{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T06:06:56Z","timestamp":1785564416022,"version":"3.56.0"},"reference-count":20,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":1859,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2004,1]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>The interaction of lidocaine\u2010like local anaesthetics with voltage\u2010operated sodium channels is traditionally assumed to be characterized by tighter binding of the drugs to depolarized channels. As inactivated and drug\u2010bound channels are both unavailable on depolarization, an indirect approach is required to yield estimates for the dissociation constants from channels in inactivated states. The established model, originally described by Bean <jats:italic>et al.<\/jats:italic>, describes the difference in affinity between resting and inactivated states in terms of the concentration dependence of the voltage shift in the availability curve. We have tested the hypothesis that this model, which assumes a simple Langmuir relationship, could be improved by introducing a Hill\u2010type exponent, which would take into account potential sources of cooperativity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Steady\u2010state block by lidocaine was studied in heterologously (HEK 293) expressed human skeletal muscle sodium channels and compared with experimental data previously obtained for 2,6\u2010dimethylphenol, 3,5\u2010dimethyl\u20104\u2010chlorophenol, and 4\u2010chlorophenol. Cells were clamped to membrane potentials from \u2212150 to \u22125 mV, and a subsequent test pulse was used to assess the number of channels available to open.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>All compounds shifted the voltage dependence of channel availability in the direction of negative prepulse potentials. Prediction of the concentration dependence of the voltage shift in the availability curve was improved by the modified model, as shown by a marked reduction in the residual sum of squares.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>For all compounds, the Hill\u2010type exponent was significantly greater than one. These results could be interpreted in the light of the contemporary hypothesis that lidocaine functions as an allosteric gating effector to enhance sodium channel inactivation by strengthening the latch mechanism of inactivation, which is considered to be a particle\u2010binding process allosterically coupled to activation. Alternatively, they could be interpreted by postulating additional binding sites for lidocaine on fast\u2010inactivated sodium channels.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2004) <jats:bold>141<\/jats:bold>, 47\u201354. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705594\">10.1038\/sj.bjp.0705594<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705594","type":"journal-article","created":{"date-parts":[[2004,1,7]],"date-time":"2004-01-07T13:53:00Z","timestamp":1073483580000},"page":"47-54","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["An improved model for the binding of lidocaine and structurally related local anaesthetics to fast\u2010inactivated voltage\u2010operated sodium channels, showing evidence of cooperativity"],"prefix":"10.1111","volume":"141","author":[{"given":"Martin","family":"Leuwer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gertrud","family":"Haeseler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Hecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Bufler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Dengler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey K","family":"Aronson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119116"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.107.5.643"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.81.5.613"},{"key":"e_1_2_7_5_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1152\/physrev.1992.72.suppl_4.S15","article-title":"Cellular and molecular biology of voltage\u2010gated sodium channels","volume":"72","author":"CATTERALL W.A.","year":"1992","journal-title":"Physiol. 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