These experiments were designed to assess the ability of the new nonpeptide angiotensin II antagonist DuP 753 to inhibit the binding and, particularly, to antagonize the cellular response to angiotensin II in human platelets and primary cultures of rat aortic smooth muscle cells (SMC). The binding of 125I-angiotensin II was competitively inhibited by DuP 753 with a 50% binding inhibition (IC50) of 5 to 6 x 10(-8) mol/L in platelets and 1 x 10(-8) mol/L in vascular SMC as compared to an IC50 of 5 to 7.5 x 10(-9) mol/L with nonlabeled angiotensin II. In vascular SMC, DuP 753 completely abolished the effects of angiotensin II on 45CaCl2 efflux and 45CaCl2 uptake. Moreover, in these latter cells, DuP 753 prevented the angiotensin II but not the vasopressin induced increase in cytosolic calcium. These results demonstrate that DuP 753 competes with angiotensin II binding to its receptor in both animal and human cells and selectively blocks the cellular response to angiotensin II.