg/kg, i.v.) prolonged refractoriness in ischemically injured epicardium to an extent similar to that caused by lidocaine (3 and 6 mg/kg i.v.). BRB-I-28 produced less rate-dependent epicardial delay and, unlike lidocaine, failed to facilitate reentrant arrhythmia formation. Lidocaine and BRB-I-28 (3 and 6 mg/kg i.v.) produced similar rate-dependent prolongation of HV intervals in the normal His-Purkinje system, and produced both tonic and use-dependent conduction block in the ischemically injured His-Purkinje system studied 2 h after anteroseptal coronary artery ligation. In isolated superfused ventricular epicardium studied 1-4 days after anterior descending coronary artery ligation, BRB-I-28 reduced action potential amplitude (APA) and maximum phase 0 upstroke (Vmax) in normal (3.2 mg/L) and ischemically injured (1 and 3.2 mg/L) tissue, with marked tonic and use-dependent conduction block (3.2 mg/L). AP potential duration (APD) was unaltered. In isolated, superfused, ischemically injured canine endocardium studied 24 h after anterior descending coronary artery occlusion, BRB-I-28 (3.2 and 10 ml/L) reduced APA and Vmax and prolonged refractoriness and conduction times in ischemically injured tissue without altering APD. Tonic block was more prominent, and use-dependent block was observed at lower drug concentrations in ischemically injured tissue. The data demonstrate selective conduction depression and prolongation of refractoriness for BRB-I-28 in ischemically injured tissues. Both use-dependent and tonic conduction block contribute to the decrease in conduction observed with BRB-I-28 in ischemically injured myocardium, with more prominent tonic conduction block present in ischemically injured epicardium and His-Purkinje tissue at 2-24 h after coronary artery occlusion than in ischemically injured left ventricular (LV) epicardium studied 4 days after coronary artery occlusion.
Patterson
E
E
Department of Pharmacology, University of Oklahoma Health Sciences Center, Oklahoma City.
Scherlag
B J
BJ
Berlin
K D
KD
Lazzara
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology*
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