Document Detail

Downregulation of Kv7.4 channel activity in primary and secondary hypertension.
MedLine Citation:
PMID:  21747056     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3 structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals.
METHODS AND RESULTS: Precontracted thoracic aorta and mesenteric artery segments from normotensive rats were relaxed by all 3 Kv7 activators, with potencies of BMS-204352=S-1>retigabine. We also tested these agents in the coronary circulation using the Langendorff heart preparation. BMS-204352 and S-1 dose dependently increased coronary perfusion at concentrations between 0.1 and 10 μmol/L, whereas retigabine was effective at 1 to 10 μmol/L. In addition, S-1 increased K(+) currents in isolated mesenteric artery myocytes. The ability of these agents to relax precontracted vessels, increase coronary flow, or augment K(+) currents was impaired considerably in tissues isolated from spontaneously hypertensive rats (SHRs). Of the 5 KCNQ genes, only the expression of KCNQ4 was reduced (≈3.7 fold) in SHRs aorta. Kv7.4 protein levels were ≈50% lower in aortas and mesenteric arteries from spontaneously hypertensive rats compared with normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 were observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared with normotensive controls.
CONCLUSIONS: In 2 different rat and mouse models of hypertension, the functional impact of Kv7 channels was dramatically downregulated.
Thomas A Jepps; Preet S Chadha; Alison J Davis; Maksym I Harhun; Gillian W Cockerill; Søren P Olesen; Rie S Hansen; Iain A Greenwood
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-11
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-03     Completed Date:  2012-01-11     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  602-11     Citation Subset:  AIM; IM    
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MeSH Terms
Angiotensin II / pharmacology
Aorta, Thoracic / physiology
Blood Pressure / physiology
Carbamates / pharmacology
Down-Regulation / physiology
Hypertension / chemically induced,  physiopathology*
Indoles / pharmacology
KCNQ Potassium Channels / agonists,  physiology*
Membrane Potentials / drug effects,  physiology
Mesenteric Arteries / physiology
Phenylenediamines / pharmacology
Rats, Inbred SHR
Rats, Wistar
Vasoconstrictor Agents / pharmacology
Grant Support
BB/G016321/1//Biotechnology and Biological Sciences Research Council; FS/06/077//British Heart Foundation; PG/07/127/24235//British Heart Foundation; PG/09/104//British Heart Foundation; PG/09/104/28136//British Heart Foundation
Reg. No./Substance:
0/BMS204352; 0/Carbamates; 0/Indoles; 0/KCNQ Potassium Channels; 0/Kcnq4 protein, mouse; 0/Kcnq4 protein, rat; 0/Phenylenediamines; 0/Vasoconstrictor Agents; 11128-99-7/Angiotensin II; 12G01I6BBU/ezogabine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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