© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes
aDepartment of Medicine, Institut de Cardiologie de Montréal and Université de Montréal, McGill University, Montreal, Quebec, Canada
bDepartment of Pharmacology, Université de Montréal, McGill University, Montreal, Quebec, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
* Corresponding author. Research Center, Montreal Heart Institute, 5000 Bélanger Street East, Montreal, Quebec, Canada H1T 1C8. Tel.: +1 (514) 376 3330; Fax: +1 (514) 376 1355; E-mail: nattel@icm.umontreal.ca
Background: Alkalinizing agents reverse cardiotoxicity of a variety of sodium channel blockers, including tricyclic antidepressants, but their mechanisms of action are poorly understood. Purpose: To establish the mechanisms by which alkalinization diminishes the sodium channel blocking action of imipramine. Methods: The whole-cell voltage-clamp technique was used to measure INa during a variety of depolarizing pulse protocols in isolated human atrial myocytes, in the presence and absence of imipramine. A three-state model was used to analyze state-dependent INa block. Results: Imipramine (1 and 5 µM) strongly inhibited INa. Experimental data and piecewise exponential analysis suggested significant binding to both activated and inactivated states. Alkalosis antagonized imipramine-induced INa blockade by increasing the unbinding rate, with intracellular alkalosis being more effective than extracellular alkalosis. The dissociation constant (Kd) for the inactivated state was increased from 0.55 to 1.40 µM by extracellular alkalosis and to 2.51 µM by intracellular alkalosis. Along with the reversal of drug-induced shifts in the inactivation curve, these data indicate that alkalosis on either side of the membrane antagonized drug interactions with the inactivated state. On the other hand, only intracellular alkalosis antagonized activated state block, increasing the Kd from 0.67 µM to 2.18 µM, while extracellular alkalosis left the activated state Kd unaltered at 0.67 µM. Conclusions: Alkalinization antagonizes the INa-blocking action of imipramine by promoting unbinding from the receptor. Intracellular alkalosis has a particularly important effect related to the activated-state interaction. The lipid-soluble, uncharged moiety appears to be a critical determinant of imipramine's ability to dissociate from the Na+ channel receptor.
KEYWORDS Sodium channel; Cardiac arrhythmias; Local anesthetics; pH; Antiarrhythmic drugs
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