Limits of brain tolerance to daily increments in serum sodium in chronically hyponatraemic rats treated with hypertonic saline or urea: advantages of urea. 1. At present there is no consensus about the optimal management of hyponatraemia to prevent demyelinating brain lesions. We have evaluated in a large series of rats (n = 136) the protective role of urea for the brain in the treatment of severe chronic hyponatraemia. Urea (group I, n = 51) was compared with hypertonic saline in boluses (group II, n = 46) and with hypertonic saline in divided doses (group III, n = 39). Treatment was administered intraperitoneally over 48 h. The severity of brain lesions was assessed by histological scoring. 2. For 95% of the injured animals treated with hypertonic saline, brain lesions appeared for an absolute increment in serum Na+ concentration (delta SNa+) of 20 mmol day-1 l-1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (delta SNa+ greater than or equal to 20 less than or equal to 23 mmol day-1 l-1) 89% (group III) to 100% (group II) of the animals were injured. This limit can be reached rapidly, as attested by the comparable severity of brain lesions observed in group II (mean delta SNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean delta SNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily delta SNa+. 3. A correction above the threshold of 20 mmol day-1 l-1 is as toxic during the first 24 h as during the second day of the treatment. 