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An elevation in plasma osmolality elicits a complex neurohumoral response, including an activation of the sympathetic nervous system and an increase in arterial pressure. Using a combination of in vivo and in situ rat preparations, we sought to investigate whether hypothalamic vasopressinergic spinally projecting neurones are activated during increases in plasma osmolality to elicit sympathoexcitation. Hypertonic saline (HS, i.v. bolus), which produced a physiological increase in plasma osmolality to 299 ± 1 mosmol (kg water)⁻¹, elicited an immediate increase in mean arterial pressure (MAP) (from 101 ± 1 to 121 ± 3 mmHg) in vivo. Pre‐treatment with prazosin reversed the HS‐induced pressor response to a hypotensive response (from 121 ± 3 to 68 ± 2 mmHg), indicating significant activation of the sympathetic nervous system. In an in situ arterially perfused decorticate rat preparation, hyperosmotic perfusate …