Brain renin-angiotensin--a new look at an old system

The classic renin-angiotensin system (RAS) is described as a circulating hormone system focused on cardiovascular and body water regulation, with angiotensin II as its major effector. Detlef Ganten's discovery some years ago of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2) and AT(4) receptor proteins. We discuss the characterization and distribution of the AT(1) and AT(2) receptor subtypes and the current controversy over the identity of the AT(4) receptor subtype. Research findings favoring the candidates insulin-regulated aminopeptidase (IRAP) and the type 1 tyrosine kinase receptor c-Met, are presented. Next, we summarize current research efforts directed at the use of angiotensin analogues in the treatment of clinical disorders such as memory dysfunction, cerebral blood flow and cerebroprotection, stress, depression, alcohol consumption, seizure, Alzheimer's and Parkinson's diseases, and diabetes. The use of ACE inhibitors, and AT(1) and/or AT(2) receptor blockers, has shown promise in the treatment of several of these pathologies. The development of blood-brain barrier penetrant AT(4) receptor agonists and antagonists is of major importance regarding the continuing evaluation of the efficacy of new treatment approaches.