This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 99/11/1252    most recent 01.RES.0000250821.32324.e1v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ishiguro, M. Articles by Wellman, G. C. Search for Related Content PubMed PubMed Citation Articles by Ishiguro, M. Articles by Wellman, G. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 4-AMINOPYRIDINE Related Collections Cerebrovascular disease/stroke Calcium cycling/excitation-contraction coupling Ion channels/membrane transport Cerebral Aneurysm, AVM, & Subarachnoid hemorrhage Other Vascular biology

(Circulation Research. 2006;99:1252.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Oxyhemoglobin-Induced Suppression of Voltage-Dependent K⁺ Channels in Cerebral Arteries by Enhanced Tyrosine Kinase Activity

Masanori Ishiguro, Anthony D. Morielli, Katarina Zvarova, Bruce I. Tranmer, Paul L. Penar, George C. Wellman

From the Department of Pharmacology (M.I., A.D.M., K.Z., G.C.W.); and Department of Surgery (B.I.T., P.L.P., G.C.W.), Division of Neurological Surgery, University of Vermont College of Medicine, Burlington.

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

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences. Oxyhemoglobin (oxyhb) has been implicated in SAH-induced cerebral vasospasm as it causes cerebral artery constriction and increases tyrosine kinase activity. Voltage-dependent, Ca²⁺-selective and K⁺-selective ion channels play an important role in the regulation of cerebral artery diameter and represent potential targets of oxyhb. Here we provide novel evidence that oxyhb selectively decreases 4-aminopyridine sensitive, voltage-dependent K⁺ channel (K_v) currents by 30% in myocytes isolated from rabbit cerebral arteries but did not directly alter the activity of voltage-dependent Ca²⁺ channels or large conductance Ca²⁺-activated (BK) channels. A combination of tyrosine kinase inhibitors (tyrphostin AG1478, tyrphostin A23, tyrphostin A25, genistein) abolished both oxyhb-induced suppression of K_v channel currents and oxyhb-induced constriction of isolated cerebral arteries. The K_v channel blocker 4-aminopyridine also inhibited oxyhb-induced cerebral artery constriction. The observed oxyhb-induced decrease in K_v channel activity could represent either channel block, or a decrease in K_v channel density on the plasma membrane. To explore whether oxyhb altered trafficking of K_v channels to the plasma membrane, we used an antibody generated against an extracellular epitope of K_v1.5 channels. In the presence of oxyhb, staining of K_v1.5 on the plasma membrane surface was markedly reduced. Furthermore, oxyhb caused a loss of spatial distinction between staining with K_v1.5 and the general anti-phosphotyrosine antibody PY-102. We propose that oxyhb-induced suppression of K_v currents occurs via a mechanism involving enhanced tyrosine kinase activity and channel endocytosis. This novel mechanism may contribute to oxyhb-induced cerebral artery constriction following SAH.

Key Words: voltage-dependent potassium channels • vascular smooth muscle • cerebral arteries • subarachnoid hemorrhage • oxyhemoglobin

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