No abstract

This study was undertaken to investigate the biological activity of the cyclic amide-linked analogue of angiotensin II (ANG II), [Sar~,Lys3,GIuS]ANG II, in both ex vivo and in vivo experiments. This constrained analogue was designed on the basis of a recently suggested conformational model for ANG II-induced receptor activation, which is characterized by a Tyr-Ile-His backbone bend and the clustering of the three aromatic rings (Tyr, His, Phe). After [Sarl,Lys3,GluS]ANG II was found to have contractile activity (-15% of ANG II in the rat uterus assay), it was administered in anesthetized rabbits where it produced an immediate and dose-dependent increase in blood pressure, which peaked within minutes, was sustained as long as the drug was given, and was gradually returned to baseline after discontinuation of the drip. The blood pressure response to the cyclic analogue was of less magnitude compared to that elicited by an isovolemic and equimolar solution of ANG II. These data confirm the importance of a properly oriented ring cluster, allowing the charge-relay conformation proposed for ANG II.