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Original Article

Antimony-Based Antileishmanial Compounds Prolong the Cardiac Action Potential by an Increase in Cardiac Calcium Currents

Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio (Y.A.K., L.W., X.W., E.F.); and ChanXpress, Inc., Cleveland, Ohio (B.A.W.)

Abstract

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/I_Kr 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/I_Kr currents but—for the first time—by an increase in cardiac calcium currents.

Address correspondence to: Dr. Eckhard Ficker, Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. E-mail: eficker{at}metrohealth.org