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Bupivacaine Destabilizes Action Potential Duration in Cellular and Computational Models of Long QT Syndrome 1.
MedLine Citation:
PMID:  22003215     Owner:  NLM     Status:  Publisher    
Background:The effects of the local anesthetic bupivacaine on cardiac action potentials (APs) are mainly attributed to inhibition of cardiac Na(+) channels. The relevance of its ability to also induce high-affinity blockade of human ether-à-gogo-related gene (hERG) channels is unclear. We investigated whether this interaction may functionally become more significant in cellular and computational models of long (L)QT syndromes.Methods:Left ventricular cardiomyocytes were isolated from adult guinea pig hearts, and bupivacaine-induced effects on APs were investigated using the patch-clamp technique. LQT-like states were pharmacologically induced by either blocking I(Ks) (LQT1-like, 10 μmol/L chromanol 293B), or I(Kr) (LQT2-like, 10 μmol/L E4031). Computational analysis of bupivacaine's effects was based on the Luo-Rudy dynamic model.Results:Bupivacaine induced dose-dependent AP shortening in control myocytes. However, in the presence of 1 to 30 μmol/L bupivacaine, a high variability in AP duration with AP prolongations of up to 40% was observed. This destabilizing effect on AP duration was significantly increased in LQT1-like but not in LQT2-like myocytes. Similarly, the incidence of AP prolongations in the presence of 3 μmol/L bupivacaine was significantly increased from 6% in control myocytes to 24% in LQT1-like but not in LQT2-like myocytes. Computational modeling supported the concept that this bupivacaine-induced AP instability and the AP prolongations in the control and LQT1-like myocytes were caused by inhibition of hERG channels.Conclusions:This study provides evidence that bupivacaine induces inhibition of hERG channels, which is functionally silent under normal conditions but will become more relevant in LQT1-like states in which repolarization relies to a larger degree on hERG channels. Interactions with ion channels other than cardiac Na(+) channels may, therefore, determine the net cardiac effects of bupivacaine when the normal balance of ionic currents is altered.
Alexander P Schwoerer; Roman Zenouzi; Heimo Ehmke; Patrick Friederich
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-10-14
Journal Detail:
Title:  Anesthesia and analgesia     Volume:  -     ISSN:  1526-7598     ISO Abbreviation:  -     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1310650     Medline TA:  Anesth Analg     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
From the *Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg; and.
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