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dc.contributor.authorIvy, Jessica R.
dc.contributor.authorOosthuyzen, Wilna
dc.contributor.authorPeltz, Theresa S.
dc.contributor.authorHowarth, Amelia R.
dc.contributor.authorHunter, Robert W.
dc.contributor.authorDhaun, Neeraj
dc.contributor.authorAl-Dujaili, Emad A. S.
dc.contributor.authorWebb, David J.
dc.contributor.authorDear, James W.
dc.contributor.authorFlatman, Peter W.
dc.contributor.authorBailey, Matthew A.
dc.date.accessioned2018-06-29T21:33:32Z
dc.date.available2018-06-29T21:33:32Z
dc.date.issued2016-03-07
dc.identifierER4331
dc.identifier.citationIvy, J., Oosthuyzen, W., Peltz, T., Howarth, A., Hunter, R., Dhaun, N., Al-Dujaili, E., Webb, D., Dear, J., Flatman, P. & Bailey, M. (2016) Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive CotransporterNovelty and Significance, Hypertension, vol. 67, , pp. 1029-1037,
dc.identifier.issn0194-911X
dc.identifier.urihttp://doi.org/10.1161/HYPERTENSIONAHA.115.06977
dc.identifier.urihttps://eresearch.qmu.ac.uk/handle/20.500.12289/4331
dc.description.abstractBlood pressure (BP) normally dips during sleep, and nondipping increases cardiovascular risk. Hydrochlorothiazide restores the dipping BP profile in nondipping patients, suggesting that the NaCl cotransporter, NCC, is an important determinant of daily BP variation. NCC activity in cells is regulated by the circadian transcription factor per1. In vivo, circadian genes are entrained via the hypothalamic-pituitary-adrenal axis. Here, we test whether abnormalities in the day:night variation of circulating glucocorticoid influence NCC activity and BP control. C57BL6/J mice were culled at the peak (1:00 AM) and trough (1:00 PM) of BP. We found no day:night variation in NCC mRNA or protein but NCC phosphorylation on threonine53 (pNCC), required for NCC activation, was higher when mice were awake, as was excretion of NCC in urinary exosomes. Peak NCC activity correlated with peak expression of per2 and bmal1 (clock genes) and sgk1 and tsc22d3 (glucocorticoid-responsive kinases). Adrenalectomy reduced NCC abundance and blunted the daily variation in pNCC levels without affecting variation in clock gene transcription. Chronic corticosterone infusion increased bmal1, per1, sgk1, and tsc22d3 expression during the inactive phase. Inactive phase pNCC was also elevated by corticosterone, and a nondipping BP profile was induced. Hydrochlorothiazide restored rhythmicity of BP in corticosterone-treated mice without affecting BP in controls. Glucocorticoids influence the day:night variation in NCC activity via kinases that control phosphorylation. Abnormal glucocorticoid rhythms impair NCC and induce nondipping. Night-time dosing of thiazides may be particularly beneficial in patients with modest glucocorticoid excess.
dc.format.extent1029-1037
dc.publisherAmerican Heart Association
dc.relation.ispartofHypertension
dc.titleGlucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive CotransporterNovelty and Significance
dc.typearticle
dcterms.accessRightsnone
dc.description.facultysch_die
dc.description.volume67
dc.identifier.doihttp://doi:10.1161/HYPERTENSIONAHA.115.06977
dc.description.ispublishedpub
dc.description.eprintid4331
rioxxterms.typearticle
refterms.dateAccepted2016-02-08
qmu.authorAl-Dujaili, Emad A. S.
dc.description.statuspub
dc.description.number5


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