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The relative roles of alkalinization and increased sodium concentration ([Na<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>) for various drugs are incompletely known.<\/jats:p><jats:p><jats:italic>Methods and Results<\/jats:italic>The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equi-effective concentrations (disopyramide 30 \u03bcmol\/L, mexiletine 80 \u03bcmol\/L, flecainide 7 \u03bcmol\/L, imipramine 5 \u03bcmol\/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (V<jats:sub>max<\/jats:sub>) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>contributed to the interaction with flecainide and mexiletine. The reversal of V<jats:sub>max<\/jats:sub>depression by increased [Na<jats:sup>+<\/jats:sup>]<jats:sub>o<\/jats:sub>and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in V<jats:sub>max<\/jats:sub>inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine.<\/jats:p><jats:p><jats:italic>Conclusions<\/jats:italic>Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel\u2013blocking drugs.<\/jats:p>","DOI":"10.1161\/01.cir.94.8.1954","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:34:42Z","timestamp":1339461282000},"page":"1954-1961","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":60,"title":["Relative Role of Alkalosis and Sodium Ions in Reversal of Class I Antiarrhythmic Drug\u2013Induced Sodium Channel Blockade by Sodium Bicarbonate"],"prefix":"10.1161","volume":"94","author":[{"given":"Elias","family":"Bou-Abboud","sequence":"first","affiliation":[{"name":"the Department of Pharmacology, University of Montreal (E.B.-A., S.N.); the Department of Medicine, Montreal Heart Institute and University of Montreal, the Department of Pharmacology and Therapeutics, McGill University, and the Research Center of the Montreal Heart Institute (S.N.); Montreal, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Nattel","sequence":"additional","affiliation":[{"name":"the Department of Pharmacology, University of Montreal (E.B.-A., S.N.); the Department of Medicine, Montreal Heart Institute and University of Montreal, the Department of Pharmacology and Therapeutics, McGill University, and the Research Center of the Montreal Heart Institute (S.N.); Montreal, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM195810232591701"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-195902000-00005"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-195902000-00004"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X7300100302"},{"key":"e_1_3_2_5_2","first-page":"2277","volume":"48","year":"1968","unstructured":"Bismuth C, Bodin F, Pebay-Peroula F, Frejaville J-P. 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