Comparative in vitro electrophysiology of quinidine, its major metabolites and dihydroquinidine.
Although metabolites of quinidine are active in animal models and can accumulate to plasma levels similar to those of quinidine during chronic therapy, their effects on cardiac transmembrane action potentials have not been reported. We therefore examined the effects of quinidine, its major metabolites, 3-hydroxyquinidine, quinidine-N-oxide, O-desmethylquinidine, and 2'-oxoquinidinone, and a common commercial impurity, dihydroquinidine, on action potentials from canine Purkinje fibers. Using standard microelectrode techniques, measurements at stimulation basic cycle lengths (BCLs) of 300 to 8000 msec were made at base line and repeated after a 1 hr of superfusion with a 10 microM concentration of drug or vehicle controls. Vehicle controls (n = 5) produced no change in maximum phase 0 upstoke slope of the action potential (Vmax) or action potential duration at 90% repolarization (APD90). Vmax depression when present was greatest at short BCL with statistically significant changes seen at BCL = 300 msec with all compounds tested except quinidine-N-oxide. The time constants for the onset of and recovery from frequency-dependent Vmax depression were similar to those of quinidine. In contrast, changes in APD90 were greatest at long BCL, with significant prolongation seen with all drugs at BCL = 4000 msec. In addition, the agents prolonging repolarization to the greatest extent, quinidine, dihydroquinidine, 3-hydroxyquinidine and O-desmethylquinidine, caused early afterdepolarizations at long BCL. We conclude that these metabolites and dihydroquinidine may contribute to the antiarrhythmic and/or arrhythmogenic effects of quinidine therapy.
D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D004285:Dogs; D004594:Electrophysiology; D007700:Kinetics; D011802:Quinidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C014486:hydroquinidine; D011802:Quinidine