Adrenal Medullary Stimulation Induced by Angiotensin I, Angiotensin II, and Analogues

A structure-activity relationship study was attempted to determine the structural specificity of the no. 8 amino acid residue of 1-asp,5-ileu-angiotensin II for adrenal medullary stimulation. Isolated cat adrenal glands were perfused retrograde at a flow rate of 1 ml/min with phosphate-buffered Locke's solution at 23 to 25 C. Continuous catecholamine analysis was performed using an automated trihydroxyindole procedure. All drugs were administered either by single injection (0.05 to 0.1 ml) or by perfusion. Angiotensin analogues studied were: 8-(OMe)tyr-angiotensin II; 8-tyr-angiotensin II; 8-ala-angiotensin II; 5-ileu,8-(3-amino-4-phenylbutyric acid)-angiotensin II (referred to as 8-APB-angiotensin II); 5-ileu,8-(DL-3-amino-3'-phenylisobutyric acid)-angiotensin II (referred to as 8-APIB-angiotensin II); 1-asp(NH 2 ),5-val-angiotensin II; 1-asp,5-ileu-angiotensin I; tetradecapeptide. Three peptides (angiotensin II, 8-tyr-angiotensin II, and 8-ala-angiotensin II) were studied in vivo for stimulation of adrenal catecholamine secretion. For maximum pressor activity, angiotensin must be an octapeptide with an aromatic amino acid and free COOH group in the no. 8 position. None of these three are structural requirements in adrenal chromaffin tissue. There was cross-tachyphylaxis between angiotensin II and all the analogues studied except two (8-APB- and 8-APIB-angiotensin II). In vitro studies with 10-leu-C 14 -angiotensin I and angiotensin II antibody indicated that angiotensin I has a marked, direct stimulatory effect on the adrenal medulla. Adrenal medullary catecholamine secretion induced by angiotensin I and II was greatly potentiated by DMAE perfusions. Responses to nicotine were blocked by DMAE and bradykinin-induced catecholamine release was unchanged. The cross-tachyphylaxis and DMAE studies suggest that several of the analogues and angiotensin II are interacting with a common adrenal medullary receptor.