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Electrophysiological effects of demethylimipramine and demethyldoxepin on canine cardiac purkinje fibers






Toxicology & Applied Pharmacology 74(2): 195-200

Electrophysiological effects of demethylimipramine and demethyldoxepin on canine cardiac purkinje fibers

Although the tricyclic antidepressant drugs imipramine and doxepin exert similar direct electrophysiological effects on cardiac cells, toxic cardiac arrhythmias and conduction disturbances are more commonly associated with imipramine in clinical use. To ascertain if this discrepancy could be due to different cellular electrophysiological actions of active metabolites of imipramine and doxepin, the effects of demethylimipramine (DMI) and demethyldoxepin (DMD) on isolated, superfused, canine cardiac Purkinje fibers were studied by glass microelectrodes and programmed stimulation. At 50 ng/ml DMI or DMD did not affect the resting membrane potential (RMP), action potential amplitude (Amp), maximum upstroke velocity of phase 0 (.ovrhdot.Vmax), action potential duration to repolarization to 50 and 100% of the amplitude (APD50, APD100), effective refractory period (ERP) or conduction velocity (CV). At 250 ng/ml neither drug affected Amp, APD100 or CV; both compounds reduced APD50 by 10-15%; and DMD but not DMI caused small reductions of RMP, .ovrhdot.Vmax and ERP. At 1000 ng/ml DMI or DMD did not affect RMP but both caused more marked reductions of ADP50 (31-35%) and ERP (21-23%). At this concentration both substances also reduced Amp by 6-7%, .ovrhdot.Vmax by 28-35%, ADP100 by 7-12% and CV by 15-25%. These effects of DMI and DMD were similar to those produced by the parent drugs. Differences in cardiotoxicity between imipramine and doxepin in clinical use were probably not due to different direct cellular electrophysiological effects of the circulating demethylated metabolites of these drugs.


Accession: 005349561

PMID: 6740670



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