Sodium lactate reversal of electrophysiological effects of imipramine in guinea-pig ventricular myocardium.
Overdose cardiac effects of imipramine are due to fast Na channel blockade and are clinically reversed by administration of sodium lactate which induces alkalosis (about pH 7.50) and hypernatremia (about 8 mM). The mechanisms of this beneficial effect of Na lactate were explored in vitro on guinea-pig ventricular myocardium using the microelectrode technique. The time-course effects of the clinically relevant concentration of 10 microM imipramine on action potential characteristics were examined at pH 7.20 and pH 7.50. To test whether alkalinisation per se is important or whether an increase in Na concentration plays a major role in the reversal effect, preparations were exposed to increasing concentrations (1, 3, 10, 30, 100 mM) of either Na lactate, bicarbonate or chloride in the absence or in the presence of 10 microM imipramine at pH 7.50. The influence of elevating osmolality was evaluated with equivalent concentrations of sucrose. Imipramine alone significantly depressed Vmax and shortened action potential duration at all phases of repolarisation. All three high sodium solutions reversed imipramine effects. However the reversal effect was already obvious with 10 mM Na lactate and 10 mM NaHCO3 but not 10 mM NaCl. Osmolality did not reverse the imipramine-induced Vmax depression. The results suggest that at the clinically relevant 10 mM concentration, sodium lactate and bicarbonate may displace imipramine from its receptor site on the Na channel by causing alkalosis at the membrane level without profoundly affecting the driving force of the Na current, whereas at the upper concentrations, the increase in Na ion concentrations is predominantly involved in the reversal of imipramine effects.
Adamantidis
M M
MM
Laboratoire de Pharmacologie, Faculté de Médecine, Lille, France.
Adnet-Bonte
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Adnet
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Durocher
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Dupuis
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D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001639:Bicarbonates / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007099:Imipramine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007773:Lactates / Q000494:pharmacology*; D019344:Lactic Acid; D008297:Male; D009206:Myocardium / Q000737:chemistry*; D009994:Osmolar Concentration; D012964:Sodium / Q000494:pharmacology; D017693:Sodium Bicarbonate; D012965:Sodium Chloride / Q000494:pharmacology
D001639:Bicarbonates; D007773:Lactates; D019344:Lactic Acid; D012965:Sodium Chloride; D017693:Sodium Bicarbonate; D012964:Sodium; D007099:Imipramine