BACKGROUND Salt restriction, an important approach for primary and secondary prevention of hypertension, is undermined by unsatisfactory adherence. A salt-restriction study tested the efficacy and safety of a compound ion salt (CISalt) with low sodium content in an animal model and in a community-based population. METHODS In part 1, 8-week-old male spontaneously hypertensive rats (SHRs) were fed 1% CISalt in the study group and 8% or 1% normal salt (NSalt) in controls (n = 10 each) for 12 weeks. Blood pressure (BP) and urinary electrolytes were measured every 3 weeks. After 12 weeks, collagen deposition in the heart and kidney and the levels of angiotensin II (Ang II) and nitric oxide (NO) in plasma and renal cortex were measured. In part 2, a single-blind, randomized, 6-month controlled trial with CISalt was conducted in 248 persons (age >or=65 years) in 10 rural communities. Plasma renin activity and Ang II were included in blood and urinary measures at baseline and 6 months. RESULTS Reduced BP urinary protein excretion and reduced collagen in the heart and kidneys were significantly different in animals fed CISalt compared to controls. In human studies, at 6 months, mean systolic BP (SBP) was decreased by 9.6 mm Hg (95% confidence interval (CI): 13.1 to 6.1, P < 0.001) and diastolic BP (DBP) by 5.3 mm Hg (95% CI: 7.9 to 2.6, P < 0.001), respectively, compared to controls; urinary sodium excretion also decreased by 67.4 mmol/24 h (95% CI: 84.8 to 50.0, P < 0.001), and plasma renin activity was slightly increased by 0.19 ng/ml/h (95% CI: 0.04-0.33, P = 0.013). No adverse cardiovascular events were reported. CONCLUSIONS In these studies, CISalt lowered BP and showed end-organ protection in hypertensive animals and BP reduction in humans. CISalt appears to be a safe and acceptable strategy to reduce BP.