RT Journal Article SR Electronic T1 Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1216 OP 1225 DO 10.1124/mol.105.019281 VO 69 IS 4 A1 Yuri A. Kuryshev A1 Lu Wang A1 Barbara A. Wible A1 Xiaoping Wan A1 Eckhard Ficker YR 2006 UL http://molpharm.aspetjournals.org/content/69/4/1216.abstract AB Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases that includes 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 human ether a-go-go related gene (hERG) trafficking and an increase of cardiac calcium currents. In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC50, 11.8 μM) and inhibits hERG maturation on Western blots (IC50, 62 μM). Therapeutic concentrations of 0.3 μM PAT increase cardiac calcium currents from -4.8 ± 0.7 to -7.3 ± 0.5 pA/pF at 10 mV. 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 long-term exposure to 30 μM 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 10 mV 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.