This Article Full Text Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: 50/4/643    most recent HYPERTENSIONAHA.107.096057v1 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 Dong, D.-L. Articles by Wang, W.-H. Search for Related Content PubMed PubMed Citation Articles by Dong, D.-L. Articles by Wang, W.-H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL CARBON MONOXIDE NITRIC OXIDE Related Collections Hypertension - basic studies Ion channels/membrane transport Endothelium/vascular type/nitric oxide Other Vascular biology

(Hypertension. 2007;50:643.)
© 2007 American Heart Association, Inc.

Original Articles

Carbon Monoxide Stimulates the Ca²⁺–Activated Big Conductance K Channels in Cultured Human Endothelial Cells

De-Li Dong; Yan Zhang; Dao-Hong Lin; Jun Chen; Susann Patschan; Michael S. Goligorsky; Alberto Nasjletti; Bao-Feng Yang; Wen-Hui Wang

From the Department of Pharmacology (D.-L.D., B.-F.Y.), Harbin Medical University, Harbin, China; and the Departments of Pharmacology (D.-L.D., Y.Z., D.-H.L., A.N., W.-H.W.) and Medicine (J.C., S.P., M.S.G.), New York Medical College, Valhalla, NY.

Correspondence to Wen-Hui Wang, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail wenhui_wang{at}nymc.edu

We used the whole-cell patch-clamp technique to study K channels in the human umbilical vein endothelial cells and identified a 201 pS K channel, which was blocked by tetraethylammonium and iberiotoxin but not by TRAM34 and apamin. This suggests that the Ca²⁺-activated big-conductance K channel (BK) is expressed in endothelial cells. Application of carbon monoxide (CO) or tricarbonylchloro(glycinato)ruthenium(II), a water soluble CO donor, stimulated the BK channels. Moreover, application of hemin, a substrate of heme oxygenase, mimicked the effect of CO and increased the BK channel activity. The stimulatory effect of hemin was significantly diminished by tin mesoporphyrin, an inhibitor of heme oxygenase. To determine whether the stimulatory effect of CO on the BK channel was mediated by NO and the cGMP-dependent pathway, we examined the effect of CO on BK channels in cells treated with, N^G-nitro-L-arginine methyl ester, 1H(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, or KT5823, an inhibitor of protein kinase G. Addition of either diethylamine NONOate or sodium nitroprusside significantly increased BK channel activity. Inhibition of endogenous NO synthesis with N^G-nitro-L-arginine methyl ester, blocking soluble guanylate cyclase or protein kinase G, delayed but did not prevent the CO-induced activation of BK channels. Finally, application of an antioxidant agent, ebselen, had no effect on CO-mediated stimulation of BK channels in human umbilical vein endothelial cells. We conclude that BK channels are expressed in human umbilical vein endothelial cells and that they are activated by both CO and NO. CO activates BK channels directly, as well as via a mechanism involving NO or the cGMP-dependent pathway.

Key Words: heme oxygenase • NO • cGMP • reactive oxygen species • K channel

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