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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a</title><author><name sortKey="Lei, Ming" sort="Lei, Ming" uniqKey="Lei M" first="Ming" last="Lei">Ming Lei</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goddard, Catharine" sort="Goddard, Catharine" uniqKey="Goddard C" first="Catharine" last="Goddard">Catharine Goddard</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jie" sort="Liu, Jie" uniqKey="Liu J" first="Jie" last="Liu">Jie Liu</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Leoni, Anne Laure" sort="Leoni, Anne Laure" uniqKey="Leoni A" first="Anne-Laure" last="Léoni">Anne-Laure Léoni</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Royer, Anne" sort="Royer, Anne" uniqKey="Royer A" first="Anne" last="Royer">Anne Royer</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fung, Simon S M" sort="Fung, Simon S M" uniqKey="Fung S" first="Simon S-M" last="Fung">Simon S-M Fung</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Xiao, Guosheng" sort="Xiao, Guosheng" uniqKey="Xiao G" first="Guosheng" last="Xiao">Guosheng Xiao</name><affiliation><nlm:aff id="au4"><institution>Union Hospital, Huazhong University of Science and Technology, Wuhan</institution><addr-line>The People's Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ma, Aiqun" sort="Ma, Aiqun" uniqKey="Ma A" first="Aiqun" last="Ma">Aiqun Ma</name><affiliation><nlm:aff id="au5"><institution>First Hospital, Xi'an Medical School, Xi'an Jiaotong University</institution><addr-line>The People's Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhang, Henggui" sort="Zhang, Henggui" uniqKey="Zhang H" first="Henggui" last="Zhang">Henggui Zhang</name><affiliation><nlm:aff id="au6"><institution>Biological Physics Group Physics, Department, UMIST, Manchester</institution><addr-line>M60 1QD UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Charpentier, Flavien" sort="Charpentier, Flavien" uniqKey="Charpentier F" first="Flavien" last="Charpentier">Flavien Charpentier</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vandenberg, Jamie I" sort="Vandenberg, Jamie I" uniqKey="Vandenberg J" first="Jamie I" last="Vandenberg">Jamie I. Vandenberg</name><affiliation><nlm:aff id="au7"><institution>Electrophysiology and Biophysics Program, Victor Chang Cardiac Research Institute</institution><addr-line>384 Victoria Street, Darlinghurst, NSW2010, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Colledge, William H" sort="Colledge, William H" uniqKey="Colledge W" first="William H" last="Colledge">William H. Colledge</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Grace, Andrew A" sort="Grace, Andrew A" uniqKey="Grace A" first="Andrew A" last="Grace">Andrew A. Grace</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huang, Christopher L H" sort="Huang, Christopher L H" uniqKey="Huang C" first="Christopher L-H" last="Huang">Christopher L-H Huang</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15932895</idno><idno type="pmc">1474188</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1474188</idno><idno type="RBID">PMC:1474188</idno><idno type="doi">10.1113/jphysiol.2005.083188</idno><date when="2005">2005</date><idno type="wicri:Area/Pmc/Corpus">001A02</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001A02</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a</title><author><name sortKey="Lei, Ming" sort="Lei, Ming" uniqKey="Lei M" first="Ming" last="Lei">Ming Lei</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goddard, Catharine" sort="Goddard, Catharine" uniqKey="Goddard C" first="Catharine" last="Goddard">Catharine Goddard</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jie" sort="Liu, Jie" uniqKey="Liu J" first="Jie" last="Liu">Jie Liu</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Leoni, Anne Laure" sort="Leoni, Anne Laure" uniqKey="Leoni A" first="Anne-Laure" last="Léoni">Anne-Laure Léoni</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Royer, Anne" sort="Royer, Anne" uniqKey="Royer A" first="Anne" last="Royer">Anne Royer</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fung, Simon S M" sort="Fung, Simon S M" uniqKey="Fung S" first="Simon S-M" last="Fung">Simon S-M Fung</name><affiliation><nlm:aff id="au1"><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Xiao, Guosheng" sort="Xiao, Guosheng" uniqKey="Xiao G" first="Guosheng" last="Xiao">Guosheng Xiao</name><affiliation><nlm:aff id="au4"><institution>Union Hospital, Huazhong University of Science and Technology, Wuhan</institution><addr-line>The People's Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ma, Aiqun" sort="Ma, Aiqun" uniqKey="Ma A" first="Aiqun" last="Ma">Aiqun Ma</name><affiliation><nlm:aff id="au5"><institution>First Hospital, Xi'an Medical School, Xi'an Jiaotong University</institution><addr-line>The People's Republic of China</addr-line></nlm:aff></affiliation></author><author><name sortKey="Zhang, Henggui" sort="Zhang, Henggui" uniqKey="Zhang H" first="Henggui" last="Zhang">Henggui Zhang</name><affiliation><nlm:aff id="au6"><institution>Biological Physics Group Physics, Department, UMIST, Manchester</institution><addr-line>M60 1QD UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Charpentier, Flavien" sort="Charpentier, Flavien" uniqKey="Charpentier F" first="Flavien" last="Charpentier">Flavien Charpentier</name><affiliation><nlm:aff id="au3"><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vandenberg, Jamie I" sort="Vandenberg, Jamie I" uniqKey="Vandenberg J" first="Jamie I" last="Vandenberg">Jamie I. Vandenberg</name><affiliation><nlm:aff id="au7"><institution>Electrophysiology and Biophysics Program, Victor Chang Cardiac Research Institute</institution><addr-line>384 Victoria Street, Darlinghurst, NSW2010, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Colledge, William H" sort="Colledge, William H" uniqKey="Colledge W" first="William H" last="Colledge">William H. Colledge</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Grace, Andrew A" sort="Grace, Andrew A" uniqKey="Grace A" first="Andrew A" last="Grace">Andrew A. Grace</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huang, Christopher L H" sort="Huang, Christopher L H" uniqKey="Huang C" first="Christopher L-H" last="Huang">Christopher L-H Huang</name><affiliation><nlm:aff id="au2"><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Physiology</title><idno type="ISSN">0022-3751</idno><idno type="eISSN">1469-7793</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the <italic>Scn5a</italic> gene to clarify the role of Scn5a-encoded cardiac Na<sup>+</sup> channels in normal SAN function and the mechanism(s) by which reduced Na<sup>+</sup> channel function might cause sinus node dysfunction. <italic>Scn5a</italic><sup>+/−</sup> mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na<sup>+</sup> channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a<sup>+/−</sup> SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a<sup>+/−</sup> SAN preparations. Furthermore, isolated WT and Scn5a<sup>+/−</sup> 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<sup>+/−</sup> myocytes. These findings were successfully reproduced in a model that implicated <italic>i</italic><sub>Na</sub> 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 <italic>Scn5a</italic> 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<sup>+</sup> channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Physiol</journal-id><journal-id journal-id-type="publisher-id">tjp</journal-id><journal-title>The Journal of Physiology</journal-title><issn pub-type="ppub">0022-3751</issn><issn pub-type="epub">1469-7793</issn><publisher><publisher-name>Blackwell Science Inc</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15932895</article-id><article-id pub-id-type="pmc">1474188</article-id><article-id pub-id-type="doi">10.1113/jphysiol.2005.083188</article-id><article-categories><subj-group subj-group-type="heading"><subject>Cell Physiology</subject><subj-group><subject>Research Papers</subject></subj-group></subj-group></article-categories><title-group><article-title>Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lei</surname><given-names>Ming</given-names></name><xref rid="au1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Goddard</surname><given-names>Catharine</given-names></name><xref rid="au2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jie</given-names></name><xref rid="au1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Léoni</surname><given-names>Anne-Laure</given-names></name><xref rid="au3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Royer</surname><given-names>Anne</given-names></name><xref rid="au3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Fung</surname><given-names>Simon S-M</given-names></name><xref rid="au1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Xiao</surname><given-names>Guosheng</given-names></name><xref rid="au4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Aiqun</given-names></name><xref rid="au5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Henggui</given-names></name><xref rid="au6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Charpentier</surname><given-names>Flavien</given-names></name><xref rid="au3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Vandenberg</surname><given-names>Jamie I</given-names></name><xref rid="au7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Colledge</surname><given-names>William H</given-names></name><xref rid="au2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Grace</surname><given-names>Andrew A</given-names></name><xref rid="au2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Christopher L-H</given-names></name><xref rid="au2" ref-type="aff">2</xref></contrib><aff id="au1"><label>1</label><institution>University Laboratory of Physiology, University of Oxford</institution><addr-line>Oxford, OX1 3PT UK</addr-line></aff><aff id="au2"><label>2</label><institution>Cardiovascular Group, Departments of Biochemistry and Physiology, University of Cambridge</institution><addr-line>Tennis Court Road, Cambridge CB2 1QW UK</addr-line></aff><aff id="au3"><label>3</label><institution>INSERM U533, Laboratoire de Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine</institution><addr-line>Nantes, France</addr-line></aff><aff id="au4"><label>4</label><institution>Union Hospital, Huazhong University of Science and Technology, Wuhan</institution><addr-line>The People's Republic of China</addr-line></aff><aff id="au5"><label>5</label><institution>First Hospital, Xi'an Medical School, Xi'an Jiaotong University</institution><addr-line>The People's Republic of China</addr-line></aff><aff id="au6"><label>6</label><institution>Biological Physics Group Physics, Department, UMIST, Manchester</institution><addr-line>M60 1QD UK</addr-line></aff><aff id="au7"><label>7</label><institution>Electrophysiology and Biophysics Program, Victor Chang Cardiac Research Institute</institution><addr-line>384 Victoria Street, Darlinghurst, NSW2010, Australia</addr-line></aff></contrib-group><author-notes><corresp id="cor1"><bold>Corresponding authors</bold> M. Lei: University Laboratory of Physiology, University of Oxford, Oxford, OX1 3PT UK. Email: <email>ming.lei@physiol.ox.ac.uk</email> or C. L.-H. Huang: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Email: <email>clh11@cam.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>01</day><month>9</month><year>2005</year></pub-date><pub-date pub-type="epub"><day>2</day><month>6</month><year>2005</year></pub-date><volume>567</volume><issue>Pt 2</issue><fpage>387</fpage><lpage>400</lpage><history><date date-type="rev-recd"><day>16</day><month>1</month><year>2005</year></date><date date-type="accepted"><day>31</day><month>5</month><year>2005</year></date></history><copyright-statement>© The Physiological society 2005</copyright-statement><copyright-year>2005</copyright-year><abstract><p>We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the <italic>Scn5a</italic> gene to clarify the role of Scn5a-encoded cardiac Na<sup>+</sup> channels in normal SAN function and the mechanism(s) by which reduced Na<sup>+</sup> channel function might cause sinus node dysfunction. <italic>Scn5a</italic><sup>+/−</sup> mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na<sup>+</sup> channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a<sup>+/−</sup> SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a<sup>+/−</sup> SAN preparations. Furthermore, isolated WT and Scn5a<sup>+/−</sup> 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<sup>+/−</sup> myocytes. These findings were successfully reproduced in a model that implicated <italic>i</italic><sub>Na</sub> 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 <italic>Scn5a</italic> 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<sup>+</sup> channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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