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(Circulation. 2006;114:1360-1371.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Localization of Na⁺ Channel Isoforms at the Atrioventricular Junction and Atrioventricular Node in the Rat

Shin Yoo, MSc; Halina Dobrzynski, PhD; Vadim V. Fedorov, PhD; Shang-Zhong Xu, PhD; Tomoko T. Yamanushi, PhD; Sandra A. Jones, PhD; Mitsuru Yamamoto, MD; Vladmir P. Nikolski, PhD; Igor R. Efimov, PhD; Mark R. Boyett, PhD

From the Cardiovascular Research Group (S.Y., H.D., M.R.B.), School of Medicine, University of Manchester, Core Technology Facility, Manchester, United Kingdom; Washington University (V.V.F., V.P.N., I.R.E.), St Louis, Mo; Postgraduate Medical Institute and Hull York Medical School (S.-Z.X.), University of Hull, Hull, United Kingdom; Kagawa Prefectural College of Health Science (T.T.Y.), Kagawa, Japan; School of Biomedical Sciences, University of Leeds (S.A.J.), Leeds, United Kingdom; and Research Institute of Environmental Medicine (M.Y.), Nagoya University, Nagoya, Japan.

Correspondence to Professor M.R. Boyett, Cardiovascular Research Group, School of Medicine, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester M13 9NT, United Kingdom. E-mail mark.boyett{at}manchester.ac.uk

Received January 13, 2006; revision received July 7, 2006; accepted July 13, 2006.

Background— The electrical activity of the atrioventricular node (AVN) is functionally heterogeneous, but how this relates to distinct cell types and the 3-dimensional structure of the AVN is unknown. To address this, we have studied the expression of Na_v1.5 and other Na⁺ channel isoforms in the AVN.

Methods and Results— The rat AVN was identified by Masson’s trichrome staining together with immunolabeling of marker proteins: connexin40, connexin43, desmoplakin, atrial natriuretic peptide, and hyperpolarization-activated and cyclic nucleotide–gated channel 4. Na⁺ channel expression was investigated with immunohistochemistry with isoform-specific Na⁺ channel antibodies. Na_v1.1 was distributed in a similar manner to Na_v1.5. Na_v1.2 was not detected. Na_v1.3 labeling was present in nerve fibers and cell bodies (but not myocytes) and was abundant in the penetrating atrioventricular (AV) bundle and the common bundle but was much less abundant in other regions. Na_v1.5 labeling was abundant in the atrial and ventricular myocardium and the left bundle branch. Na_v1.5 labeling was absent in the open node, penetrating AV bundle, AV ring bundle, and common bundle but present at a reduced level in the inferior nodal extension and transitional zone. Na_v1.6 was not detected.

Conclusions— Our findings provide molecular evidence of multiple electrophysiological cell types at the AV junction. Impaired AV conduction as a result of mutations in or loss of Na_v1.5 must be the result of impaired conduction in the AVN inputs (inferior nodal extension and transitional zone) or output (bundle branches) rather than the AVN itself (open node and penetrating AV bundle).

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