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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Human lymphatic vessel contractile activity is inhibited <italic>in vitro</italic> but not <italic>in vivo</italic> by the calcium channel blocker nifedipine</title><author><name sortKey="Telinius, Niklas" sort="Telinius, Niklas" uniqKey="Telinius N" first="Niklas" last="Telinius">Niklas Telinius</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mohanakumar, Sheyanth" sort="Mohanakumar, Sheyanth" uniqKey="Mohanakumar S" first="Sheyanth" last="Mohanakumar">Sheyanth Mohanakumar</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Majgaard, Jens" sort="Majgaard, Jens" uniqKey="Majgaard J" first="Jens" last="Majgaard">Jens Majgaard</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kim, Sukhan" sort="Kim, Sukhan" uniqKey="Kim S" first="Sukhan" last="Kim">Sukhan Kim</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pilegaard, Hans" sort="Pilegaard, Hans" uniqKey="Pilegaard H" first="Hans" last="Pilegaard">Hans Pilegaard</name><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pahle, Einar" sort="Pahle, Einar" uniqKey="Pahle E" first="Einar" last="Pahle">Einar Pahle</name><affiliation><nlm:aff id="au3"><institution>Department of Surgery, Viborg Hospital</institution><addr-line>Viborg, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nielsen, J Rn" sort="Nielsen, J Rn" uniqKey="Nielsen J" first="J Rn" last="Nielsen">J Rn Nielsen</name><affiliation><nlm:aff id="au3"><institution>Department of Surgery, Viborg Hospital</institution><addr-line>Viborg, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Leval, Marc" sort="De Leval, Marc" uniqKey="De Leval M" first="Marc" last="De Leval">Marc De Leval</name><affiliation><nlm:aff id="au4"><institution>International Congenital Cardiac Centre</institution><addr-line>Harley Street Clinic, London, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aalkjaer, Christian" sort="Aalkjaer, Christian" uniqKey="Aalkjaer C" first="Christian" last="Aalkjaer">Christian Aalkjaer</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hjortdal, Vibeke" sort="Hjortdal, Vibeke" uniqKey="Hjortdal V" first="Vibeke" last="Hjortdal">Vibeke Hjortdal</name><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boedtkjer, Donna Briggs" sort="Boedtkjer, Donna Briggs" uniqKey="Boedtkjer D" first="Donna Briggs" last="Boedtkjer">Donna Briggs Boedtkjer</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25172950</idno><idno type="pmc">4253471</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253471</idno><idno type="RBID">PMC:4253471</idno><idno type="doi">10.1113/jphysiol.2014.276683</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002F81</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002F81</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Human lymphatic vessel contractile activity is inhibited <italic>in vitro</italic> but not <italic>in vivo</italic> by the calcium channel blocker nifedipine</title><author><name sortKey="Telinius, Niklas" sort="Telinius, Niklas" uniqKey="Telinius N" first="Niklas" last="Telinius">Niklas Telinius</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mohanakumar, Sheyanth" sort="Mohanakumar, Sheyanth" uniqKey="Mohanakumar S" first="Sheyanth" last="Mohanakumar">Sheyanth Mohanakumar</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Majgaard, Jens" sort="Majgaard, Jens" uniqKey="Majgaard J" first="Jens" last="Majgaard">Jens Majgaard</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kim, Sukhan" sort="Kim, Sukhan" uniqKey="Kim S" first="Sukhan" last="Kim">Sukhan Kim</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pilegaard, Hans" sort="Pilegaard, Hans" uniqKey="Pilegaard H" first="Hans" last="Pilegaard">Hans Pilegaard</name><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pahle, Einar" sort="Pahle, Einar" uniqKey="Pahle E" first="Einar" last="Pahle">Einar Pahle</name><affiliation><nlm:aff id="au3"><institution>Department of Surgery, Viborg Hospital</institution><addr-line>Viborg, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nielsen, J Rn" sort="Nielsen, J Rn" uniqKey="Nielsen J" first="J Rn" last="Nielsen">J Rn Nielsen</name><affiliation><nlm:aff id="au3"><institution>Department of Surgery, Viborg Hospital</institution><addr-line>Viborg, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Leval, Marc" sort="De Leval, Marc" uniqKey="De Leval M" first="Marc" last="De Leval">Marc De Leval</name><affiliation><nlm:aff id="au4"><institution>International Congenital Cardiac Centre</institution><addr-line>Harley Street Clinic, London, UK</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aalkjaer, Christian" sort="Aalkjaer, Christian" uniqKey="Aalkjaer C" first="Christian" last="Aalkjaer">Christian Aalkjaer</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hjortdal, Vibeke" sort="Hjortdal, Vibeke" uniqKey="Hjortdal V" first="Vibeke" last="Hjortdal">Vibeke Hjortdal</name><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boedtkjer, Donna Briggs" sort="Boedtkjer, Donna Briggs" uniqKey="Boedtkjer D" first="Donna Briggs" last="Boedtkjer">Donna Briggs Boedtkjer</name><affiliation><nlm:aff id="au1"><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="au2"><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</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="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l<sup>−1</sup> nifedipine. Transcripts for the L-type calcium channel gene <italic>CACNA1C</italic> were consistently detected from human thoracic duct samples examined and the Ca<sub>V</sub>1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics <italic>ex vivo</italic> were highly sensitive to nifedipine, this was not apparent <italic>in vivo</italic> when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine <italic>in vitro</italic> but that care must be taken when extrapolating <italic>in vitro</italic> observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.</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="iso-abbrev">J. Physiol. (Lond.)</journal-id><journal-id journal-id-type="publisher-id">tjp</journal-id><journal-title-group><journal-title>The Journal of Physiology</journal-title></journal-title-group><issn pub-type="ppub">0022-3751</issn><issn pub-type="epub">1469-7793</issn><publisher><publisher-name>BlackWell Publishing Ltd</publisher-name><publisher-loc>Oxford, UK</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25172950</article-id><article-id pub-id-type="pmc">4253471</article-id><article-id pub-id-type="doi">10.1113/jphysiol.2014.276683</article-id><article-categories><subj-group subj-group-type="heading"><subject>Cardiovascular</subject></subj-group></article-categories><title-group><article-title>Human lymphatic vessel contractile activity is inhibited <italic>in vitro</italic> but not <italic>in vivo</italic> by the calcium channel blocker nifedipine</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Telinius</surname><given-names>Niklas</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref><xref ref-type="corresp" rid="cor1"></xref></contrib><contrib contrib-type="author"><name><surname>Mohanakumar</surname><given-names>Sheyanth</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Majgaard</surname><given-names>Jens</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Sukhan</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pilegaard</surname><given-names>Hans</given-names></name><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pahle</surname><given-names>Einar</given-names></name><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Nielsen</surname><given-names>Jørn</given-names></name><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>de Leval</surname><given-names>Marc</given-names></name><xref ref-type="aff" rid="au4">4</xref></contrib><contrib contrib-type="author"><name><surname>Aalkjaer</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="au1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hjortdal</surname><given-names>Vibeke</given-names></name><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Boedtkjer</surname><given-names>Donna Briggs</given-names></name><xref ref-type="aff" rid="au1">1</xref><xref ref-type="aff" rid="au2">2</xref></contrib><aff id="au1"><label>1</label><institution>Department of Biomedicine, Aarhus University</institution><addr-line>Aarhus, Denmark</addr-line></aff><aff id="au2"><label>2</label><institution>Department of Cardiothoracic Surgery, Aarhus University Hospital</institution><addr-line>Aarhus, Denmark</addr-line></aff><aff id="au3"><label>3</label><institution>Department of Surgery, Viborg Hospital</institution><addr-line>Viborg, Denmark</addr-line></aff><aff id="au4"><label>4</label><institution>International Congenital Cardiac Centre</institution><addr-line>Harley Street Clinic, London, UK</addr-line></aff></contrib-group><author-notes><corresp id="cor1"><bold>Corresponding author</bold> N. Telinius: Department of Biomedicine, Ole Worms Allé 6, Aarhus University, 8000 Aarhus C, Denmark. Email: <email>telinius@me.com</email></corresp></author-notes><pub-date pub-type="ppub"><day>01</day><month>11</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>29</day><month>9</month><year>2014</year></pub-date><volume>592</volume><issue>Pt 21</issue><fpage>4697</fpage><lpage>4714</lpage><history><date date-type="received"><day>28</day><month>4</month><year>2014</year></date><date date-type="accepted"><day>12</day><month>8</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society</copyright-statement><copyright-year>2014</copyright-year></permissions><abstract><p>Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l<sup>−1</sup> nifedipine. Transcripts for the L-type calcium channel gene <italic>CACNA1C</italic> were consistently detected from human thoracic duct samples examined and the Ca<sub>V</sub>1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics <italic>ex vivo</italic> were highly sensitive to nifedipine, this was not apparent <italic>in vivo</italic> when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine <italic>in vitro</italic> but that care must be taken when extrapolating <italic>in vitro</italic> observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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