Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 579, Issue 1-3, Pages 98-103Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2007.10.051
Keywords
antihypertensive drug; apoptosis; congestive heart failure; doxazosin; hERG channel; potassium channel
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Funding
- NHLBI NIH HHS [R01 HL071789, R01 HL071789-04] Funding Source: Medline
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The antihypertensive drug doxazosin has been associated with an increased risk for congestive heart failure and cardiomyocyte apoptosis. Human ether-a-go-go-related gene (hERG) K+ channels, previously shown to be blocked by doxazosin at therapeutically relevant concentrations, represent plasma membrane receptors for the antihypertensive drug. To elucidate the molecular basis for doxazosin-associated pro-apoptotic effects, cell death was studied in human embryonic kidney cells using three independent apoptosis assays. Doxazosin specifically induced apoptosis in hERG-expressing HEK cells, while untransfected control groups were insensitive to treatment with the antihypertensive agent. An unexpected biological mechanism has emerged: binding of doxazosin to its novel membrane receptor, hERG, triggers apoptosis, possibly representing a broader pathophysiological mechanism in drug-induced heart failure. (C) 2007 Elsevier B.V. All rights reserved.
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