Aldosterone is a steroid hormone produced by the adrenal cortex and functions as the body’s principal physiological salt-regulating hormone. Aldosterone excess leads to excessive sodium and water retention and, consequentially, increased blood pressure (BP). Furthermore, aldosterone is associated with target-organ deterioration and increased cardiovascular morbidity independently of its effects on BP. High dietary salt intake is not only associated with development of hypertension, but also aggravates hypertension that is already present. Experimental studies have indicated that the combination of aldosterone excess and high-salt ingestion is necessary for induction of target-organ damage. This thesis comprises studies on the BP effects of dietary sodium restriction in patients with resistant hypertension, the effect of salt in determining urinary protein excretion and changes in the left ventricular (LV) structure and the relationship between aldosterone and salt appetite in patients with primary aldosteronism (PA).
Salt and resistant hypertension
Twelve subjects with resistant hypertension entered into a randomized crossover evaluation of low (50 mmol/24-hr X 7 days) and high (250 mmol/24-hr for X 7 days) sodium diets separated by a 2-week washout period. Office and 24-hr ambulatory BP was compared between dietary treatment periods. Mean urinary sodium (UNa) excretion was 46.1±26.8 (SD) versus 252.2±64.6 mmol/24-hr during low- versus high-salt intake. Low- compared to high-salt diet decreased office systolic and diastolic BP by 22.7 and 9.1 mm Hg respectively.
Aldosterone, salt and urinary protein
Twenty-four subjects with aldosterone producing adenoma (APA) underwent measurement of 24-hr urinary protein (Uprot) and UNa before and after unilateral adrenalectomy (ADX - follow-up 15.0±11.9 months). Following surgery, mean clinic systolic BP fell (150.4±18.2 vs 134.5±14.5mmHg, p=0.0008), despite a reduction in number of antihypertensive medications, and Uprot (211.2±101.6 vs 106.0±41.8mg per day, P<0.0001) decreased. There was a positive correlation between Uprot and UNa both before (r=0.5477, p=0.0056) and after (r=0.5097, p=0.0109) ADX. Changes in UNa independently predicted Uprot reduction (p=0.0189).
Aldosterone, salt and LV hypertrophy
A case-control study included 21 patients with confirmed PA and 21 control patients with essential hypertension matched for age, gender, duration of hypertension and 24-hr systolic and diastolic BP. Patients were evaluated by echocardiography and UNa excretion while consuming their usual diets. Patients with PA had significantly greater mean LV wall thicknesses and LV mass than control patients. UNa significantly positively correlated with, and was an independent predictor of, LV wall thicknesses and LV mass in patients with PA, but not in control patients.
Aldosterone and salt appetite
We compared pre- and post-operative UNa, collected on the last day (day 4) of fludrocortisone suppression testing (FST) in 93 patients with APA before and after ADX. In 35 of these patients, we also analysed UNa collected out of hospital. For the total cohort of 93 patients, day 4 UNa decreased from 328.2±78.5 mmol/day pre-operatively to 271.5±69.1 mmol/day (p<0.0001) postoperatively despite equal salt supplementation. Out of hospital UNa fell from 172.1±57.2 to 146.9±55.7 mmol/day (p=0.0183) after ADX. Interestingly, on subgroup analysis, UNa on day 4 FST fell significantly only in patients whose FST after ADX showed biochemical cure of PA (n=78), but not in those whose FST showed any remaining autonomous aldosterone production (n=15).
These results indicate that excessive dietary sodium ingestion contributes importantly to resistance to antihypertensive treatment and that dietary salt modulates aldosterone-induced renal and cardiac damage in patients with PA. Our findings suggest that treatment strategies to substantially reduce dietary salt intake should be part of the overall treatment of resistant hypertension. Furthermore, in patients with PA, dietary salt restriction should provide additional target-organ protection to that afforded by reduction of aldosterone effects (by ADX or mineralocorticoid receptor blockade). This may be easier to achieve in treated patients as aldosterone reduction appears to reduce salt appetite.