The Pressor and Myotropic Effects and the Antagonistic Properties of Several Analogues of Angiotensin II

The substitution of an unnatural amino acid, 1-aminocyclopentanecarboxylic acid (Acpc), for each of the eight amino acids of angiotensin (AT) has been used to study the relationship between chemical structure and biological activities of angiotensin. The pressor and the myotropic activities of the various AT II derivatives have been tested on the rat blood pressure and on three isolated organs: rat isolated colon, rat stomach strip, and rabbit isolated kidney.The results indicate that 6-His and 8-Phe are essential for the activities of angiotensin II. Moreover, (8-Acpc)-AT II , but not (6-Acpc)-AT II , antagonizes the pressor and myotropic effects of AT II and AT I . α E and pD 2 of all analogues have been estimated on the isolated rat stomach strip to evaluate intrinsic activity and affinity for the receptors. (1-, (2-, (3-, (4-, and (5-Acpc)-AT II have the same intrinsic activities as AT II , while those of (6-, (7-, and (8-Acpc)-AT II are much lower.Analogues of AT II substituted in position 8 antagonize specifically the myotropic and pressor effects of AT II and AT I . On the contrary, the effects of other smooth muscle stimulating agents (acetylcholine, 5-hydroxytryptamine, bradykinin, and vasopressin) are not modified.Log dose response curves of AT II and AT I are shifted to the right in the presence of antagonists, but remain parallel. The antagonism is rapidly reversible and may be competitive.