We studied the responses of the hypothalamo-neurohypophysial system to intravenous infusions of 18% saline, 25% mannitol and a combination of 15% mannitol and 1.35% saline in conscious, chronically catheterized Long-Evans rats. Infusions of 18% saline and 25% mannitol produced similar increases in plasma osmolality (Posm) and plasma vasopressin-associated neurophysin concentration ([VP-RNP]). As expected, plasma sodium concentration ([Na+]) for the 18% saline-treated animals was significantly elevated while that for the 25% mannitol-treated animals was significantly reduced. Mannitol infusion caused a significantly greater loss of body weight. The slopes of the relationship between Δ[VP-RNP] and ΔPosm were almost identical for the two groups. Infusion of a combination of 15% mannitol and 1.35% saline produced a rise in Posm comparable to that observed for the other two infusion regimens, but caused smaller increases in [VP-RNP], the slope of the relationship between Δ[VP-RNP] and ΔPosm being about half of those for the infusion with 18% saline or 25% mannitol. This combination also maintained [Na+] close to normal levels and in these animals there was a loss of body weight that was significantly smaller than that for those rats receiving 25% mannitol. The results of this study imply that factors other than osmoreceptors and/or sodium receptors are involved in causing a release of neurohypophysial principles during acute infusion of hypertonic soluti