We studied pharmacologic profiles of KRH-594, dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4 -thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarb oxylate, a novel angiotensin II (AII)-receptor antagonist. KRH-594 potently displaced specific binding of [125I]-AII from AT1 receptor with a Ki of 0.39 nM in rat liver membranes, but not from AT2 receptor in bovine cerebellar membranes (Ki > 10 microM). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 microM], demonstrating its high specificity toward AT1 receptors. In isolated rabbit aorta, KRH-594 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response with a pK(B) of 10.4. We evaluated the in vivo efficacy and the duration of action in freely moving rats under nonfasting conditions. In normotensive rats, orally administered KRH-594 inhibited AII-induced pressor responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensive rats (SHRs), both KRH-594 (1 mg/kg p.o.) and losartan (10 mg/kg p.o.) exerted similar blood pressure-reducing effects, and their effects were still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT1 antagonist that may find its use in the treatment of human hypertension.