(Des-Asp1)-Angiotensin I

The effects of [des-Asp1]angiotensin I and angiotensin III on mesenteric blood flow were compared in 15 pentobarbital-anesthetized dogs. These agonists were administered as bolus injections directly into the vasculature supplied by the superior mesenteric artery. Both [des-Asp1]angiotensin I and angiotensin III produced dose-dependent decreases in mesenteric blood flow, with angiotensin III being more potent than [des-Asp1]angiotensin I at all doses tested. The constrictor responses to [des-Asp1]angiotensin I were markedly attenuated in the presence of an angiotensin-converting enzyme inhibitor (SQ20881); SQ20881 did not alter responses to angiotensin III or norepinephrine. The administration of [Ile7]angiotensin III (an angiotensin III antagonist) attenuated the responses to both [des-Asp1]angiotensin I and angiotensin III, without altering the responses to norepinephrine. These results suggest that the decrease in mesenteric blood flow produced by [des-Asp1]angiotensin I is largely caused by its local enzymatic conversion to angiotensin III. This conversion in one transit through the mesenteric vasculature is approximately 24%.

The steroidogenic and pressor activities of the nonapeptide (des-Asp1) angiotensin I [(des-Asp)-AI] were tested in conscious rats. (des-Asp)-AI caused dose related increases in mean arterial pressure (MAP), serum aldosterone, and serum corticosterone in doses between 3 and 3,000 ng/kg/min. (des-Asp)-AI was 14% as potent as angiotensin I and angiotensin II and 60% as potent as (des-Asp1) angiotensin II [des-Asp)-AII] in raising MAP. (des-Asp)-AI was less active than AI, AII, or (des-Asp)-AII in causing increased release of aldosterone, possessing only 8%, 11%, and 17% of the potency of AII, (des-Asp)-AII, and AI, respectively. Each of these angiotensin peptides was equally potent in elevating serum corticosterone levels. Infusions of a nonapeptide inhibitor of converting enzyme (CEI, 0.5 mg/kg/min iv) did not alter control MAP or blood pressure responses to AII or (des-Asp-)-AII but inhibited equally the blood pressure effects of AI and (des-Asp)-AI. CEI also inhibited the ability of (des-Asp)-AI (67% inhibition) and AI (34% inhibition) to increase the serum aldosterone concentration, but had no effect on basal aldosterone levels. These data indicate that (des-Asp)-AI has pressor and steroidogenic effects, but requires conversion to (des-Asp)-AII for a major portion of its activity. These results further substantiate the hypothesis that (des-Asp)-AII, recently recognized as a hormone of the renin-angiotensin system, may be produced without the formation of AII as an intermediate and provide in vivo evidence for the conversion of (des-Asp)-AI to (des-Asp)-AII.

The administration of radioactive angiotensin I to the retrogradely perfused feline adrenal gland caused a brisk discharge of catecholamines. Recovery of the labelled decapeptide and metabolites in the adrenal effluent fluid was complete in 5 min. Radioimmunoassay of this perfusate revealed that most of the peptide remained as angiotensin I, but chromatographic and electrophoretic evaluation indicated that greater than 68% of the peptide had been metabolized to des-asp1 -angiotensin I. The absence of des-asp1 -angiotensin II, angiotensin II or his-3H-leu in adrenal effluent fluid suggested minimal dipeptidyl carboxypeptidase activity in this preparation. In addition, the profile of angiotensin I metabolites from the perfused adrenal was not altered by treatment with a converting enzyme inhibitor B. jararaca nonapeptide. The des-asp1-angiotensin I peptide was a very weak secretagogue in the adrenal medulla. If metabolism of the decapeptide to the nonapeptide occurs in the medulla, this may represent a pathway to limit the secretory action of angiotensin I. These results suggest a high degree of adrenal aminopeptidase activity which may be primarily localized in the adrenal cortex.