Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter

Mar 9, 2016Hypertension (Dallas, Tex. : 1979)

Stress Hormones May Cause Nighttime Blood Pressure to Stay High by Activating a Salt Transporter

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Hydrochlorothiazide restores rhythmicity of blood pressure in mice with induced nondipping profiles.

Nondipping blood pressure is associated with increased cardiovascular risk.
NCC activity does not show day:night variation in mRNA or protein levels.
Phosphorylation of NCC is higher during wakefulness, correlating with the expression of specific clock genes.
Adrenalectomy decreases NCC levels and affects daily variation in NCC phosphorylation without altering clock gene transcription.
Chronic corticosterone infusion disrupts normal NCC activity and induces a nondipping blood pressure profile.
Night-time dosing of thiazides may benefit patients experiencing modest glucocorticoid excess.

AI simplified

Blood 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 threonine(53) (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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text ↗

Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief