Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents.
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 microM) and inhibits hERG maturation on Western blots (IC50, 62 microM). Therapeutic concentrations of 0.3 microM 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 microM 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.
Kuryshev
Yuri A
YA
Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
Wang
Lu
L
Wible
Barbara A
BA
Wan
Xiaoping
X
Ficker
Eckhard
E
D000200:Action Potentials / Q000187:drug effects*; D000965:Antimony / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008133:Long QT Syndrome / Q000139:chemically induced; D009206:Myocardium / Q000378:metabolism*; D016171:Torsades de Pointes / Q000139:chemically induced
D000981:Antiprotozoal Agents; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D000965:Antimony; D002118:Calcium