1. We have shown previously that N-acetylcysteine (NAC) prevents the increase in blood pressure induced by adrenocorticotropin treatment. The present study investigated the effect of NAC on dexamethasone (Dex)-induced hypertension. 2. Male Sprague-Dawley rats were randomly divided into six groups (n = 10 in each). In a prevention study, NAC (10 g/L in the drinking water) was given for 4 days prior to and 11 days during concurrent treatment with saline (0.1 mL/rat per day) or with Dex (10 mg/rat per day). In a reversal study, daily injections of Dex or saline began 8 days before NAC and cotreatment continued for 5 days. Systolic blood pressure (SBP) was measured on alternate days using a tail-cuff system. 3. Dexamethasone significantly increased SBP from 113 +/- 4 to 139 +/- 6 mmHg (n = 10; P < 0.01). N-Acetylcysteine alone had no effect on SBP. In NAC + Dex-treated rats, SBP was significantly lower than that of Dex-treated rats (P cent < 0.01). In fully established Dex-hypertension NAC was ineffective and SBP remained high. 4. Both Dex and NAC treatments decreased bodyweight gain. N-Acetylcysteine reduced food and water consumption. Dexamethasone reduced thymus weight (P cent < 0.01) but NAC treatment did not alter this marker of glucocorticoid activity. 5. Dexamethasone tended to decrease plasma NO(x), whereas NAC restored plasma NO(x) concentrations to control levels. N-Acetylcysteine had no effect on Dex-induced increased plasma F(2)-isoprostane concentrations. 6. In conclusion, NAC partially prevented, but did not reverse, Dex-induced hypertension.