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Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes.

Abstract：

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 microM) 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 microM by extracellular alkalosis and to 2.51 microM 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 microM to 2.18 microM, while extracellular alkalosis left the activated state Kd unaltered at 0.67 microM. 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Bou-Abboud E,Nattel S

doi

10.1016/s0008-6363(98)00011-x

subject

Has Abstract

pub_date

1998-05-01 00:00:00

pages

395-404

issue

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(98)00011-X

journal_volume

pub_type

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Molecular mechanisms of the reversal of imipramine-induced sodium channel blockade by alkalinization in human cardiac myocytes.