{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T03:15:37Z","timestamp":1761016537440},"reference-count":22,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2006,10,16]],"date-time":"2006-10-16T00:00:00Z","timestamp":1160956800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin Exp Pharma Physio"],"published-print":{"date-parts":[[2006,11]]},"abstract":"<jats:title>SUMMARY<\/jats:title><jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Drug\u2010induced block of the rapidly activating delayed rectifier K<jats:sup>+<\/jats:sup> current (I<jats:sub>Kr<\/jats:sub>), encoded by human <jats:italic>ether\u2010a\u2010go\u2010go<\/jats:italic>\u2010related gene (hERG), has been linked to acquired long QT syndrome (aLQTS). Hypokalaemia is a recognized risk factor in aLQTS. To further understand why hypokalaemia is a risk factor in aLQTS, we examined the effect of [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> on drug block of the hERG potassium channel stably expressed in human embryonic kidney (HEK\u2010293) cells using whole\u2010cell voltage\u2010clamp techniques.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The effects of selected [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> (1\u201320\u00a0mmol\/L) on hERG block with four structurally diverse compounds (dofetilide, mesoridazine, quinidine and terfenadine) from different therapeutic classes were evaluated. Reducing [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> from 20 to 1\u00a0mmol\/L had little effect on IC<jats:sub>50<\/jats:sub> values for hERG current block for all four compounds. For example, evaluating quinidine in external potassium concentrations of 20, 10, 5 and 1\u00a0mmol\/L resulted in IC<jats:sub>50<\/jats:sub> values of 1.82\u00a0\u00b1\u00a00.33, 2.04\u00a0\u00b1\u00a00.28, 1.57\u00a0\u00b1\u00a00.52 and 1.14\u00a0\u00b1\u00a00.21 mmol\/L, respectively. No statistically significant difference (<jats:italic>P<\/jats:italic>\u00a0&gt; 0.35, <jats:sc> anova<\/jats:sc>) was observed between drug block of hERG in different external potassium concentrations. These data are in contrast with previously reported results examining hERG channel modulation expressed in AT\u20101 cells under similar experimental conditions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results demonstrate that [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub> does not directly modulate drug block of hERG channels expressed in an HEK\u2010293 cell line. The enhanced risk of Torsades de Pointes associated with hypokalaemia in aLQTS may be due to reduction of other (non\u2010hERG) potassium currents, further reducing the repolarization reserve, and not due to direct modulation of hERG block by [K<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>","DOI":"10.1111\/j.1440-1681.2006.04487.x","type":"journal-article","created":{"date-parts":[[2006,10,18]],"date-time":"2006-10-18T06:43:00Z","timestamp":1161153780000},"page":"1059-1065","source":"Crossref","is-referenced-by-count":13,"title":["ALTERING EXTRACELLULAR POTASSIUM CONCENTRATION DOES NOT MODULATE DRUG BLOCK OF HUMAN <i>ETHER\u2010A\u2010GO\u2010GO<\/i>\u2010RELATED GENE (hERG) CHANNELS"],"prefix":"10.1111","volume":"33","author":[{"given":"James T","family":"Limberis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan F","family":"Cox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary A","family":"Gintant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth L","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,10,16]]},"reference":[{"key":"e_1_2_5_2_2","first-page":"360","volume-title":"Medicine","author":"Goldfarb S","year":"2000"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000085057.63483.9b"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199424020-00003"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00054193"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007743521932"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.93.3.407"},{"key":"e_1_2_5_8_2","first-page":"554","article-title":"Inactivation gating determines drug potency: A common mechanism for drug blockade of HERG channels","volume":"25","author":"Yang B","year":"2004","journal-title":"Acta Pharmacol. 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