Although experimental evidence supports peripheral osmoreceptor modulation of arginine vasopressin (AVP) release, a local osmotic signal required for osmoreceptor activation has yet to be identified using physiological sodium loads. Additionally, the central pathway involved in peripheral control of AVP has not been clearly established. Experiments were conducted to examine the effect of intragastric saline on portal venous osmolarity, plasma AVP (P(AVP)), and Fos immunoreactivity. In anesthetized rats, intragastric infusion (2.9 ml) of hypertonic (600 mosM) saline significantly increased portal venous osmolarity while systemic blood osmolarity remained constant. In conscious rats, intragastric hypertonic saline significantly elevated P(AVP) (3.6 +/- 1.3 to 5.8 +/- 1.9 pg/ml), whereas no changes were observed in plasma osmolarity in either the isotonic (296.2 +/- 1.4 to 297.6 +/- 1.1 mosM) or hypertonic (291.7 +/- 1.7 to 291.4 +/- 1.8 mosM) group. Finally, intragastric hypertonic saline significantly increased Fos immunoreactivity in the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPBN), supraoptic nucleus (SON), and paraventricular nucleus (PVN). These results indicate that intragastric hypertonic saline produces a portal venous osmotic signal that triggers peripheral osmoreceptors to stimulate AVP release while activating the NTS, AP, and LPBN in addition to the SON and PVN.