Alveolar hypoxia (AH) induces widespread systemic inflammation. Previous studies have shown dissociation between microvascular PO₂ and inflammation. Furthermore, plasma from AH rats (PAHR) induces mast cell (MC) activation, inflammation, and vasoconstriction in normoxic cremasters, while plasma from normoxic rats does not produce these responses. These results suggest that inflammation of AH is triggered by a blood-carried mediator. This study investigates the involvement of the renin-angiotensin system (RAS) in the inflammation of AH. Both an angiotensin converting enzyme (ACE) inhibitor and an angiotensin II (ANG II) receptor blocker (ANGIIRB) inhibited the leukocyte-endothelial adherence produced by AH, as well as the inflammation produced by PAHR in normoxic rat cremasters. MC stabilization with cromolyn blocked the effects of PAHR but not those of topical ANGII on normoxic cremasters, suggesting ANGII generation via MC activation by PAHR. This was supported by the observation that ACE inhibition and ANGIIRB blocked the leukocyte endothelial adherence produced by the MC secretagogue c48/80. These results suggest that the mediator contained in PAHR activates MC and stimulates the RAS leading to inflammation, and imply an RAS role in AH-induced inflammation