Hemodynamic and electrophysiologic effects of ontazolast in dogs.
OBJECTIVE
To determine whether QT interval is prolonged or sudden death is caused by ventricular fibrillation resulting from torsades de pointes and to identify hemodynamic effects of ontazolast.


METHODS
28 Beagles.


METHODS
Physiologic variables were measured for 2 hours in conscious dogs given ontazolast (0, 1, or 3 mg/kg of body weight, IV) and for 1 hour in anesthetized dogs given cumulative doses of ontazolast (0, 1, 3, 6, or 8 mg/kg, IV).


RESULTS
Ontazolast prolonged QT interval and QT interval corrected for heart rate (QTc) at doses of 6 mg/kg in anesthetized dogs. At 8 mg/kg, both variables remained prolonged but tended to decrease. In conscious dogs, ontazolast increased QT interval and QTc 15 minutes after administration, but both variables returned to reference ranges by 60 minutes. In conscious dogs, ontazolast increased maximum rate of increase of left ventricular pressure and maximal velocity of fiber shortening, indicators of inotropy, and increased tau, indicating a decreased rate of relaxation. One conscious dog receiving 3 mg/kg developed nonfatal torsades de pointes, but another conscious dog developed ventricular fibrillation. Two anesthetized dogs receiving 6 mg/kg developed early afterdepolarizations, and all dogs developed secondary components in theirT waves.


CONCLUSIONS
Ontazolast possesses potent class-III antiarrhythmic properties and induces prolongation of QTc in a dose-dependent fashion. Because there was a clear dose-dependent prolongation of QT interval in all instances, ontazolast may serve as a positive-control compound for studying other compounds that are believed to prolong the QT interval.
Hamlin
R L
RL
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus 43210-1092, USA.
Nakayama
T
T
Brady
J T
JT
Stoll
R E
RE
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia / Q000662:veterinary; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001583:Benzoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004283:Dog Diseases / Q000139:chemically induced*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004562:Electrocardiography / Q000662:veterinary; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced / Q000662:veterinary*; D008297:Male; D016171:Torsades de Pointes / Q000139:chemically induced / Q000662:veterinary; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000662:veterinary
D000889:Anti-Arrhythmia Agents; D001583:Benzoxazoles; D002316:Cardiotonic Agents; C090950:ontazolast