| Background. Overdose cardiac effects of class I antiarrhythmic drugs, tricyclic antidepressants and psychotropic drugs are mainly due to their block of the fast sodium current. These deleterious effects are clinically reversed by the administration of hypertonic sodium salts (that induce alkalosis and hypernatremia) but the associated underlying molecular mechanisms are still poorly understood.;Methods and results. We assessed (using the standard microelectrode technique on canine Purkinje fibers) the relative role of increasing the sodium load alone, the bicarbonate moiety alone and the combination of both on the action potential characteristics in the absence and in the presence of equieffective doses (IC50 for Vmax block) of four sodium channel blockers, (disopyramide 30 muM, mexiletine 80 muM, flecainide 7 muM, imipramine 5 muM). The combination of high sodium and high pH was beneficial in reversing Vmax (phase 0 upstroke) depression (about 36% reversal) in the presence of all agents except for disopyramide. The reversal effect of sodium bicarbonate was entirely due to the bicarbonate moiety in the case of imipramine, and partially for flecainide and mexiletine where an increase in the sodium load was equally effective (about 17% reversal for each). The reversal of Vmax depression by increased sodium and pH was due in part to hyperpolarization of the membrane activating potential. In addition, alkalosis directly reversed the shift in Vmax inactivation caused by imipramine and flecainide but not disopyramide and mexiletine. To study the direct interaction with the sodium channel independent of any ancillary variables, we used the whole-cell mode of the voltage-clamp technique on isolated human atrial myocytes. Both imipramine and mexiletine inhibited all the states of the channel with a higher affinity for the inactivated and activated states. Our experimental and modelling data revealed an attenuation of the imipramine-induced INa blockade by both intracellular and extracellular alkalosis, with the former being more effective by virtue of its additional attenuation of the activated state block (increasing its Kd from 0.67 M to 2.18 M by intracellular alkalosis while extracellular alkalosis left the activated state Kd unaltered). In the case of mexiletine, extracellular (ALK e) and intracellular (ALKi) alkalosis had opposite modulatory effects on INa, blockade. ALKe enhanced whereas ALKi attenuated the kinetics and magnitude of steady state and use-dependent block. This was also confirmed by the derived kinetic rates.;Conclusions. We have proven that sodium bicarbonate is beneficial against most but not all sodium channel blockers. In addition, we found a moiety-specific variability among the probed drugs. In the case of pH, the variability seems to be related to a differential modulatory effect between extracellular and intracellular pH on the magnitude and kinetics of block of the sodium channel. The primary effect of extracellular pH seems to be a combination of a screening effect of the surface charges and a probable increase of the drug concentration to the receptor site. Intracellular pH seems to affect the state of drug ionization near the receptor and has no clear effects on the drug-receptor complex. |
