Effects of AHR-12234 on cardiac transmembrane action potentials, in situ cardiac electrophysiology and experimental models for arrhythmias.
We studied the effects of AHR-12234, a new antiarrhythmic agent, on cardiac transmembrane action potentials, in situ cardiac electrophysiology and in several models for arrhythmias in the dog. AHR-12234 (5 x 10(-5)-2 x 10(-4) M) induced a dose-related and use-dependent decrease in dV/dtmax in canine Purkinje fibers and ventricular muscles. Action potential duration was shortened in Purkinje fibers but lengthened in ventricular muscle. In the anesthetized dog, AHR-12234 at a lower dose (2.64 mg/kg) increased AH intervals and effective refractory period of atrium, and AV node. At higher cumulative doses of 7.92 and 13.2 mg/kg, AHR-12234 increased the effective refractory period and conduction time in the atrium, AV node and ventricle. It also increased Purkinje system conduction time and sinus nodal recovery time. In the conscious dog model for reentrant atrial tachycardia, i.v. (effective doses: 12.3 +/- 4.2 mg/kg), or oral (20 to 60 mg/kg) administration of AHR-12234 prolonged the cycle length of the tachycardia and terminated the arrhythmia. The duration of action of oral AHR-12234 against this arrhythmia persisted for 24 hr. In the 1-day infarcted conscious dogs, AHR-12234 administered either i.v. (effective doses: 3.8 +/- 0.9 mg/kg) or orally (20 mg/kg), effectively converted the ventricular arrhythmia into sinus rhythm. AHR-12234 did not produce any adverse side effects in the above two conscious dog models. AHR-12234 was also effective in ablating ouabain-induced ventricular tachycardias in anesthetized dogs following an i.v. dose of 5 mg/kg. These results indicate that the structurally novel AHR-12234 is effective against arrhythmias due to abnormal automaticity, triggered activity and reentry.
Wu
K M
KM
Department of Pharmacology, A. H. Robins Research Laboratory, Richmond, VA 23261.
Proakis
A G
AG
Hunter
T L
TL
Shanklin
J R
JR
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D004048:Diethylamines / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D004048:Diethylamines; D013453:Sulfonylurea Compounds; C063013:AHR 12234; D010042:Ouabain