Angiotensin receptor subtype mediated physiologies and behaviors: new discoveries and clinical targets.

The renin-angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure, cyclicity of reproductive hormones and sexual behaviors, and the regulation of pituitary gland hormones. These functions appear to be mediated by the angiotensin II (AngII)/AT(1) receptor subtype system. More recently, the angiotensin IV (AngIV)/AT(4) receptor subtype system has been implicated in cognitive processing, cerebroprotection, local blood flow, stress, anxiety and depression. There is accumulating evidence to suggest an inhibitory influence by AngII acting at the AT(1) subtype, and a facilitory role by AngIV acting at the AT(4) subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning, and memory. This review initially describes the biochemical pathways that permit synthesis and degradation of active angiotensin peptides and three receptor subtypes (AT(1), AT(2) and AT(4)) thus far characterized. There is vigorous debate concerning the identity of the most recently discovered receptor subtype, AT(4). Descriptions of classic and novel physiologies and behaviors controlled by the RAS are presented. This review concludes with a consideration of the emerging therapeutic applications suggested by these newly discovered functions of the RAS.