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

Ivana Y. Kuo, Anthie Ellis, Victoria A. Seymour, Shaun L. Sandow, Caryl E. Hill

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    67 Citations (Scopus)

    Abstract

    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 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.

    Original languageEnglish
    Pages (from-to)1226-1239
    Number of pages14
    JournalJournal of Cerebral Blood Flow and Metabolism
    Volume30
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

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