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First published on January 17, 2006; DOI: 10.1124/mol.105.019281

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Received for publication September 29, 2005.
Revised December 21, 2005.
Accepted for publication January 13, 2006.

Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents

Yuri A Kuryshev 1, Lu Wang 1, Barbara A Wible 2, Xiaoping Wan 1, Eckhard Ficker 3*

1 Case Western Reserve University 2 ChanXpress 3 MetroHealth Medical Center

* Address correspondence to: E-mail: eficker{at}metrohealth.org

Abstract

Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases including visceral leishmaniasis or kala-azar. Chemotherapy with trivalent potassium antimony tartrate (PAT) and, more importantly, pentavalent antimony-carbohydrate complexes such as sodium stibogluconate (SSG) has been reported to prolong the QT interval and produce life-threatening arrhythmias. PAT is chemically related to As2O3 which alters cardiac excitability by inhibition of hERG trafficking and an increase of cardiac calcium currents. Here we report that PAT does not block hERG currents on acute exposure but reduces current density on chronic exposure (IC50, 11.8µM) and inhibits hERG maturation on Western blots (IC50, 62µM). Therapeutic concentrations of 0.3µM PAT increase cardiac calcium currents from -4.8±0.7 pA/pF to -7.3±0.5 pA/pF at 10mV. In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/IKr or any other cardiac potassium current at therapeutic concentrations. However, both cardiac sodium and calcium currents were significantly increased on chronic exposure to 30µM SSG in isolated guinea pig ventricular myocytes. We propose that the increase in calcium currents from 3.2±0.3 to 5.1±0.3 pA/pF at 10mV prolongs APD90 from 464±35 to 892±64 ms. Our data suggest that conversion of Sb(V) into active Sb(III) in patients produces a common mode of action for antimonial drugs, which define a novel compound class that increases cardiac risk not by a reduction of hERG/IKr currents but -for the first time- by an increase in cardiac calcium currents.


Key words: Ion channel regulation, Calcium (Votage-Gated Channels), Sodium, Potassium, Structure/function/mechanism, Oxidative stress/antioxidants, Antiprotozoal drugs




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