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Pentamidine-induced long QT syndrome and block of hERG trafficking.
J Pharmacol Exp Ther. 2005 Jan; 312(1):316-23.JP

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+Show Affiliations

Rammelkamp Center, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15340016

Citation

Kuryshev, Yuri A., et al. "Pentamidine-induced Long QT Syndrome and Block of hERG Trafficking." The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 1, 2005, pp. 316-23.
Kuryshev YA, Ficker E, Wang L, et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther. 2005;312(1):316-23.
Kuryshev, Y. A., Ficker, E., Wang, L., Hawryluk, P., Dennis, A. T., Wible, B. A., Brown, A. M., Kang, J., Chen, X. L., Sawamura, K., Reynolds, W., & Rampe, D. (2005). Pentamidine-induced long QT syndrome and block of hERG trafficking. The Journal of Pharmacology and Experimental Therapeutics, 312(1), 316-23.
Kuryshev YA, et al. Pentamidine-induced Long QT Syndrome and Block of hERG Trafficking. J Pharmacol Exp Ther. 2005;312(1):316-23. PubMed PMID: 15340016.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pentamidine-induced long QT syndrome and block of hERG trafficking. AU - Kuryshev,Yuri A, AU - Ficker,Eckhard, AU - Wang,Lu, AU - Hawryluk,Peter, AU - Dennis,Adrienne T, AU - Wible,Barbara A, AU - Brown,Arthur M, AU - Kang,Jiesheng, AU - Chen,Xiao-Liang, AU - Sawamura,Kaoru, AU - Reynolds,William, AU - Rampe,David, Y1 - 2004/08/31/ PY - 2004/9/2/pubmed PY - 2005/4/14/medline PY - 2004/9/2/entrez SP - 316 EP - 23 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 312 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15340016/Pentamidine_induced_long_QT_syndrome_and_block_of_hERG_trafficking_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15340016 DB - PRIME DP - Unbound Medicine ER -