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1 University Laboratory of Physiology, University of Oxford, Oxford, OX1 3PT UK
2 Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW UK
3 INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine, Nantes, France
4 Union Hospital, Huazhong University of Science and Technology, Wuhan, The People's Republic of China
5 First Hospital, Xi'an Medical School, Xi'an Jiaotong University, The People's Republic of China
6 Biological Physics Group, Physics Department, UMIST, Manchester, M60 1QD UK
7 Electrophysiology and Biophysics Program, Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst, NSW2010, Australia
We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a+/– mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/– SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/– SAN preparations. Furthermore, isolated WT and Scn5a+/– SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/– myocytes. These findings were successfully reproduced in a model that implicated iNa directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.
(Received 16 January 2005;
accepted after revision 31 May 2005;
first published online 2 June 2005)
Corresponding authors M. Lei: University Laboratory of Physiology, University of Oxford, Oxford, OX1 3PT UK. Email: ming.lei{at}physiol.ox.ac.uk or C. L.-H. Huang: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: clh11{at}cam.ac.uk
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