Angiotensin-[1-7]

Abstract

Summary: Structure-activity studies of angiotensin II (Ang II) have clearly established that the carboxyl-ter-minal phenylalanine is crucial for activation of angiotensin receptors associated with a broad range of effects including vasoconstriction, aldosterone release, and dipsogenesis. Thus, the heptapeptide angiotensin-[1-7] (Ang-[1-7]) has been classified as an inactive metabolite of the hormone Ang II. This assumption was seriously questioned in light of the report from our laboratory that Ang-[1-7] is the major metabolite of dog brainstem homogenates both in the absence and in the presence of angiotensin-converting enzyme inhibitors. These data raised the possibility of a functional role for Ang-[1-7] in the brain. Subsequent studies in the in vitro hypothala-moneurohypophysial system of the rat demonstrated that Ang-[1-7] is equipotent with Ang II in its activation of AVP release. Other Ang II-like actions have since been identified for Ang-[1-7] in the brain. For example, microinjection of Ang-[1-7] into brainstem nuclei of the rat promotes bradycardia and hypotension; in addition, Ang-[1-7] mimics the effect of Ang II in augmenting the intrinsic discharge rate of neurons within the vagal-solitary complex of the dog. Our laboratory has also provided evidence for synthesis and storage of Ang-[1-7] in the brain. Immunocytochemical studies have localized Ang-[1-7] in neuronal cell bodies and fiber tracts of magno-cellular nuclei in the rat hypothalamus; in addition, analysis of rat brain extracts by high-performance liquid chro-matography (HPLC) and radioimmunoassay (RIA) has demonstrated that Ang-[1-7] is a predominant angiotensin peptide in the hypothalamus and medulla oblongata of the rat. These studies have been complemented by preliminary identification of a specific class of high-affinity (nM) binding sites for Ang-[1-7] in subnuclear regions of the dog brainstem. Given that Ang-[1-7] is distinguished by its lack of angiotensinergic effects, such as vasoconstriction and dipsogenesis, the recent identification of actions and binding sites for Ang-[1-7] in the brain is indicative of multiple subclasses of angiotensin binding sites. Moreover, biochemical evidence of Ang-[1-7] distribution in the brainstem suggests that some of the biological actions of Ang II in the brain are mediated by other angiotensin peptides, including Ang-[1-7].