Europace Advance Access originally published online on December 3, 2007
Europace 2008 10(2):257; doi:10.1093/europace/eum266
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LETTERS
Effects of heart failure on brain-type Na+ channels in rabbit ventricular myocytes
Department of Pharmacology and Toxicology
University of Lausanne
Bugnon 27
1005 Lausanne
Switzerland
Department of Pharmacology and Toxicology
University of Lausanne
Bugnon 27
1005 Lausanne
Switzerland;
Service of Cardiology
University of Lausanne
CHUV
Lausanne
Switzerland
Tel: +41-21-6925364
Fax: +41-21-6935355
E-mail address: hugues.abriel{at}unil.ch
Not only we have read with great interest the recent study by Verkerk et al.1
, but we were also impressed by the originality of their experimental approach. In this study, macropatch recordings were conducted from the lateral membranes of rabbit cardiomyocytes or from intercalated disc areas. Both regions exhibited fast transient sodium currents. However, the current was 8.5 times larger at intercalated discs. Fifty nanomolar tetrodotoxin (TTX) did not block the intercalated disc current, but inhibited it at the lateral membranes, suggesting that the latter current is mediated by neuronal-type voltage-gated sodium (Nav) channels that are TTX-sensitive.
Recently, we planed to perform similar experiments to study the mechanisms underlying the targeting and anchoring of the ‘cardiac’ isoform of the sodium channel, Nav1.5, to the lateral membranes vs. intercalated discs of cardiomyocytes. Specifically, we wanted to investigate this point in dystrophin-deficient mice as we observed that in myocytes from this mouse strain, the whole-cell sodium current was decreased by 
50% compared with wild-type cells.2 Since dystrophin is exclusively found at the lateral membranes, we hypothesized that only Nav1.5 channels found in this compartment are down-regulated in dystrophin-deficient myocytes.2 However, Verkerk et al. conclude that almost no Nav1.5 channels are present in this lateral membrane compartment.
The discussion by Verkerk et al. is well balanced and points to possible limitations of their technical approach. Here, we would like to address a point that has not been explicitly discussed. On the basis of a commonly admitted model of a cardiomyocyte,3 one may consider a ventricular myocyte as a cylinder 100 µm in length and 11 µm in radius. The intercalated disc area would be 760 µm2, and the lateral membrane area 6910 µm2, thus 9 times larger than the intercalated disc area. In Fig. 1 of Verkerk et al.,1 the ‘quasi-macroscopic’ currents obtained at the lateral membrane were 70 pA and 600 pA at the intercalated discs. If we extrapolate these values, the current generated by channels from the lateral membrane would be about the same amplitude as compared with intercalated discs (483'700 pA vs. 456'000 pA per unit of area under the pipette). This would mean that the contribution of TTX-sensitive neuronal-type Navs in cardiomyocytes is comparable to the one of Nav1.5 channels, and that these channels are almost excluded from the lateral membrane compartment. These conclusions contrast with the observations made by several groups indicating that TTX-sensitive-neuronal channels account only for 5–14% of total sodium current in ventricular myocytes in various species.4 Furthermore, recent studies using different specific anti-Nav1.5 antibodies provided evidence that this channel is also found in lateral membranes.5,6
The points we are raising here are significant since it is clear that Nav1.5 is playing an important role in many different genetic and, most likely, acquired cardiac diseases. The study by Verkerk et al.1 is an important one since it shows the feasibility to investigate the distinct membrane localizations of Nav channels, but it also raises further interesting questions.
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[1] Verkerk AO, van Ginneken ACG, van Veen TAB, Tan HL. Effects of heart failure on brain-type Na+ channels in rabbit ventricular myocytes. Europace (2007) 9:571–7.
[2] Gavillet B, Rougier JS, Domenighetti AA, Behar R, Boixel C, Ruchat P, et al. Cardiac sodium channel Nav1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circ Res (2006) 99:407–14.
[3] Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res (1994) 74:1071–96.
[4] Haufe V, Chamberland C, Dumaine R. The promiscuous nature of the cardiac sodium current. J Mol Cell Cardiol (2007) 42:469–77.[CrossRef][Web of Science][Medline]
[5] Baba S, Dun W, Cabo C, Boyden PA. Remodeling in cells from different regions of the reentrant circuit during ventricular tachycardia. Circulation (2005) 112:2386–96.
[6] Mohler PJ, Rivolta I, Napolitano C, Lemaillet G, Lambert S, Priori SG, et al. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci USA (2004) 101:17533–8.
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