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Dihydropyridine-insensitive calcium currents contribute to function of small cerebral arteries

Kuo, Ivana; Ellis, Anthie; Seymour, Victoria; Sandow, Shaun, L; Hill, Caryl

Description

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV 1.2) and T-type (Ca V 3.1 and CaV 3.2) channels in adult rat basilar and...[Show more]

dc.contributor.authorKuo, Ivana
dc.contributor.authorEllis, Anthie
dc.contributor.authorSeymour, Victoria
dc.contributor.authorSandow, Shaun, L
dc.contributor.authorHill, Caryl
dc.date.accessioned2015-12-07T22:16:39Z
dc.identifier.issn0271-678X
dc.identifier.urihttp://hdl.handle.net/1885/18123
dc.description.abstractAlthough dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV 1.2) and T-type (Ca V 3.1 and CaV 3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L-and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised 20% of current in SMCs of the main arteries and 45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.
dc.publisherNature Publishing Group
dc.sourceJournal of Cerebral Blood Flow and Metabolism
dc.subjectKeywords: calcium channel blocking agent; calcium channel L type; calcium channel T type; efonidipine; messenger RNA; mibefradil; nifedipine; nimodipine; nnc 550396; unclassified drug; animal tissue; arterial pressure; artery constriction; artery diameter; artery t Arterial size; Calcium channels; Cerebral vasoconstriction; Dihydropyridines; T-type channels
dc.titleDihydropyridine-insensitive calcium currents contribute to function of small cerebral arteries
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume30
dc.date.issued2010
local.identifier.absfor111501 - Basic Pharmacology
local.identifier.ariespublicationu4897219xPUB3
local.type.statusPublished Version
local.contributor.affiliationKuo, Ivana, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationEllis, Anthie, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationSeymour, Victoria, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationSandow, Shaun, L, University of New South Wales
local.contributor.affiliationHill, Caryl, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue6
local.bibliographicCitation.startpage1226
local.bibliographicCitation.lastpage1239
local.identifier.doi10.1038/jcbfm.2010.11
dc.date.updated2016-02-24T11:26:27Z
local.identifier.scopusID2-s2.0-77953137740
local.identifier.thomsonID000278267000015
CollectionsANU Research Publications

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