I read with great interest the Review by He and MacGregor (Role of salt intake in prevention of cardiovascular disease: controversies and challenges. Nat. Rev. Cardiol. 15, 371–377; 2018)1 in which they put forward a very convincing case for populations in all countries of the world to decrease their salt — or rather sodium — intake in order to reduce the risk of cardiovascular disease, as demonstrated in the many clinical trials cited in the article. The Review is very comprehensive, but physiology seems to have been overlooked.

A. C. Guyton stated that “the control of sodium concentration in the intact state is accomplished mainly by the [antidiuretic hormone] (ADH)–thirst feedback mechanism” (refs2,3). Furthermore, “increased salt intake results in increased thirst; therefore, a proportionate amount of water is consumed to match the salt” (ref.4). Guyton and colleagues talk about the need to drink water with sodium intake, but at no point in the Review by He and MacGregor is water intake mentioned. The appropriate physiological responses to increased plasma levels of sodium (that is, increased osmolality) are thirst and release of ADH (also known as vasopressin). A thirst-induced increase in fluid intake leads, initially, to an increase in blood volume, which persists until urine and sodium excretion return volume and osmolality to the normal range following reduced release of ADH and the sodium-retaining hormone aldosterone. Guyton’s work was in dogs, but the regulation of hydromineral balance is not known to differ between mammalian species, especially between rats and dogs (in which much work has been performed to understand the mechanisms of this complex regulation) and humans5.

A clinical trial showed that a diet high in salt normally increases blood pressure and decreases plasma renin activity and aldosterone levels in the blood and urine6. Similar results with appropriate fluid intake have been observed in rats7. However, in humans, increased fluid intake does not seem to occur with increased sodium intake, and this hypohydration affects both the intracellular and especially the extracellular fluid compartments, the latter being associated with hypovolaemia. The physiological mechanisms regulating decreased volume are thirst; ADH, angiotensin, and aldosterone release; and salt appetite mediated by a central synergistic action of the released angiotensin and aldosterone8. These two hormones continue to be released and salt consumed unless blood volume is restored by increased drinking.

Interestingly, the majority of medications used to combat cardiovascular disease are blockers of the renin–angiotensin system9 and, more recently, antagonists of aldosterone10. However, according to normal physiology, increased salt intake should already have decreased the levels of these two hormones. Knowing that the physiology of hydromineral balance regulation is similar in most mammals, this observation suggests that humans are chronically, but mildly, hypohydrated.

In conclusion, physiological regulation suggests that no matter how much dietary sodium intake is reduced, angiotensin and aldosterone will continue to be released — and salt intake and cardiovascular disease propagated — unless blood volume is restored. The part of physiological regulation that is often overlooked is that blood volume can very effectively be restored by drinking appropriate quantities of water.