Important role for angiotensin III and IV in the brain renin-angiotensin system

Considerable evidence now suggests that the precursors and enzymes necessary for the formation and degradation of biologically active forms of angiotensins are present in brain tissues, accompanied by at least three specific binding sites. It also appears that several forms of angiotensin may serve as signaling agents at these sites. There is accumulating support for the notion that AngII must be converted to AngIII in order to bind at the AT1 and AT2 receptor subtypes, and AngIII must be converted to AngIV in order to activate the AT4 receptor subtype. Further, AngII(1-7) may activate a separate binding site concerned with antidiuresis, however, characterization of this site has not been completed. The AT1 site appears to mediate the classic angiotensin functions concerned with body water balance, maintenance of blood pressure, and cyclicity of reproductive hormones and sexual behaviors. This receptor site also exerts some control over the secretion of pituitary hormones. Less is known about the functional importance of the AT2 site, however, it has been implicated in vascular growth, control of blood flow, and perhaps modulation of NMDA receptors. The AT4 site is heavily distributed in neocortex, hippocampus, cerebellum, and basal ganglia structures, as well as several peripheral tissues. This site appears to mediate memory acquisition and retrieval, the regulation of blood flow, neurite outgrowth, angiogenesis, and kidney function. In addition to the well-studied functions of the brain renin-angiotensin system, additional less well investigated responses are reviewed. These include electrophysiological activation, tachyphylaxis, long term potentiation, learning and memory, and cognitive affect.