Document Detail


Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia.
MedLine Citation:
PMID:  22689747     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Obstructive sleep apnea, a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for stroke and dementia, but the mechanisms of the effect are unknown. We tested the hypothesis that CIH increases cerebrovascular risk by altering critical mechanisms regulating cerebral blood flow thereby lowering cerebrovascular reserves. Male C57Bl6/J mice were subjected to CIH (10% O(2) for 90 seconds/room air for 90 seconds; during sleep hours) or sham treatment for 35 days. Somatosensory cortex blood flow was assessed by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure (from 74±2 to 83±3 mm Hg; P<0.05) and attenuated the blood flow increase produced by neural activity (whisker stimulation; -39±2%; P<0.05) or neocortical application of endothelium-dependent vasodilators (acetylcholine response: -41±3%; P<0.05). The cerebrovascular dysfunction was associated with oxidative stress in cerebral resistance arterioles and was abrogated by free radical scavenging or NADPH oxidase inhibition. Furthermore, cerebrovascular dysfunction and free radical increase were not observed in mice lacking the NOX2 subunit of NADPH oxidase. CIH markedly increased endothelin 1 in cerebral blood vessels, whereas cerebrovascular dysfunction and oxidative stress were abrogated by neocortical application of the endothelin type A receptor antagonist BQ123. These data demonstrate for the first time that CIH alters key regulatory mechanisms of the cerebral circulation through endothelin 1 and NADPH oxidase-derived radicals. The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain's susceptibility to cerebral ischemia.
Authors:
Carmen Capone; Giuseppe Faraco; Christal Coleman; Colin N Young; Virginia M Pickel; Josef Anrather; Robin L Davisson; Costantino Iadecola
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-11
Journal Detail:
Title:  Hypertension     Volume:  60     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-15     Completed Date:  2012-09-07     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  106-13     Citation Subset:  IM    
Affiliation:
Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylcholine / pharmacology
Animals
Anoxia / blood,  metabolism,  physiopathology*
Antihypertensive Agents / pharmacology
Aspartic Acid Endopeptidases / genetics,  metabolism
Blood Pressure / drug effects,  physiology
Cerebrovascular Circulation / drug effects,  physiology*
Chronic Disease
Endothelin-1 / blood,  metabolism*
Enzyme-Linked Immunosorbent Assay
Laser-Doppler Flowmetry
Male
Membrane Glycoproteins / deficiency,  genetics
Metalloendopeptidases / genetics,  metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase / deficiency,  genetics
Peptides, Cyclic / pharmacology
Reactive Oxygen Species / metabolism
Receptors, Endothelin / antagonists & inhibitors,  genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Somatosensory Cortex / blood supply*,  drug effects,  metabolism
Vasodilator Agents / pharmacology
Grant Support
ID/Acronym/Agency:
HL96571/HL/NHLBI NIH HHS; NS73666/NS/NINDS NIH HHS; P01 HL096571/HL/NHLBI NIH HHS; R01 HL063887/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Endothelin-1; 0/Membrane Glycoproteins; 0/Peptides, Cyclic; 0/Reactive Oxygen Species; 0/Receptors, Endothelin; 0/Vasodilator Agents; 136553-81-6/cyclo(Trp-Asp-Pro-Val-Leu); 51-84-3/Acetylcholine; EC 1.6.3.1/Cybb protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.71/endothelin-converting enzyme
Comments/Corrections
Comment In:
Hypertension. 2012 Jul;60(1):22-4   [PMID:  22689744 ]

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


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