The prolonged exposure to microgravity (MG) or simulated MG (SMG) has been reported to cause hypotension, mainly due to reduced vascular contractility, and dysregulation of fluid and electrolyte balance. However, the mechanism(s) involved in these MG- or SMG-induced effects is(are) not yet completely elucidated. Hence, we investigated in the rat the effect of prolonged (15-day) SMG, in the form of hindlimb unweighting, on renin-angiotensin-aldosterone system (RAAS), as well as on atrial natriuretic peptide (ANP) and adrenomedullin (ADM), two hypotensive peptides which play a major role in the regulation of RAAS activity by inhibiting adrenal aldosterone secretion. SMG caused a mild hypotension in rats, associated by the blockade of body-wt gain. Plasma aldosterone concentration and basal and agonist-stimulated in vitro aldosterone secretion from adrenal slices were decreased, and PRA was moderately increased. Neither Na+ and K+ serum concentrations nor ACTH and corticosterone blood levels were significantly affected. Plasma ANP concentration did not display significant alterations, while ADM blood concentration underwent a marked rise. The administration of the ADM-receptor antagonist ADM(22-52) during the last three days of hindlimb unweighting reversed the SMG-induced hypotension and hypoaldosteronism. Collectively, these findings allow us to suggest that prolonged SMG impairs RAAS activity in rats, through a mechanism probably involving upregulation of ADM system. Both hypoaldosteronism and increased ADM secretion may contribute to the development of hypotension during prolonged exposure to SMG.