Pathways of Angiotensin Formation and Function in the Brain

New findings from this laboratory suggest that fragments of angiotensin derived from the amino (N-)terminus are biologically active end products of the renin-angiotensin system. In vitro and in vivo experiments revealed that the heptapeptide angiotensin-(l-7) [Ang-(l-7)] is a major endogenous product of the renin-angiotensin system cascade in the brains of rats and dogs. Additional studies with enzyme inhibitors showed that Ang- (1–7) is produced directly from angiotensin I by an enzyme other than the angiotensin converting enzyme. Immunocytochemical analysis revealed the presence of specific staining for immunoreactive Ang-(l-7) in neurons and fibers within the hypothalamo-neurohypophyseal vasopressinergic system of the rat. Although Ang-(l-7) is as potent as angiotensin II (Ang II) in stimulating release of vasopressin from superperfused hypothalamo-neurohypophyseal explants, the heptapeptide has no dipsogenic or vasoconstrictor activity. In contrast, Ang- (1–7) mimics the effects of Ang II in augmenting the intrinsic discharge rate of neurons within the vagal-solitary complex and in causing monophasic depressor responses after microlnjection into the medial region of the nucleus tractus solitarii. The evidence obtained in these experiments suggests novel mechanisms for the generation of angiotensin peptides in the brain. Additionally, the findings suggest that some of the biological actions ascribed to Ang II might be conveyed by the endogenous production of other angiotensin peptides that are generated by enzymatic pathways alternate to those described in the peripheral circulation.