Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA144

Poster Communications

Impairment of pressure natriuresis in a mouse model of ACTH-dependent Cushing Syndrome

H. M. Costello1, K. Stewart1, N. K. Jones1, D. Livingstone1, N. Dhaun1, M. A. Bailey1

1. Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Abnormal activation of the hypothalamic-pituitary-adrenocortical axis increases circulating glucocorticoids (cortisol in humans, corticosterone in rodents) to cause metabolic and electrolyte abnormalities. Hypertension is a common feature of ACTH excess. We have previously used a mouse model of ACTH-dependent Cushing Syndrome to show that increased blood pressure (BP) is associated with enhanced ENaC-mediated sodium reabsorption in the distal nephron (1). In the present study, we used this model to determine whether ACTH-excess altered the acute pressure diuresis and natriuresis response, i.e. the positive relationship between arterial pressure and renal sodium and water excretion. Osmotic minipumps were implanted s.c. into adult male C57BL/6J mice under isoflurane anaesthesia, delivering ACTH (2.5µg/d; n=6) or saline (n=6) for 10-12 days. Mice were then anaesthetised with Inactin (120mg/kg IP) and isotonic saline containing FITC-inulin (0.25%w/v) infused (0.3ml/h/10g) through the jugular vein. BP was measured via the carotid artery. A laparotomy was performed and ligatures loosely tied around the isolated mesenteric and coeliac arteries and the distal aorta. Urine was collected from the bladder. After a 30 minute baseline period, the mesenteric and coeliac arteries were ligated to induce a rise in BP. After 30 minutes of urine collection the aorta was ligated to further increase BP and urine again collected. Data are mean±SEM. BP was higher in ACTH-treated mice (98±3mmHg) than in controls (81±3mmHg; p=0.001, Student's t test, n=6 per group). The sequential ligation of arteries significantly increased BP in both groups (p<0.0001, 2way ANOVA). The first ligation increased BP by 37mmHg in ACTH and by 44mmHg in vehicle; aortic ligation further increased BP by 38mmHg (ACTH) and 33mmHg (vehicle). The applied increased BP induced a significant diuresis in both groups of mice, but this was less extensive in the ACTH group, particularly in the final period when urine flow rate was ~50% that of control mice (ACTH=10.6±1.6µl/min/gkw vs vehicle=21.1±3.5µl/min/gkw. p=0.0005, 2way ANOVA with Holm-Sidak's post hoctest, n=5/6 per group). Similarly, the sequential rise in pressure caused a significant increase in sodium excretion but the natriuresis was suppressed in the ACTH group (ACTH=2.9±0.6µmol/min vs vehicle= 7.8±2.3µmol/min. p=0.01, 2way ANOVA with Holm-Sidak's post hoctest, n=5/6 per group). Glomerular filtration rate did not change significantly with BP in either group, consistent with intact renal autoregulation. These data show that chronic glucocorticoid excess impairs the acute natriuretic and diuretic response to increased BP. The underlying mechanisms have not been investigated but sustained tubular sodium reabsorption is indicated.

Where applicable, experiments conform with Society ethical requirements