Mechanisms of Salt‐Sensitive Hypertension in a Mouse Model of ACTH‐Dependent Cushing Syndrome

Abstract

Salt‐sensitive blood pressure (BP) reflects underlying renal and vascular (endothelial) dysfunction. People with abnormal glucocorticoid homeostasis, such as in Cushing syndrome and obesity, are often salt‐sensitive but the underlying mechanisms are not clearly defined1,2. Here, we used a mouse model to examine the effect of ACTH excess on blood pressure and salt‐sensitivity. To test this, radio telemetry was used to track BP longitudinally and measure the effect of high salt diet before and after chronic ACTH treatment in C57BL/6J mice (n=6). Data are mean ± SD. After 7 days of baseline measurements, mean BP was 105.8 ± 6.5mmHg before being placed on a high salt diet (3 % Na+ by weight) for a further 7 days. BP increased ~12 mmHg over the first 3 days before declining to 113.1 ± 7.2mmHg. BP returned to 107.7 ± 10.4mmHg, similar to baseline, after a 5‐day washout period. Mice were then treated with ACTH (2.5μg/day). ACTH increased mean BP to 115.5 ± 5.0mmHg with a flattening of the diurnal rhythm following 13 days infusion. When placing these mice on a high salt diet, mean BP increased and stabilised to 136.1 ± 13.4mmHg after 14 days. These data show that chronic ACTH excess contributes to salt‐sensitivity. To investigate potential mechanisms of salt‐sensitivity, the acute pressure natriuresis (PN) response of renal artery function were examined in separate cohorts of mice treated with either vehicle or ACTH (2.5μg/day; n=6 per group) for 14 days. PN response was induced in anaesthesised mice (120mg/kg Inactin) by sequential arterial ligation. BP increased ~40mmHg following ligations in both vehicle and ACTH groups. In vehicle‐treated mice, fractional sodium excretion increased from 0.2 ± 0.2 to 5.0 ± 4.2μmol/min. The natriuretic response was significantly blunted in ACTH‐treated mice, reaching 2.1 ± 1.1μmol/min at its peak. We next investigated vascular function in ACTH‐excess ex vivo by wire myography in isolated mesenteric and renal arteries. Vascular reactivity to phenylephrine (PHE), acetylcholine (ACh) and sodium nitroprusside (SNP) was assessed. ACTH‐excess caused vascular dysfunction in the renal artery but not in the mesenteric artery. ACTH‐excess resulted in a reduction in sensitivity to vasoconstrictor PHE (p=0.0005) and endothelium dependent (ACh) and endothelium independent (SNP) vasodilators (p=0.0128 and p=0.0002, respectively). These data show that chronic glucocorticoid excess contributes to salt‐sensitivity with potential mechanisms behind this being impairment of the acute natriuretic and diuretic response to increased BP and renal vascular dysfunction.Support or Funding InformationSupported by British Heart Foundation PhD studentships FS/16/54/32730 & FS/15/63/32033.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.