Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries

• Published in: Journal of cerebral blood flow and metabolism 2010-06, Vol.30 (6), p.1226-1239
• Main Authors: Kuo, Ivana Y, Ellis, Anthie, Seymour, Victoria AL, Sandow, Shaun L, Hill, Caryl E
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - metabolism; Calcium Channels, T-Type - metabolism; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cerebral Arteries - metabolism; Cerebral Arteries - ultrastructure; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Dihydropyridines - pharmacology; Fundamental and applied biological sciences. Psychology; Male; Medical sciences; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - ultrastructure; Neurology; Original; Rats; Rats, Wistar; Vascular diseases and vascular malformations of the nervous system; Vasoconstriction - drug effects; Vasoconstriction - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.11

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 (CaV1.2) and T-type (CaV3.1 and CaV3.2) 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.