In vivo canine cardiac electrophysiologic profile of 1,4-benzodiazepine IKs blockers.
Previous cardiac electrophysiologic studies of blockers of the slowly activating delayed rectifier (IKs) current have focused primarily on ventricular repolarization. This report summarizes an extensive in vivo cardiac electrophysiologic profile of four 1,4-benzodiazepine IKs blocker analogues (L-761334, L-763540, L-761710, and L-768673) in dogs. At 3.0 mg/kg intravenously, all four analogues elicited 14.5%-21.4% increases in ventricular refractoriness and 19.2%-22.6% increases in QTc interval. Concomitant 11.1%-13.5% increases in atrial refractoriness were noted with all four analogues. Decreases in sinus heart rate of 8.4%-17.3% were noted with all four compounds. No effects on atrial, His Purkinje, ventricular conduction or atrial and ventricular excitation were observed. One analogue, L-761710, significantly delayed atrioventricular (AV) nodal conduction (40.7+/-17.4% increase in atrial-to-His interval) and increased the AV conduction system functional refractory period 19.9+/-6.2%. The lack of effect of the other three 1,4-benzodiazepine IKs blockers on AV nodal function at dosages producing comparable effects on atrial and ventricular refractoriness suggest that the AV nodal effects of L-761710 were unrelated to IKs blockade. These findings indicate IKs plays important roles in both atrial and ventricular refractoriness as well as pacemaker function in the dog heart, suggesting potential utility for IKs blockers in the treatment of atrial and ventricular arrhythmias.
Stump
Gary L
GL
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Smith
Garry R
GR
Tebben
Andrew J
AJ
Jahansouz
Hossain
H
Salata
Joseph J
JJ
Selnick
Harold G
HG
Claremon
David A
DA
Lynch
Joseph J
JJ
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D002036:Bundle of His / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*
D026902:Potassium Channel Blockers; D001569:Benzodiazepines