|Openers of SKCa and IKCa channels enhance agonist-evoked endothelial nitric oxide synthesis and arteriolar vasodilation.|
|PMID: 19074509 Owner: NLM Status: MEDLINE|
|Recent data have led us to hypothesize that selective activation of endothelial small- and/or intermediate-conductance, calcium-activated potassium channels (SK(Ca) and IK(Ca) channels, respectively) by the opener compounds NS309 and DCEBIO would augment stimulated nitric oxide (NO) synthesis and vasodilation in resistance arteries. Experimentally, ATP-evoked changes in membrane potential, cytosolic Ca(2+), and NO synthesis were recorded by patch clamp and microfluorimetry in single human endothelial cells. Agonist-evoked inhibition of myogenic tone in isolated, pressurized arterioles from rat cremaster skeletal muscle was analyzed by video microscopy. NS309 and DCEBIO enhanced ATP-evoked membrane hyperpolarization and cytosolic Ca(2+) transients, along with acute NO synthesis in isolated endothelial cells. The acetylcholine-mediated inhibition of myogenic tone (IC(50)=237 nM) was left-shifted in the presence of NS309 and DCEBIO (10, 100, and 1000 nM) to IC(50) values of 101, 78, and 43 nM; endothelial denudation inhibited this drug effect. L-NAME attenuated the acetylcholine-induced inhibition of myogenic tone but did not interfere with NS309 and DCEBIO-evoked vasodilation. Collectively, our data demonstrate that drug-induced enhancement of endothelial SK(Ca) and IK(Ca) channel activities represents a novel cellular mechanism to increase vasodilation of small-resistance arterioles, thereby highlighting these channels as potential therapeutic targets in cardiovascular disease states associated with compromised NO signaling.|
|Jian-zhong Sheng; Srikanth Ella; Michael J Davis; Michael A Hill; Andrew P Braun|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-12-12|
|Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 23 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2009 Apr|
|Created Date: 2009-04-01 Completed Date: 2009-05-01 Revised Date: 2012-02-15|
Medline Journal Info:
|Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States|
|Languages: eng Pagination: 1138-45 Citation Subset: IM|
|Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.|
|APA/MLA Format Download EndNote Download BibTex|
Adenosine Triphosphate / pharmacology
Arterioles / drug effects, metabolism
Benzimidazoles / pharmacology*
Calcium / metabolism
Cytosol / metabolism
Dose-Response Relationship, Drug
Endothelial Cells / drug effects, metabolism
Ethylamines / metabolism
Fluoresceins / metabolism
Indoles / pharmacology*
Inhibitory Concentration 50
Membrane Potentials / drug effects
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / biosynthesis*
Oximes / pharmacology*
Potassium Channels, Calcium-Activated / agonists, metabolism*
Small-Conductance Calcium-Activated Potassium Channels / agonists, metabolism*
Vasodilation / drug effects*, physiology
|0/3-amino-4-monomethylamino-2',7'-difluorofluorecein; 0/5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; 0/6,7-dichloro-1H-indole-2,3-dione 3-oxime; 0/Benzimidazoles; 0/Ethylamines; 0/Fluoresceins; 0/Indoles; 0/Oximes; 0/Potassium Channels, Calcium-Activated; 0/Small-Conductance Calcium-Activated Potassium Channels; 10102-43-9/Nitric Oxide; 50903-99-6/NG-Nitroarginine Methyl Ester; 51-84-3/Acetylcholine; 56-65-5/Adenosine Triphosphate; 7440-70-2/Calcium|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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