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

• Published in: Molecular pharmacology 2006-04, Vol.69 (4), p.1216-1225
• Main Authors: Kuryshev, Yuri A, Wang, Lu, Wible, Barbara A, Wan, Xiaoping, Ficker, Eckhard
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Antimony - adverse effects; Antimony - pharmacology; Antimony - therapeutic use; Antiprotozoal Agents - adverse effects; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Calcium - metabolism; Cell Line; Ether-A-Go-Go Potassium Channels - genetics; Humans; Leishmaniasis, Visceral - drug therapy; Long QT Syndrome - chemically induced; Myocardium - metabolism; Torsades de Pointes - chemically induced
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.105.019281

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 As 2 O 3 , 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 (IC 50 , 11.8 μM) and inhibits hERG maturation on Western blots (IC 50 , 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 APD 90 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.