title: Pentamidine-induced long QT syndrome and block of hERG trafficking.
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 alpha 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 IC(50) values of 5 to 8 microM similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 microM 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 microM pentamidine prolonged action potential duration APD(90) 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.
authors.affiliation: Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Kuryshev
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Hawryluk
authors.forename: Adrienne T
authors.initials: AT
authors.lastname: Dennis
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wible
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Brown
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Chen
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sawamura
authors.forename: William
authors.initials: W
authors.lastname: Reynolds
authors.forename: David
authors.initials: D
authors.lastname: Rampe
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006168:Guinea Pigs; D006801:Humans; D008133:Long QT Syndrome; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010419:Pentamidine / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated; D010419:Pentamidine