Document Detail


Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery.
MedLine Citation:
PMID:  21323904     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Cerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (K(v) 7) potassium channels in rat basilar artery myocytes, and determined the efficacy of K(v) 7 channel activators in relieving spasmogen-induced basilar artery constriction.
EXPERIMENTAL APPROACH: Expression and function of K(v) 7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to K(v) 7 channel modulators were studied in intact artery segments using pressure myography.
KEY RESULTS: All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. K(v) currents were attributed to K(v) 7 channel activity based on their voltage dependence of activation (V(0.5) ∼-34 mV), lack of inactivation, enhancement by flupirtine (a selective K(v) 7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective K(v) 7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced K(v) 7 currents but also inhibited voltage-sensitive Ca(2+) currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca(2+) channel blocker.
CONCLUSIONS AND IMPLICATIONS: K(v) 7 channels are important determinants of basilar artery contractile status. Targeting the K(v) 7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm.
LINKED ARTICLES: To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x.
Authors:
Bharath K Mani; Lioubov I Brueggemann; Leanne L Cribbs; Kenneth L Byron
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  164     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-02     Completed Date:  2012-04-16     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  237-49     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Animals
Basilar Artery / drug effects,  physiopathology
Electrophysiology
Gene Expression Regulation / physiology
KCNQ Potassium Channels / agonists*
Male
Membrane Potentials / drug effects
Myocytes, Smooth Muscle / drug effects,  physiology
Nimodipine / pharmacology*
Pyrazoles / pharmacology*
Rats
Rats, Sprague-Dawley
Sulfonamides / pharmacology*
Vasoconstrictor Agents / pharmacology*
Vasodilator Agents / pharmacology
Vasospasm, Intracranial / drug therapy*
Grant Support
ID/Acronym/Agency:
R01 HL089564/HL/NHLBI NIH HHS; R01 HL089564-04/HL/NHLBI NIH HHS; R01-HL089564/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/KCNQ Potassium Channels; 0/Pyrazoles; 0/Sulfonamides; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 169590-42-5/celecoxib; 57WA9QZ5WH/Nimodipine
Comments/Corrections
Comment In:
Br J Pharmacol. 2011 Sep;164(2):250-1; author reply 252-3   [PMID:  21518334 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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