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(Stroke. 2008;39:2122.)
© 2008 American Heart Association, Inc.

Original Contributions

Oxyhemoglobin-Induced Expression of R-Type Ca²⁺ Channels in Cerebral Arteries

Timothy E. Link, MD; Kentaro Murakami, PhD; Micah Beem-Miller, BS; Bruce I. Tranmer, MD George C. Wellman, PhD

From the Department of Surgery, Division of Neurosurgery (T.E.L., B.I.T., G.C.W.) and the Department of Pharmacology (K.M., M.B.-M., G.C.W.), University of Vermont College of Medicine, Burlington.

Correspondence to Dr George C. Wellman, Department of Pharmacology, University of Vermont College of Medicine, 86 Beaumont Ave, Burlington, VT 05405. E-mail George.Wellman{at}uvm.edu

Background and Purpose— Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major contributor to mortality and morbidity after aneurysm rupture. Recently, R-type voltage-dependent Ca²⁺ channel (VDCC) expression has been associated with increased cerebral artery constriction in a rabbit model of SAH. The goal of the present study was to examine whether the blood component oxyhemoglobin (oxyHb) can mimic the ability of SAH to cause R-type VDCC expression in the cerebral vasculature.

Methods— Rabbit cerebral arteries were organ cultured in serum-free media for up to 5 days in the presence or absence of purified oxyHb (10 µmol/L). Diameter changes in response to diltiazem, (L-type VDCC antagonist) and SNX-482 (R-type VDCC antagonist) were recorded at day 1, 3, or 5 in arteries constricted by elevated extracellular potassium. RT-PCR was performed on RNA extracted from arteries cultured for 5 days (±oxyHb) to assess VDCC expression.

Results— After 5 days, oxyHb-treated arteries were less sensitive and partially resistant to diltiazem compared to similar arteries organ cultured in the absence of oxyHb. Further, SNX-482 dilated arteries organ cultured for 5 days in the presence, but not in the absence, of oxyHb. RT-PCR revealed that oxyHb treated arteries expressed R-type VDCCs (Ca_V 2.3) in addition to L-type VDCCs (Ca_V 1.2), whereas untreated arteries expressed only Ca_V 1.2.

Conclusions— These results demonstrate that oxyhemoglobin exposure for 5 days induces the expression of Ca_V 2.3 in cerebral arteries. We propose that oxyhemoglobin contributes to enhanced cerebral artery constriction after SAH via the emergence of R-type VDCCs.

Key Words: calcium channels • cerebral arteries • subarachnoid hemorrhage • vasospasm • vascular smooth muscle

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