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      The Effect of High Extracellular Potassium on IKr Inhibition by Anti-Arrhythmic Agents

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          Abstract

          Background: Hyperkalemia is a potentially life-threatening disorder frequently occurring in hospitalized patients. The ischemic myocardium releases potassium into the extracellular space which can cause regional hyperkalemia. These changes may modify the effects of anti-arrhythmic drugs acting on the rapid component of the delayed rectifier potassium current (IKr). We evaluated the influence of increased extracellular potassium concentration [K<sup>+</sup>]<sub>e</sub> on IKr inhibition by amiodarone, azimilide, dofetilide, quinidine and sotalol. Methods and Results: Experiments were performed at room temperature. IKr current was studied by using HERG gene expressed in Xenopus oocytes as a model of cardiac IKr. Two-electrode voltage clamp technique was employed. The recording bath solutions contained either 5 or 10 mmol/l KCl. Amiodarone, azimilide, dofetilide, quinidine and sotalol all produced a dose-dependent inhibition of HERG current. At 5 mmol/l [K<sup>+</sup>]<sub>e</sub>, the IC<sub>50</sub> was 37.0 ± 12.5 µ M for amiodarone, 5.8 ± 0.4 µ M for azimilide, 1.5 ± 0. 2 µ M for dofetilide, 9.1 ± 1.5 µ M for quinidine, and 5.1 ± 0.8 m M for sotalol. Raising the extracellular potassium to 10 mmol/l, HERG block by azimilide, dofetilide, quinidine and sotalol was significantly decreased, while the block by amiodarone was unchanged. The differences in the percentage current block produced by 3 µ M drugs at 5 and 10 mmol/l [K<sup>+</sup>]<sub>e</sub> were: –0.9% for amiodarone, 13.8% for quinidine, 20.5% for azimilide, and 16.2% for dofetilide. The differences in percentage block between 5 and 10 mmol/l [K<sup>+</sup>]<sub>e</sub> by sotalol 10 and 30 m M were 7.1 and 5.6%. At 10 mmol/l [K<sup>+</sup>]<sub>e</sub>, the IC<sub>50</sub> was increased for azimilide, dofetilide, quinidine and sotalol but not for amiodarone; the IC<sub>50</sub> was 24.7 ± 7.4 µ M for amiodarone, 29.3 ± 3.9 µ M for azimilide, 2.7 ± 0.2 µ M for dofetilide, 27.6 ± 4.0 µ M for quinidine, and 7.2 ± 1.7 m M for sotalol. Conclusion: Inhibition of IKr by azimilide, quinidine, dofetilide and sotalol was diminished by increasing [K<sup>+</sup>]<sub>e</sub>, while the inhibition by amiodarone was unchanged at normal and high [K<sup>+</sup>]<sub>e</sub>. The differential effects of azimilide, dofetilide, quinidine and sotalol at normal and high [K<sup>+</sup>]<sub>e</sub> could be pro-arrhythmic by favoring re-entry arrhythmias. These results further support the unique electrophysiological effect of amiodarone.

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          Most cited references 19

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          HERG, a human inward rectifier in the voltage-gated potassium channel family

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            Hyperkalaemia in patients in hospital.

            Significant hyperkalaemia occurred in 406 out of 29 063 patients admitted to a major Scottish teaching hospital in one year (1.4%). Mortality was higher in these patients than in control patients and was strongly correlated with the severity of the hyperkalaemia. Overall seven deaths were directly due to hyperkalaemia (out of 58 deaths among patients with hyperkalaemia). Factors contributing to a poor prognosis were severity and speed of onset of hyperkalaemia and the presence of appreciable renal impairment. Patients with hyperkalaemia were older and more likely to be male; this trend was present in all diagnostic subcategories. Genitourinary disease, gastrointestinal disease, and cancer were significantly more common among the patients with hyperkalaemia than the controls. Hyperkalaemia due to drug treatment was invariably mild and non-fatal, whereas genitourinary disease was often associated with moderate to severe hyperkalaemia, which in two cases proved fatal. Use of electrocardiographic monitoring was rare, and although the treatment of hyperkalaemia was effective, it was often used when not required. Hyperkalaemia is a potential hazard in diabetic ketoacidosis, and use of potassium supplements should be carefully monitored during correction of the acidosis.
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              Hyperkalemia in Hospitalized Patients

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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2007
                June 2007
                08 September 2006
                : 108
                : 1
                : 18-27
                Affiliations
                Department of Pharmacology, Rush University Medical Center, Chicago, Ill., USA
                Article
                95596 Cardiology 2007;108:18–27
                10.1159/000095596
                16960444
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, Tables: 1, References: 29, Pages: 10
                Categories
                Original Research

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