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Article: Therapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation

TitleTherapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation
Authors
KeywordsEndothelial nitric oxide synthase
Mesenteric artery
Myogenic tone
Raloxifene
Selective estrogen receptor modulator
Issue Date2010
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642
Citation
Arteriosclerosis, Thrombosis, And Vascular Biology, 2010, v. 30 n. 5, p. 992-999 How to Cite?
AbstractObjective-: Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries.Methods and results-: Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca]i images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N-nitro-l-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca]i and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca]i and in eNOS phosphorylation were prevented by removal of extracellular Ca ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca]i, eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Conclusion-: Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca]i in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation. © 2010 American Heart Association, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/133496
ISSN
2015 Impact Factor: 5.969
2015 SCImago Journal Rankings: 3.356
ISI Accession Number ID
Funding AgencyGrant Number
RGC EarmarkedCUHK 4362/04M
465308
CUHK Focused Investment Scheme
CUHK Li Ka Shing Institute of Health Sciences
Funding Information:

This study was supported by an RGC Earmarked grant (CUHK 4362/04M and 465308), CUHK Focused Investment Scheme, and the CUHK Li Ka Shing Institute of Health Sciences.

References

 

DC FieldValueLanguage
dc.contributor.authorChan, YCen_HK
dc.contributor.authorLeung, FPen_HK
dc.contributor.authorWong, WTen_HK
dc.contributor.authorTian, XYen_HK
dc.contributor.authorYung, LMen_HK
dc.contributor.authorLau, CWen_HK
dc.contributor.authorTsang, SYen_HK
dc.contributor.authorYao, Xen_HK
dc.contributor.authorChen, ZYen_HK
dc.contributor.authorHuang, Yen_HK
dc.date.accessioned2011-05-16T08:28:32Z-
dc.date.available2011-05-16T08:28:32Z-
dc.date.issued2010en_HK
dc.identifier.citationArteriosclerosis, Thrombosis, And Vascular Biology, 2010, v. 30 n. 5, p. 992-999en_HK
dc.identifier.issn1079-5642en_HK
dc.identifier.urihttp://hdl.handle.net/10722/133496-
dc.description.abstractObjective-: Selective estrogen receptor modulators (SERMs) inhibit constriction of mammalian conduit arteries. However, it is unknown whether SERMs at therapeutically achievable concentrations could reduce vascular tone in resistance arteries. The present study aimed to examine roles of Ca influx in endothelium and endothelial nitric oxide synthase (eNOS) activation in dilatations induced by raloxifene, a second-generation SERM in myogenically active arteries.Methods and results-: Small mesenteric arteries from Sprague-Dawley rats were isolated and mounted in a pressure myograph for measurement of changes in vessel diameter. [Ca]i images on native endothelial cells of intact arteries were determined by the fluorescence imaging technique, and phosphorylation of eNOS was assayed by Western blotting. Raloxifene (0.3 to 10 nmol/L) produced dilatations on established steady myogenic constriction. Female rat arteries dilated significantly more in response to raloxifene than male arteries. Raloxifene-induced dilatations of female arteries were blunted by N-nitro-l-arginine methyl ester but unaffected by 1400W, charybdotoxin plus apamin, wortmannin, or LY294002. Raloxifene (3 nmol/L) triggered rises in endothelial cell [Ca]i and increased eNOS phosphorylation at Ser1177. Both effects were greater in arteries from female rats than in arteries from male rats. Increases in endothelial cell [Ca]i and in eNOS phosphorylation were prevented by removal of extracellular Ca ions. Finally, ICI 182,780 did not affect the raloxifene-stimulated rise in endothelial cell [Ca]i, eNOS phosphorylation, and vasodilatations. Chronic raloxifene treatment reduced myogenic constriction in arteries from female but not male rats. Conclusion-: Raloxifene at therapeutically relevant concentrations inhibits myogenic constriction by an NO-dependent mechanism that causally involves the elevated [Ca]i in endothelial cells and subsequent eNOS activation. Raloxifene dilates resistance arteries more effectively in female rats, indicating its significant gender-related action on endothelial cells in microcirculation. © 2010 American Heart Association, Inc.en_HK
dc.languageeng-
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.lww.com/product/?1079-5642en_HK
dc.relation.ispartofArteriosclerosis, Thrombosis, and Vascular Biologyen_HK
dc.subjectEndothelial nitric oxide synthaseen_HK
dc.subjectMesenteric arteryen_HK
dc.subjectMyogenic toneen_HK
dc.subjectRaloxifeneen_HK
dc.subjectSelective estrogen receptor modulatoren_HK
dc.subject.meshCalcium Signaling - drug effects-
dc.subject.meshMesenteric Arteries - drug effects - enzymology-
dc.subject.meshNitric Oxide Synthase Type III - antagonists and inhibitors - metabolism-
dc.subject.meshRaloxifene - pharmacology-
dc.subject.meshSelective Estrogen Receptor Modulators - pharmacology-
dc.titleTherapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1079-5642&volume=30&issue=5&spage=992&epage=999&date=2010&atitle=Therapeutically+relevant+concentrations+of+raloxifene+dilate+pressurized+rat+resistance+arteries+via+calcium-dependent+endothelial+nitric+oxide+synthase+activation-
dc.identifier.emailChan, YC:yauchi@graduate.hku.hken_HK
dc.identifier.authorityChan, YC=rp01502en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1161/ATVBAHA.110.203935en_HK
dc.identifier.pmid20185791en_HK
dc.identifier.scopuseid_2-s2.0-77951454070en_HK
dc.identifier.hkuros172188-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77951454070&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume30en_HK
dc.identifier.issue5en_HK
dc.identifier.spage992en_HK
dc.identifier.epage999en_HK
dc.identifier.isiWOS:000276677700016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridChan, YC=7403676116en_HK
dc.identifier.scopusauthoridLeung, FP=8615375300en_HK
dc.identifier.scopusauthoridWong, WT=35932584500en_HK
dc.identifier.scopusauthoridTian, XY=35768379500en_HK
dc.identifier.scopusauthoridYung, LM=13807768200en_HK
dc.identifier.scopusauthoridLau, CW=7401968520en_HK
dc.identifier.scopusauthoridTsang, SY=7102255908en_HK
dc.identifier.scopusauthoridYao, X=7402529434en_HK
dc.identifier.scopusauthoridChen, ZY=7409487061en_HK
dc.identifier.scopusauthoridHuang, Y=7501573013en_HK

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