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(Circulation Research. 2005;96:419.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Emergence of a R-Type Ca²⁺ Channel (Ca_V 2.3) Contributes to Cerebral Artery Constriction After Subarachnoid Hemorrhage

Masanori Ishiguro, Theresa L. Wellman, Akira Honda, Sheila R. Russell, Bruce I. Tranmer, George C. Wellman

From the Department of Pharmacology (M.I., T.L.W., A.H., G.C.W.), University of Vermont College of Medicine, Burlington, Vt; Department of Neurosurgery (M.I.), Sapporo Medical University, Sapporo, Japan; and the Department of Surgery (S.R.R., B.L.T., G.C.W.), Division of Neurological Surgery, University of Vermont College of Medicine, Burlington, Vt.

Correspondence to George C. Wellman, PhD, University of Vermont, Department of Pharmacology, Given Building, 89 Beaumont Ave, Burlington, VT 05405–0068. E-mail george.wellman{at}uvm.edu

Cerebral aneurysm rupture and subarachnoid hemorrhage (SAH) inflict disability and death on thousands of individuals each year. In addition to vasospasm in large diameter arteries, enhanced constriction of resistance arteries within the cerebral vasculature may contribute to decreased cerebral blood flow and the development of delayed neurological deficits after SAH. In this study, we provide novel evidence that SAH leads to enhanced Ca²⁺ entry in myocytes of small diameter cerebral arteries through the emergence of R-type voltage-dependent Ca²⁺ channels (VDCCs) encoded by the gene Ca_V 2.3. Using in vitro diameter measurements and patch clamp electrophysiology, we have found that L-type VDCC antagonists abolish cerebral artery constriction and block VDCC currents in cerebral artery myocytes from healthy animals. However, 5 days after the intracisternal injection of blood into rabbits to mimic SAH, cerebral artery constriction and VDCC currents were enhanced and partially resistant to L-type VDCC blockers. Further, SNX-482, a blocker of R-type Ca²⁺ channels, reduced constriction and membrane currents in cerebral arteries from SAH animals, but was without effect on cerebral arteries of healthy animals. Consistent with our biophysical and functional data, cerebral arteries from healthy animals were found to express only L-type VDCCs (Ca_V 1.2), whereas after SAH, cerebral arteries were found to express both Ca_V 1.2 and Ca_V 2.3. We propose that R-type VDCCs may contribute to enhanced cerebral artery constriction after SAH and may represent a novel therapeutic target in the treatment of neurological deficits after SAH.

Key Words: calcium channels • vascular smooth muscle • cerebral arteries • subarachnoid hemorrhage • _1E

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