Recent studies have shown that angiotensin converting enzyme (ACE) inhibitors attenuate ET-1 induced hypertension, but the mechanisms for this effect have not been clarified. Initial experiments were conducted to contrast the effect of the ACE inhibitor, enalapril, the combined ACE/neutral endopeptidase (NEP) inhibitor, omapatrilat, and the angiotensin II receptor antagonist, candesartan, on the hypertensive and renal response to ET-1 in anesthetized Sprague Dawley rats. Acute intravenous infusion of ET-1 (10 pmol/kg/min) for 60 min significantly increased mean arterial pressure (MAP) from 125±8 to 145±8 mmHg (P< 0.05) and significantly decreased GFR from 0.31±0.09 to 0.13±0.05 ml/min/100g kidney weight. Pretreatment with enalapril (10 mg/kg i.v) prior ET-1 infusion inhibited the increase in MAP (121±4 vs.126±4 mmHg before and during ET-1 infusion, respectively, P< 0.05) without blocking the effect of ET-1 on GFR. In contrast, neither omapatrilat (30 mg/kg) nor candesartan (10 mg/kg) had any effect on ET-1-induced increases in MAP or decreases in GFR. To determine whether the effect of enalapril was due to the decrease in angiotensin II or increase in kinin formation, rats were given REF000359 (1 mg/kg i.v), a selective B2 receptor antagonist with or without enalapril prior to ET-1 infusion. REF000359 completely blocked the effect of enalapril on ET-1 infusion (MAP was 117±5 vs. 135±5 mmHg before and during ET-1 infusion, respectively, P< 0.05). REF000359 alone had no effect on the response to ET-1 infusion (MAP was 117±4 vs.144±4 mmHg before and during ET-1 infusion, respectively, P< 0.05). REF000359 with or without enalapril had no significant effect on the ability of ET-1 infusion to decrease GFR. These findings support the hypothesis that decreased catabolism of bradykinin and its subsequent vasodilator activity oppose the actions of ET-1 to increase MAP.