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Article: Disruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings

TitleDisruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular rings
Authors
KeywordsEndothelium
Inos
Nitric oxide
Prostacyclin
Issue Date2011
PublisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpregu.physiology.org
Citation
American Journal Of Physiology - Regulatory Integrative And Comparative Physiology, 2011, v. 301 n. 2, p. R412-R420 How to Cite?
AbstractIt was hypothesized that a serial stimulation of vascular cyclooxygenase-2 (COX-2) with subsequent activation of endothelial nitric oxide synthase (eNOS) is responsible for decrease in blood pressure, cardiac performance, and vascular reactivity in endotoxemia caused by LPS. The hypothesis was tested in catheterized, conscious, freely moving, wild-type mice and mice (C57BL/6J background) with targeted deletion of COX-2 and eNOS that were given an intravenous LPS bolus (2 mg/kg, 055:B5). In vitro studies were performed on murine aorta rings. LPS caused a concomitant decrease in mean arterial blood pressure (MAP) and heart rate (HR) that was significant after 3 h and was sustained throughout the experiment (8 h). The LPS-induced changes in MAP and HR were not different from control in COX-2 -/- and eNOS -/- mice. A prostacyclin receptor antagonist (BR5064) blocked the hypotensive effect of a prostacyclin agonist (beraprost), but did not attenuate the LPSinduced decrease in MAP and HR. LPS decreased eNOS and neuronal NOS mRNA abundances in several organs, while inducible NOS mRNA was enhanced. In aortic rings, LPS suppressed α1-adrenoceptor- mediated vascular tone. Inhibition of COX-2 activity (NS 398), disruption of COX-2, endothelium removal, or eNOS deletion (eNOS -/-) did not improve vascular reactivity after LPS, while the NO synthase blockers 1400W and NG-nitro-L-arginine methyl ester prevented loss of tone. COX-2 and eNOS activities are not necessary for LPS-induced decreases in blood pressure, heart rate, and vascular reactivity. Inducible NOS activity appears crucial. COX-2 and eNOS are not obvious therapeutic targets for cardiovascular rescue during gram-negative endotoxemic shock. © 2011 the American Physiological Society.
Persistent Identifierhttp://hdl.handle.net/10722/139596
ISSN
2015 Impact Factor: 3.168
2015 SCImago Journal Rankings: 1.663
ISI Accession Number ID
Funding AgencyGrant Number
The Danish Heart Association
The Novo Nordisk Foundation
The Danish Research Council for Health and Disease
The Danish Cardiovascular Research Academy
Leo Pharma's Hypertensionslegat
Funding Information:

This work was supported by The Danish Heart Association, The Novo Nordisk Foundation, The Danish Research Council for Health and Disease, The Danish Cardiovascular Research Academy, and Leo Pharma's Hypertensionslegat.

References

 

DC FieldValueLanguage
dc.contributor.authorStæhr, Men_HK
dc.contributor.authorMadsen, Ken_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorHansen, PBen_HK
dc.contributor.authorJensen, BLen_HK
dc.date.accessioned2011-09-23T05:52:22Z-
dc.date.available2011-09-23T05:52:22Z-
dc.date.issued2011en_HK
dc.identifier.citationAmerican Journal Of Physiology - Regulatory Integrative And Comparative Physiology, 2011, v. 301 n. 2, p. R412-R420en_HK
dc.identifier.issn0363-6119en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139596-
dc.description.abstractIt was hypothesized that a serial stimulation of vascular cyclooxygenase-2 (COX-2) with subsequent activation of endothelial nitric oxide synthase (eNOS) is responsible for decrease in blood pressure, cardiac performance, and vascular reactivity in endotoxemia caused by LPS. The hypothesis was tested in catheterized, conscious, freely moving, wild-type mice and mice (C57BL/6J background) with targeted deletion of COX-2 and eNOS that were given an intravenous LPS bolus (2 mg/kg, 055:B5). In vitro studies were performed on murine aorta rings. LPS caused a concomitant decrease in mean arterial blood pressure (MAP) and heart rate (HR) that was significant after 3 h and was sustained throughout the experiment (8 h). The LPS-induced changes in MAP and HR were not different from control in COX-2 -/- and eNOS -/- mice. A prostacyclin receptor antagonist (BR5064) blocked the hypotensive effect of a prostacyclin agonist (beraprost), but did not attenuate the LPSinduced decrease in MAP and HR. LPS decreased eNOS and neuronal NOS mRNA abundances in several organs, while inducible NOS mRNA was enhanced. In aortic rings, LPS suppressed α1-adrenoceptor- mediated vascular tone. Inhibition of COX-2 activity (NS 398), disruption of COX-2, endothelium removal, or eNOS deletion (eNOS -/-) did not improve vascular reactivity after LPS, while the NO synthase blockers 1400W and NG-nitro-L-arginine methyl ester prevented loss of tone. COX-2 and eNOS activities are not necessary for LPS-induced decreases in blood pressure, heart rate, and vascular reactivity. Inducible NOS activity appears crucial. COX-2 and eNOS are not obvious therapeutic targets for cardiovascular rescue during gram-negative endotoxemic shock. © 2011 the American Physiological Society.en_HK
dc.languageengen_US
dc.publisherAmerican Physiological Society. The Journal's web site is located at http://intl-ajpregu.physiology.orgen_HK
dc.relation.ispartofAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiologyen_HK
dc.subjectEndotheliumen_HK
dc.subjectInosen_HK
dc.subjectNitric oxideen_HK
dc.subjectProstacyclinen_HK
dc.titleDisruption of COX-2 and eNOS does not confer protection from cardiovascular failure in lipopolysaccharide-treated conscious mice and isolated vascular ringsen_HK
dc.typeArticleen_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1152/ajpregu.00823.2010en_HK
dc.identifier.pmid21543636-
dc.identifier.scopuseid_2-s2.0-79961087496en_HK
dc.identifier.hkuros193157en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79961087496&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume301en_HK
dc.identifier.issue2en_HK
dc.identifier.spageR412en_HK
dc.identifier.epageR420en_HK
dc.identifier.isiWOS:000293382300016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridStæhr, M=53982165800en_HK
dc.identifier.scopusauthoridMadsen, K=7102516941en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridHansen, PB=35472646600en_HK
dc.identifier.scopusauthoridJensen, BL=35502338900en_HK

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