Letter Regarding Article by Darbar et al, “Unmasking of Brugada Syndrome by Lithium”
To the Editor:
It was with great interest that we read the study by Darbar and colleagues in a recent issue of Circulation.1 The authors reported on 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac Na+ channels. Surprisingly, Darbar and colleagues found that LiCl caused a concentration-dependent block of peak INa, with an IC50 of 6.8±0.4 μmol/L, a level 100 times below the therapeutic range (&1 mmol/L). They concluded that lithium is a potent blocker of cardiac Na+ channels and may unmask patients with the Brugada syndrome.
It is well known from numerous studies (conducted during the last 3 decades) that Li+ ions permeate Na+ channels, as well as do Na+ ions, in a variety of excitable cell types.2 Although there is little information available concerning lithium permeation through cardiac Na+ channels, there is no reason a priori to expect a lithium block, as the selectivity sequence is largely conserved among Na+ channels from different tissues.3 Amazed by the unusual and puzzling findings of Darbar et al (that Li+ ion acts as a blocker of the cardiac Na+ channel), we conducted our own experiments on whole-cell Na+ currents in either human embryonic kidney cells stably expressing cardiac Na+ channels (SCN5a; Nav1.5) or adult rat ventricular myocytes. We used experimental conditions similar to those of Darbar et al. We found that the peak Na+ currents after administration of 10 μmol/L LiCl or even 100 μmol/L LiCl were completely unchanged from their control values (0.98±0.02, n=6 myocytes; 1.01±0.04, n=6 human embryonic kidney cells). We conclude from our experiments that Li+ ions do not block the cardiac Na+ channel at these concentrations. It seems highly unlikely that any minor difference between the experimental conditions used by Darbar et al and our experiments could explain these extremely divergent results.
In conclusion, we believe that it is indeed fortunate that Li+ ion is not a potent blocker of the cardiac Na+ channel (as was claimed by Darbar et al). If it were, administration of this commonly prescribed drug for bipolar disorder would cause a blockade of electrical conduction throughout the myocardium and result in cardiac arrest.
Darbar D, Yang T, Churchwell K, Wilde A, Roden D. Unmasking of Brugada syndrome by lithium. Circulation. 2005; 112: 1527–1531.
Hille B. Selective permeability: independence. In: Ion Channels in Excitable Cells. Boston, Mass: Sinauer Associates; 2001:chap 14.
Fozzard H, Hanck D. Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms. Physiol Rev. 1996; 76: 887–926.
Dr Josephson and colleagues suggest that lithium ion may not be a potent blocker of the cardiac Na+ channel, based on their experiments in either human embryonic kidney cells or adult rat ventricular myocytes. However, as the authors are well aware, voltage clamping the Na+ channel current is technically more challenging than other ionic channel currents because of the channels’ fast activation kinetics. Consequently, researchers often modify experimental conditions (such as altering the compositions of pipette-filling solutions or reducing the external Na+ gradient) to slow channel kinetics. Without knowing the precise experimental conditions used by Dr Josephson and colleagues, one possible explanation for why peak Na+ currents were unaffected by lithium in their experiments may relate to differences in experimental conditions.
To address the concerns raised by Josephson and colleagues, the experiments were repeated by 2 investigators independently under identical conditions (Drs Yang and Hiroshi Watanabe). We found that at 3 lithium concentrations (5, 10, and 100 μmol/L), peak Na+ currents were reduced by 53±3% (mean±SEM, n=2), 60±4% (n=4), and 84±3% (n=2), respectively, and that the extent of block was unrelated to basal INa magnitude. Because the verification data were in total agreement with our original results,1 we are confident that in the Chinese hamster ovary cell-line expression system, lithium is a potent blocker of the cardiac Na+ channel.
Another possible explanation for the findings of Dr Josephson and colleagues’ may relate to the limitations of applicability of cell-line experiments to the whole organism. It is well known that ion-current reduction not only varies according to species, cardiac cell type, and region, but also is highly dependent on in vitro and in vivo conditions. Although a variety of cell lines have been used to study ion channel physiology and pharmacology, these in vitro studies cannot hope to reproduce the exact effects of drug block in the intact human heart.