Is there a brain renin-angiotensin system?

SINCE THE original demonstration by Bickerton and Buckley 1 that angiotensin II acts directly on the central nervous system to increase arterial pressure, it has become clear that the peptide has several central actions. These include stimulation of drinking as well as increased secretion of antidiuretic hormone (ADH) and of adrenocortico-tropic hormone (ACTH) (for reviews see Ferrario et al. 2 and Severs et al. 3-4). Initially, it seemed unlikely that these effects represented physiological actions of circulating an-giotensin II since the peptide is polar and apparently does not cross the blood-brain barrier. 5 However, it was subsequently demonstrated that the receptors for at least some of the central actions of angiotensin are in areas that are outside the blood-brain barrier and, therefore, accessible to blood-borne angiotensin. These include the area pos-trema (pressor effect), 2 the subfornical organ (dipsogenic action),' 1 the median eminence (ACTH secretion), 7 and the pituitary (ACTH and ADH secretion). 8-9 On the other hand, there appear to be other angiotensin receptors in areas that are inside the blood-brain barrier; these receptors may be activated by administration of angiotensin directly into the cerebral ventricles or by iontophoretic application, but not by injecting angiotensin into the blood supply of the brain. Examples of such areas include the subnucleus medialis (pressor effect) 10-" and the supraoptic nucleus (ADH secretion). 12 At present, the significance of the angiotensin receptors that are inside the blood-brain barrier is not clear. However , a possibility that has aroused considerable interest during recent years is that angiotensin is actually synthesized within the central nervous system and is, therefore, available to interact with brain angiotensin receptors. This proposal originated in 1971 with the observations by Gan-ten et al. 13 and Fischer-Ferraro et al. 14 that the components required for the generation of angiotensin II are present within the brain. These observations have been confirmed by other investigators 15 " 18 and it is now frequently assumed that there is a functional brain renin-angiotensin system. Indeed, it has been proposed that such a system participates in the control of water intake, blood pressure, ADH secretion, and a variety of other physiological functions."'-19 " 21 The purpose of this review is to summarize the current knowledge concerning the properties of the components of the renin-angiotensin system in the brain and to critically evaluate the evidence that these interact to form a functional system which is involved in …