Organisation and functional role of the brain angiotensin system.

The discovery that all components of the renin-angiotensin system (RAS) are present in the brain led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurones have been visualised in the brain. Two major pathways were described: a forebrain pathway which connects circumventric-ular organs to the median preoptic nucleus, par-aventricular and supraoptic nuclei, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood-brain-barrier deficient circumventricular organs are rich in angiotensin II (Ang II) receptors. By activating these receptors, circulating Ang II may act on central cardiovascu-lar centres via angiotensinergic neurones, providing a link between peripheral and central Ang II systems.Among the effector peptides of the brain RAS, Ang II and angiotensin III (Ang III) have the same affinity for type 1 and type 2 Ang II receptors. When injected into the brain, both peptides increase blood pressure (BP), water intake and pituitary hormone release and may modify learning and memory. Since Ang II is converted in vivo to Ang III, the nature of the true effector is unknown. This review summarises new insights into the predominant role of brain Ang III in the control of BP and underlines the fact that brain aminopeptidase A, the enzyme forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension. Introduction All components of the RAS, including the precursor and enzymes required for the production and degradation of angiotensins and specific angiotensin receptors type 1 (AT 1) and type 2 (AT 2), have been identified in the brain. 1-4 By analogy with the systemic RAS, brain Ang II is generated by sequential cleavage of the precursor angiotensinogen by an aspartyl protease, renin (EC 3.4.23.15), producing the inactive decapeptide angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu), which is then converted to Ang II by a zinc metalloprotease, angiotensin-converting enzyme [ACE]: EC 3.4.15.1). Subsequently, Ang II is metabolised to Ang III, which is itself converted to angiotensin IV (Ang IV) by aminopeptidases (Figure 1). Among the effector peptides of the brain RAS,Ang II and Ang III display similar affinities for AT 1-and AT 2-receptors. 5-7 When injected into the brain, these peptides, by acting on AT 1