Impaired Pressure Natriuresis and Non-Dipping Blood Pressure in Rats with Early Type 1 Diabetes Mellitus: Pressure natriuresis and BP in T1DM

Geoffrey J. Culshaw, Hannah M. Costello, David Binnie, Kevin R. Stewart, Alicja Czopek, Neeraj Dhaun, Patrick W.F. Hadoke, David J. Webb, Matthew A. Bailey

Research output: Contribution to journalArticlepeer-review

Abstract

Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45mg/kg) or citrate vehicle. After three weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ~1% to ~25% of the filtered load (P<0.01); in T1DM rats, the response was significantly blunted, peaking at only ~3% (P<0.01). Mechanistically, normal lithium clearance suggested that distal tubular sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure-dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure-dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. On radiotelemetry, T1DM did not affect systolic BP, but mean diastolic BP was ~5mmHg higher than in non-diabetic controls (P<0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.
Original languageEnglish
Article number597.3
Pages (from-to)767-780
JournalJournal of Physiology
Volume597
Issue number3
Early online date7 Dec 2018
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • hypertension
  • blood pressure
  • pressure natriuresis
  • experimental type 1 diabetes
  • sodium homeostasis
  • lithium clearance

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