The synthesis of an angiotensin II (A II) antagonist, 8arcosyl1-cy8teinyl(S-methyl)8-angio- tensin II [Sar1-Cys(Me)8-A II], showing partial organ selectivity and properties of a noncompetitive antagonist, is described. The compound was found to be an extremely potent antagonist on vascular smooth muscle both in vitro (pA2for rabbit aorta s 9.2) and in vivo on rat blood pressure (dose ratio of 103 for ED25mm Hg during 1 fig/kg per min infusion of antagonist). It was without effect on norepinephrine responses in both assay systems. In contrast, it was a considerably weaker antagonist on visceral smooth muscle (pA2for guinea pig ileum = 8.5; pA2for rat uterus = 7.9). Interestingly, in the vascular smooth muscle preparations, the compound also exhibited elements of a noncompetitive antagonist in that both the slope and maximum of the A II dose-response curves were reduced markedly. Qualitatively similar results were obtained with sarcosyl1-alanyl8-angiotensin II (Saralasin) on rabbit aorta. Moderate depression of maximum response was seen in guinea pig ileum but not in rat uterus. These effects on vascular smooth muscle were reversible in vitro but only partially reversible in vivo. Circ Res 46: 720-725, 1980