Synthesis and pharmacology of a noncompetitive antagonist of angiotensin-induced contractions of vascular smooth muscle. [Sarcosyl]1-[cysteinyl (s-methyl)]8-angiotensin II.

The synthesis of an angiotensin II (A II) antagonist, sarcosyl1-cysteinyl(S-methyl)8-angiotensin 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 (pA2 for rabbit aorta approximately equal to 9.2) and in vivo on rat blood pressure (dose ratio of 103 for ED25 mm Hg during 1 microgram/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 (pA2 for guinea pig ileum = 8.5; pA2 for 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.