Ischaemia selectivity confers efficacy for suppression of ischaemia-induced arrhythmias in rats.
Eight novel and three reference antiarrhythmics were investigated in anaesthetised rats for antiarrhythmic actions, as well as for effects on the electrocardiogram (ECG) under normal and "simulated ischaemic" conditions. In rats subjected to coronary artery occlusion lidocaine, (+/-)-trans-[2-(4-morpholinyl)-cyclohexyl]naphthyl-1-acetate, RSD1000 and (+/-)-trans-[2-(4-morpholinyl)-cyclohexyl]-2-(1-naphthyl)propionate, RSD1030, (Group A) produced dose-related and complete antiarrhythmic protection. Group B compounds, such as (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-3, 4-dichlorocinnamamide, RSD995, produced complete antiarrhythmic protection but had aberrant dose-response curves. Group C compounds, such as quinidine and flecainide, failed to give full antiarrhythmic protection and had shallow dose-response curves. The potency of Group A compounds, but not Group B or C compounds, for ECG actions indicative of Na(+) channel blockade (prolongation of PR and QRS intervals) were significantly increased under "simulated ischaemic" conditions ([K(+)] 10 mM and pH 6.4) in isolated rat hearts. Thus, compounds with ischaemia-selective actions provided superior protection against ischaemia-induced arrhythmias in rats.
Barrett
T D
TD
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Medical Block C, V6T 1Z3, Vancouver, BC, Canada.
Hayes
E S
ES
Yong
S L
SL
Zolotoy
A B
AB
Abraham
S
S
Walker
M J
MJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000150:complications; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000009:adverse effects; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels