This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163 plus/minus 12 to 110 plus/minus 9 mm Hg, P < .05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 plus/minus 6 to 96 plus/minus 6 mm Hg, P < .05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156 plus/minus 9 to 132 plus/minus 5 mm Hg, P < .05) than in sham (104 plus/minus 3 to 94 plus/minus 4 mm Hg, P < .05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8 plus/minus 8.3 versus 95.7 plus/minus 10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42 plus/minus 1.58 versus 6.74 plus/minus 2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4 plus/minus 3.0 versus 26.0 plus/minus 2.4 ng Ang I/mL, P < .05) and in the artery wall of hypertensive conscious rats (103.1 plus/minus 10.3 versus 75.2 plus/minus 7.8 ng Ang I/g, P < .05). In summary, the central renin-angiotensin system does not seem to participate in the maintenance of high blood pressure in hypertensive animals. The enzymatic system present in the vascular wall appears to be activated in hypertensive rats. The hypotensive effect of EXP 3174 suggests that Ang II could be one of the factors involved in the maintenance of two-kidney, two clip hypertension. (Hypertension. 1995;25:283-287.)