Brain Angiotensin II: New Developments, Unanswered Questions and Therapeutic Opportunities
1. There are two Angiotensin II systems in the brain. The discovery of brain Angiotensin II receptors located in neurons inside the blood brain barrier confirmed the existence of an endogenous brain Angiotensin II system, responding to Angiotensin II generated in and/or transported into the brain. In addition, Angiotensin II receptors in circumventricular organs and in cerebrovascular endothelial cells respond to circulating Angiotensin II of peripheral origin. Thus, the brain responds to both circulating and tissue Angiotensin II, and the two systems are integrated.
2. The neuroanatomical location of Angiotensin II receptors and the regulation of the receptor number are most important to determine the level of activation of the brain Angiotensin II systems.
3. Classical, well-defined actions of Angiotensin II in the brain include the regulation of hormone formation and release, the control of the central and peripheral sympathoadrenal systems, and the regulation of water and sodium intake. As a consequence of changes in the hormone, sympathetic and electrolyte systems, feed back mechanisms in turn modulate the activity of the brain Angiotensin II systems. It is reasonable to hypothesize that brain Angiotensin II is involved in the regulation of multiple additional functions in the brain, including brain development, neuronal migration, process of sensory information, cognition, regulation of emotional responses, and cerebral blood flow.
4. Many of the classical and of the hypothetical functions of brain Angiotensin II are mediated by stimulation of Angiotensin II AT1 receptors.
5. Brain AT2 receptors are highly expressed during development. In the adult, AT2 receptors are restricted to areas predominantly involved in the process of sensory information. However, the role of AT2 receptors remains to be clarified.
6. Subcutaneous or oral administration of a selective and potent non-peptidic AT1 receptor antagonist with very low affinity for AT2 receptors and good bioavailability blocked AT1 receptors not only outside but also inside the blood brain barrier. The blockade of the complete brain Angiotensin II AT1 system allowed us to further clarify some of the central actions of the peptide and suggested some new potential therapeutic avenues for this class of compounds.
7. Pretreatment with peripherally administered AT1 antagonists completely prevented the hormonal and sympathoadrenal response to isolation stress. A similar pretreatment prevented the development of stress-induced gastric ulcers. These findings strongly suggest that blockade of brain AT1 receptors could be considered as a novel therapeutic approach in the treatment of stress-related disorders.
8. Peripheral administration of AT1 receptor antagonists strongly affected brain circulation and normalized some of the profound alterations in cerebrovascular structure and function characteristic of chronic genetic hypertension. AT1 receptor antagonists were capable of reversing the pathological cerebrovascular remodeling in hypertension and the shift to the right in the cerebral autoregulation, normalizing cerebrovascular compliance. In addition, AT1 receptor antagonists normalized the expression of cerebrovascular nitric oxide synthase isoenzymes and reversed the inflammatory reaction characteristic of cerebral vessels in hypertension. As a consequence of the normalization of cerebrovascular compliance and the prevention of inflammation, there was, in genetically hypertensive rats a decreased vulnerability to brain ischemia. After pretreatment with AT1 antagonists, there was a protection of cerebrovascular flow during experimental stroke, decreased neuronal death, and a substantial reduction in the size of infarct after occlusion of the middle cerebral artery. At least part of the protective effect of AT1 receptor antagonists was related to the inhibition of the Angiotensin II system, and not to the normalization of blood pressure. These results indicate that treatment with AT1 receptor antagonists appears to be a major therapeutic avenue for the prevention of ischemia and inflammatory diseases of the brain.
9. Thus, orally administered AT1 receptor antagonists may be considered as novel therapeutic compounds for the treatment of diseases of the central nervous system when stress, inflammation and ischemia play major roles.
10. Many questions remain. How is brain Angiotensin II formed, metabolized, and distributed? What is the role of brain AT2 receptors? What are the molecular mechanisms involved in the cerebrovascular remodeling and inflammation which are promoted by AT1 receptor stimulation? How does Angiotensin II regulate the stress response at higher brain centers? Does the degree of activity of the brain Angiotensin II system predict vulnerability to stress and brain ischemia? We look forward to further studies in this exiting and expanding field.
Key Wordsrenin angiotensin system angiotensin II receptors AT1 receptors AT2 receptors stress ischemia gastric ulcers sympathetic system hormones brain development sensory systems cerebrovascular circulation
Unable to display preview. Download preview PDF.
- Aguilera, G., Kiss, A., and Luo, X. (1995a). Increased expression of type1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. J. Neuroendocrinol. 7:775–783.Google Scholar
- Aguilera, G., Young, W. S., Kiss, A., and Bathia, A. (1995b). Direct regulation of hypothalamic corticotropin-releasing-hormone neurons by angiotensin II. Neuroendocrinology 61:437–444.Google Scholar
- Armando, I., Carranza, A., Nishimura, Y., Hoe, K. L., Barontini, M., Terrón, J. A., Falcón-Neri, A., Ito, T., Juorio, A. V., and Saavedra, J. M. (2001). Peripheral administration of an angiotensin II AT1 receptor antagonist decreases the hypothalamic-pituitary-adrenal response to stress. Endocrinology 142:3880–3889.CrossRefPubMedGoogle Scholar
- Braun-Menéndez, E., Fasciolo, J. C., Leloir, L. F., and Muñoz, J. M. (1940). The substance causing renal hypertension. J. Physiol. (Lond) 98:283–298.Google Scholar
- Buckley, J. P. (1988). The central effects of the renin-angiotensin system. Clin. Exp. Hypertens. (A) 10:1–16.Google Scholar
- Brunson, K. L., Grigoriadis, D. E., Lorang, M. T., and Baram, T. Z. (2002). Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp. Neurol. 176:75–86.CrossRefPubMedGoogle Scholar
- Cromheeke, K. M., Kockx, M. M., De Meyer, G. R. Y., Bosmans, J. M., Bult, H., Beelaerts, W. J. F., Vrints, C. J., and Herman, A. G., (1999). Inducible nitric oxide synthase colocalizes with signs of lipid oxidation-peroxidation in human atherosclerotic plaques. Cardiovasc. Res. 43:744–754.CrossRefPubMedGoogle Scholar
- Edvinsson, L. (1975). Neurogenic mechanisms in the cerebrovascular bed. Autonomic nerves, amine receptors and their effects on cerebral blood flow. Acta Physiol. Scand. 427(Suppl):1–35.Google Scholar
- Gallinat, S., Busche, S., Raizada, M., and Sumners, C. (2000). The angiotensin II type 2 receptor: and enigma with multiple variations. Amer. J. Physiol. 278:E357–E374.Google Scholar
- Ganten, D., Mullins, J., and Lindpaintner, K. (1989). The tissue renin-angiotensin system: a target for angiotensin-converting enzyme inhibitors. J. Hum. Hypertens. 3(Suppl 1):63–70.Google Scholar
- Hajdu, M. A., Heistad, D. D., Ghoneim, S., and Baumbach, G. F. (1991). Effects of antihypertensive treatment on composition of cerebral arterioles. Hypertension 18(Suppl. II):II-1115–II-1121.Google Scholar
- Inagami, T., Guo, D.-F., and Kitami, Y. (1994). Molecular biology of angiotensin II receptors: An overview. J. Hypertens. 12:583–594.Google Scholar
- Ito, T., Nishimura, Y., and Saavedra, J. M. (2001). Pre-treatment with candesartan protects from cerebral ischemia. J. Renin Ang. Aldost. Syst. 2:174–179.Google Scholar
- Ito, T., Yamakawa, H., Bregonzio, C., Terrón, J. A., Falcón-Neri, A., and Saavedra, J. M. (2002). Protection against ischemia and improvement of cerebral blood flow in genetically hypertensive rats by chronic pretreatment with an Angiotensin II AT1 antagonist. Stroke 33:2297–2303.CrossRefPubMedGoogle Scholar
- Jezova, M., Armando, I., Bregonzio, C., Yu, Zu-Xi., Qian, S., Ferrans, V. J., Imboden, H., and Saavedra, J. M. (2003). Angiotensin II AT1 and AT2 receptors contribute to maintain basal adrenomedullary norepinephrine synthesis and tyrosine hydroxylase transcription. Endocrinology 144:2092–2101.CrossRefPubMedGoogle Scholar
- Jöhren, O., and Saavedra, J. M. (1996a). Gene expression of angiotensin II receptor subtypes in the cerebellar cortex of young rats. Neuroreport 7:1349–1352.Google Scholar
- Jöhren, O., and Saavedra, J. M. (1996b). Expression of AT1A$ and AT1B angiotensin II receptor messenger RNA in forebrain of two-week-old rats. Am. J. Physiol. 271:E104–E112.Google Scholar
- Leker, R. R., Teichner, A., Ovadia, H., Keshet, E., Reinherz, E. and Ben-Hur, T. (2001). Expression of endothelial nitric oxide synthase in the ischemic penumbra: Relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor. Brain Res. 909:1–7.CrossRefPubMedGoogle Scholar
- Leong, D. S., Terrón, J. A., Falcón-Neri, A., Armando, I., Ito, T., Jöhren, O., Tonelli, L. H., Hoe, K.-L., and Saavedra, J. M. (2002). Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT1A, AT1B and AT2 receptors. Neuroendocrinology 75:227–240.CrossRefPubMedGoogle Scholar
- Nishimura, Y., Ito, T., and Saavedra, J. M. (2000b). Angiotensin II AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats. Stroke 31:2478–2486.Google Scholar
- Page, I. H. (1987). Hypertension Mechanisms. Grune & Stratton, New York, p. 1102.Google Scholar
- Rajagopalan, S., Kurz, S., Münzel, T., Tarpey, M., Freeman, B. A., Griendling, K. K., and Harrison, D. G. (1996). Angiotensin II-mediated hypertension in the rat increases vascular superoxide to production via membrane NADH/NADPH oxidase activation. J. Clin. Invest. 97:1916–1923.PubMedGoogle Scholar
- Serra, M., Concas, A., Mostallino, M. C., Chessa, M. F., Stomati, M., Petraglia, F., Genazzani, A. R., and Biggio, G. (1999). Antagonism by pivagabine of stress-induced changes in GABAA receptor function and corticotropin-releasing factor concentrations in rat brain. Psychoneuroendocrinology 24:269–284.CrossRefPubMedGoogle Scholar
- Timmermans, P. B. (1999). Pharmacological properties of angiotensin II receptor antagonists. Can. J. Cardiol. 15(Suppl. 7):26 F–28 F.Google Scholar
- Timmermans, P. B. M. W. M., Inagami, T., Saavedra, J. M., Ardaillou, R., Rosenfeld, C. R., and Mendelsohn, F. A. O. (1995). Angiotensin receptor subtypes and their pharmacology. In Cuello, A. C., and Collier, B. (eds.), Pharmacological Sciences: Perspectives for Research and Therapy in the Late 1990s. Birkhauser Verlag, Basel, Switzerland, pp. 37–58.Google Scholar
- Tsutsumi, K., and Saavedra, J. M. (1991a). Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. Am. J. Physiol. 261:R209–R216.Google Scholar
- Tsutsumi, K., and Saavedra, J. M. (1991b). Angiotensin II receptor subtypes in median eminence and basal forebrain areas involved in the regulation of pituitary function. Endocrinology 129:3001–3008.Google Scholar
- Tsutsumi, K., and Saavedra, J. M. (1991c). Characterization of AT2 angiotensin II receptors in rat anterior cerebral arteries. Am. J. Physiol. 261:H667–H670.Google Scholar
- Tsutsumi, K., Strömberg, C., Viswanathan, M., and Saavedra, J. M. (1991a). Angiotensin-II receptor subtypes in fetal tissues of the rat: Autoradiography, guanine nucleotide sensitivity, and association with phosphoinositide hydrolysis. Endocrinology 129:1075–1082.Google Scholar
- Yamakawa, H., Jezova, M., Ando, H., and Saavedra, J. M. (2003). Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. J. Cereb. Blood Flow Metab. 23:371–380.CrossRefPubMedGoogle Scholar
- Yogo, K., Shimokawa, H., Funakoshi, H., Kandabashi, T., Miyata, K., Okamoto, S., Egashire, K., Huang, P., Akaike, T., and Takeshita, A. (2000). Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arteriosc. Thromb. Vasc. Biol. 20:e96–e100.Google Scholar