Cardiovascular deconditioning occurs in astronauts after spaceflight or in individuals subjected to bed rest. It is often characterized by an increased incidence of orthostatic intolerance. The mechanisms responsible for orthostatic intolerance are likely multi-factorial and may include hypovolemia, autonomic dysfunction, vascular and cardiac alterations. The arterial baroreflex is an important compensatory mechanism in the response to an orthostatic stress. In a previous study, we demonstrated that arterial baroreflex mediated sympathoexcitation was blunted in hindlimb unloaded (HU) rats, a model of cardiovascular deconditioning. The arterial baroreflex also contributes to the regulation of vasoactive hormones including vasopressin and angiotensin II. In the present study we tested the hypothesis that the neurohumoral response to hypotension is also attenuated in rats after 14 days of hindlimb unloading. To test this hypothesis, the vasodilator diazoxide (15 or 25 mg/kg) or saline (0.9%) was administered to produce hypotension or control conditions, respectively, in conscious HU and control rats. Plasma samples were collected and assayed for vasopressin and plasma renin activity (PRA). Diazoxide (25 mg/kg) produced significant increases in vasopressin and PRA compared to saline controls. HU rats exhibited significantly higher levels of vasopressin at rest and the increase in vasopressin levels during hypotension was enhanced by hindlimb unloading. Neither resting nor hypotension induced plasma renin activity was altered by hindlimb unloading. These data suggest that although baroreflex mediated sympathoexcitation is blunted by hindlimb unloading, hypotension induced vasopressin release is enhanced and hypotension induced PRA is unaffected. Increased circulating vasopressin may serve to compensate for blunted baroreflex regulation of SNA produced by hindlimb unloading, or may actually contribute to it.