Mechanism of reversal of toxic effects of amitriptyline on cardiac Purkinje fibers by sodium bicarbonate.
Alkalinization with NaHCO3 can effectively reverse ventricular arrhythmias caused by amitriptyline intoxication, but the mechanism is unclear. To test whether alkalinization per se is important or whether increases in extracellular Na concentration also contribute, we exposed Purkinje fibers to 500 ng/ml (1.8 microM) of amitriptyline and then superfused them with three different test solutions, viz. 1) high Na-Tyrode's, 2) high NaHCO3-Tyrode's and 3) high pH-low pCO2-Tyrode's. Amitriptyline significantly depressed action potential amplitude and Vmax without altering resting membrane potential and abbreviated action potential duration at all phases of repolarization. Effects on phase 0 were accompanied by a depression of conduction velocity. All three test solutions produced significant hyperpolarization and improvement in action potential amplitude and Vmax. However, the magnitude of improvement of phase 0 characteristics was significantly greater after high NaHCO3 and resulted in significant improvement of conduction velocity in fibers depressed by amitriptyline. The effects of amitriptyline on phase 0 were rate-dependent. Reversal of this effect by NaHCO3 was equally effective at all rates. Improvement of Vmax was partly related to a shift of the Vmax-membrane potential relationship in the depolarizing direction. NaHCO3 had minimal and variable effects on action potential duration. The results suggest that the beneficial effects of NaHCO3 are related to a reversal of drug effects on phase 0 characteristics and that this effect is due both to alkalinization and to increases in extracellular Na concentration.
D000200:Action Potentials / Q000187:drug effects; D000639:Amitriptyline / Q000633:toxicity*; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D005110:Extracellular Space / Q000032:analysis; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D012964:Sodium / Q000032:analysis; D017693:Sodium Bicarbonate; D013997:Time Factors
D001639:Bicarbonates; D000639:Amitriptyline; D017693:Sodium Bicarbonate; D012964:Sodium