Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking (original) (raw)
Research ArticleCARDIOVASCULAR
, Eckhard Ficker, Lu Wang, Peter Hawryluk, Adrienne T. Dennis, Barbara A. Wible, Arthur M. Brown, Jiesheng Kang, Xiao-Liang Chen, Kaoru Sawamura, William Reynolds and David Rampe
Journal of Pharmacology and Experimental Therapeutics January 2005, 312 (1) 316-323; DOI: https://doi.org/10.1124/jpet.104.073692
Abstract
The diamidine pentamidine is used to treat leishmaniasis, trypanosomiasis, and Pneumocystis carinii pneumonia. Treatment may be accompanied by prolongation of the QT interval of the electrocardiogram and torsades de pointes tachycardias. Up to now, it has been thought that therapeutic compounds causing QT prolongation are associated with direct block of the cardiac potassium channel human ether a-go-go-related gene (hERG), which encodes the α subunit of cardiac _I_Kr currents. We show that pentamidine has no acute effects on currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents and the guinea pig cardiac action potential were also not affected. After overnight exposure, however, pentamidine reduced hERG currents and inhibited trafficking and maturation of hERG with IC50 values of 5 to 8 μM similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 μM pentamidine by about 30, 40, and 70%, respectively. These effects were specific for hERG since expression of hKv1.5, KvLQT1/minK, and Kv4.3 was not altered. In isolated guinea pig ventricular myocytes, 10 μM pentamidine prolonged action potential duration APD90 from 374.3 ± 57.1 to 893.9 ± 86.2 ms on overnight incubation. _I_Kr tail current density was reduced from 0.61 ± 0.09 to 0.39 ± 0.04 pA/pF. We conclude that pentamidine prolongs the cardiac action potential by block of hERG trafficking and reduction of the number of functional hERG channels at the cell surface. We propose that pentamidine, like arsenic trioxide, produces QT prolongation and torsades de pointes in patients by inhibition of hERG trafficking.
Footnotes
This work was supported by the National Institutes of Health Grants HL71789 and CA106028 (to E.F.) and HL36930 and HL55404 (to A.M.B.).
doi:10.1124/jpet.104.073692.
ABBREVIATIONS: TdP, torsades de pointes; hERG, human ether a-go-go-related gene; _I_Kr, rapidly activating delayed rectifier K current; ER, endoplasmic reticulum; HA, hemagglutinin; HEK, human embryonic kidney; APD, action potential duration.
- Received July 5, 2004.
- Accepted August 31, 2004.
The American Society for Pharmacology and Experimental Therapeutics
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