Journal of Human Hypertension (2002) 16, S64–S70 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The renin-angiotensin system in the brain: possible therapeutic implications for AT1- receptor blockers J Culman1, A Blume2, P Gohlke1 and T Unger2 1Institute of Pharmacology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany; 2Institute of Pharmacology and Toxicology, Charite´-Hospital, Humboldt University at Berlin, 10117 Berlin, Germany Biochemical, physiological and functional studies sug- the blood pressure lowering effects of AT1 receptor gest that the brain renin-angiotensin system (RAS) is blockers. Animal studies have shown that AT1 receptor regulated independently of the peripheral RAS. The antagonists enable endogenous angiotensin II to stimu- classical actions of angiotensin II in the brain include late neuronal regeneration via activation of AT2 recep- blood pressure control, drinking behaviour, natriuresis tors. In animal models, inhibition of the brain RAS and the release of vasopressin into the circulation. At proved to be beneficial with respect to stroke incidence least two subtypes of G-protein coupled receptors, the and outcome. Blockade of brain and cerebrovascular AT1 and the AT2 receptor, have been identified. Most of AT1 receptors by AT1 receptor blockers prevents the the classic actions of angiotensin II in the brain are reduction in blood flow during brain ischaemia, reduces mediated by AT1 receptors. The AT2 receptor is involved the volume of ischaemic injury and improves neurologi- in brain development and neuronal regeneration and cal outcome after brain ischaemia. This paper reviews protection. Additionally, AT2 receptors can modulate the actions of angiotensin II and its receptors in the some of the classic angiotensin II actions in the brain. brain, and discusses the possible consequences of AT1 Selective non-peptide AT1 receptor blockers, applied receptor blockade in neuroprotection, neuroregener- systemically, have been shown to inhibit both peripheral ation, cerebral haemodynamics and ischaemia. and brain AT1 receptors. In genetically hypertensive Journal of Human Hypertension (2002) 16, S64–S70. rats, inhibition of brain AT1 receptors may contribute to doi:10.1038/sj.jhh.1001442 Keywords: AT1 receptor blockers; brain; candesartan; neuroprotection; renin-angiotensin system; stroke Introduction in the brain independently of peripheral sources. Angiotensin II acts on brain structures localised The renin angiotensin system (RAS) has tradition- inside and outside the blood-brain barrier to induce ally been linked to the regulation of the salt and drinking behaviour and natriuresis, stimulate vaso- water homoeostasis. The effector peptide of the pressin release, modulate sympathetic outflow to the RAS, angiotensin II, binds at least to two receptor periphery, and attenuate the baroreceptor reflex. subtypes, referred to as the AT1 and the AT2 recep- Several lines of evidence suggest that inappropriate tors. The classical peripheral actions of angiotensin RAS activity in the brain may contribute to the II, which include vasoconstriction, facilitation of development and maintenance of arterial hyperten- sympathetic transmission and renal salt and water sion. retention are mediated by the AT1 receptor. These During the past 10 years, much has been learnt actions can be regarded as compensatory mech- about neuronal effects of angiotensin II that are not anisms to preserve salt and water, and maintain directly related to the central control of fluid and electrolyte balance and adequate organ perfusion, in electrolyte homoeostasis and the regulation of blood the face of water and salt loss. pressure. In addition, numerous findings have dem- In the last three decades, evidence has accumu- onstrated that angiotensin II, acting via the AT2 lated that angiotensin II can be formed in various receptor, may modulate embryonic development, tissues, such as brain, kidney, adrenal gland, heart tissue regeneration and protection, and initiate pro- and blood vessels. The brain has long been recog- cesses leading to programmed cell death (apoptosis). nised as a site of tissue RAS activity, and it has been There is also substantial evidence that the AT2 firmly established that angiotensin II is synthesised receptor can offset or counteract the effects mediated by the AT1 receptor, for example on cell 1,2 Correspondence: J Culman, MD, Institute of Pharmacology, Chris- proliferation, water intake and blood pressure. tian-Albrechts-University of Kiel, Hospitalstrasse 4, 24105 Kiel, This paper reviews the mechanisms of action and Germany. E-mail: juraj.culman.Ȱpharmakologie.uni-kiel.de function of angiotensin-containing pathways in the The renin-angiotensin system in the brain J Culman et al S65 brain, and possible therapeutic implications of angiotensin II-stained cells were found in the med- inhibiting the brain RAS. ulla was the nucleus of the solitary tract.9 Components of the RAS in the brain Angiotensin receptors and signal Angiotensin II in the brain is generated from angio- transduction pathways tensinogen by an enzymatic cascade involving renin and angiotensin converting enzyme (ACE). The In the adult brain, structures related to the regu- expression of renin in the brain has been clearly lation of body fluid homoeostasis and blood press- demonstrated using various biochemical and ure express mainly or exclusively AT1 receptors. As immunohistochemical techniques. The enzyme is already mentioned, the AT1 receptor mediates vir- synthesised in neurones and is present in high con- tually all of the known physiological actions of centrations in nerve terminals. ACE has also been angiotensin II in the brain, such as the regulation found in the synaptosomal fraction of brain tissue of arterial blood pressure and vasopressin release, with high concentrations in the lamina terminalis electrolyte and water balance, thirst and hormone and the circumventricular organs, hypothalamus secretion (Figure 1).10 and some brain stem nuclei. Angiotensinogen is The signalling pathways of the AT1 receptor are mostly found extracellularly, and the mRNA enco- well understood. They include the classic cascades ding for angiotensinogen is predominantly localised activated by G proteins, resulting in increases of in glial cells, although the peptide is also present in intracellular calcium and activation of protein kin- some neuronal populations.3,4 These findings sug- ase C. These signalling pathways are responsible for gest that angiotensin II is formed extracellularly in the generation and mediation of immediate the brain. However, the fact that angiotensin II in responses, such as the release of vasopressin and the brain can be found almost exclusively within oxytocin from the posterior pituitary. Other signal- synaptic vesicles in nerve endings favours an intra- ling pathways initiated by angiotensin II binding to cellular formation of angiotensin II. Another the AT1 receptor are phosphorylation-dependent unsolved question seems to be the lack of abundant reactions, some of which involve increased renin expression in those brain areas where mRNA expression of inducible transcription factors such as encoding for angiotensinogen is highly expressed c-Fos and c-Jun. These signalling cascades are and angiotensin II is present in high concentrations. believed to be involved in AT1 receptor-mediated 11 In general, angiotensin I levels are low in the brain, cell growth. Activation of periventricular AT1 which suggests that angiotensin II can be formed receptors in the rat brain induces expression of tran- directly from angiotensinogen, rather than by the scription factors in all brain regions nuclei involved enzymatic activity of renin. Non-renin, non-ACE in cardiovascular control and osmoregulation.11 pathways involving acid proteases have been A variety of signalling mediators have been 5 described. Alternatively, renin expression may be described for the AT2 receptor. The AT2 receptor strongly controlled to avoid a permanently high seems to be coupled to the Gi protein, and the signal- level of renin activity in brain areas abundant in ling mechanisms involve inhibition of mitogen- angiotensinogen.6 activated protein kinases, alteration in intracellular cGMP levels and inhibition of phosphorylation. Angiotensin pathways in the brain Recent findings indicate that angiotensin II, acting via AT2 receptors, is involved in the regulation of The distribution of angiotensin peptides and their pro- and/or antiapoptotic events (Figure 1). receptors is intimately linked to the brain areas asso- ciated with central regulation of fluid and salt homo- eostasis and blood pressure control. Angiotensin II is a principal neurotransmitter within the lamina terminalis and its neuronal connections to other brain regions related to central cardiovascular control including the hypothalamic nuclei. Angio- tensin II-stained cell bodies are prominent in the paraventricular and supraoptic nuclei. The neuro- secretory cells in these regions, which synthesise vasopressin, lie within a network of angiotensin- immunoreactive fibres and terminals.7,8 In addition, cell groups positively stained for angiotensin II are located in the stria terminalis and in the medial nucleus of the amygdala. Angiotensin receptors have also been found in the hindbrain regions involved in the modulation of sympathetic vaso- Figure 1 Effects mediated by angiotensin II (Ang II) acting on the motor tone, despite the fact that the only site where AT1 and