Brain receptor binding and central actions of angiotensin analogs in rats

The possible physiological importance of brain receptors for angiotensin was investigated. Structure-activity relationships were established for 12 fragments and analogs of angiotensin II (ANG II). 1) Affinities of the peptides were determined in an in vitro assay of rat brain angiotensin receptors. 2) Blood pressure (BP) and water intake following intracerebroventricular administration of the peptides to conscious rats were monitored. In vitro, ANG II and des-Asp1ANG II displayed the highest affinities. Trp1ANG II and Trp8ANG II had one-eighth and one-ninth the affinity of ANG II, respectively. Multiple substitutions in positions 1, 4, and 8 produced a 1,000-fold fall in binding affinity. Excellent correlation was found between the in vitro binding affinities and the in vivo central activities of the peptides on BP (r = 0.975) and on water intake (r = 0.900). The results suggest that the biochemically characterized brain angiotensin receptors may be physiologically relevant to BP and body fluid homeostasis. The brain angiotensin receptors mediating BP and thirst have very similar structural requirements.