Brain renin-angiotensin system in the pathophysiology of cardiovascular diseases

Pharmacological Research - Tập 125 - Trang 72-90 - 2017
Gianna Huber1,2, Franziska Schuster1,2, Walter Raasch1,2,3
1Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Germany
2CBBM (Center of Brain, Behavior and Metabolism), Lübeck, Germany
3DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany

Tài liệu tham khảo

Marc, 2011, The role of the brain renin-angiotensin system in hypertension: implications for new treatment, Prog. Neurobiol., 95, 89, 10.1016/j.pneurobio.2011.06.006 Kearney, 2005, Global burden of hypertension-analysis of worldwide data, Lancet, 365, 217, 10.1016/S0140-6736(05)70151-3 Balakumar, 2016, Prevalence and prevention of cardiovascular disease and diabetes[mellitus, Pharmacol. Res., 113, 600, 10.1016/j.phrs.2016.09.040 Guyenet, 2006, The sympathetic control of blood pressure, Nat. Rev. Neurosci., 7, 335, 10.1038/nrn1902 Grobe, 2009, An intracellular renin-angiotensin system in neurons: fact, hypothesis or fantasy, Physiol. Behav., 23, 187, 10.1152/physiol.00002.2008 Xu, 2011, ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good, AJP Regul, Integr. Comp. Physiol., 300, R804, 10.1152/ajpregu.00222.2010 Phillips, 1998, Angiotensin II in central nervous system physiology, Regul. Pept., 78, 1, 10.1016/S0167-0115(98)00122-0 Ganten, 1983, Angiotensin synthesis in the brain and increased turnover in hypertensive rats, Science, 221, 869, 10.1126/science.6879184 Lee-Kirsch, 1999, Distinct renin isoforms generated by tissue-specific transcription initiation and alternative splicing, Circ. Res., 84, 240, 10.1161/01.RES.84.2.240 Lavoie, 2006, Evidence supporting a functional role for intracellular renin in the brain, Hypertension, 47, 461, 10.1161/01.HYP.0000203308.52919.dc van Thiel, 2017, Brain renin–angiotensin system –does it exist?, Hypertension, 69, 1136, 10.1161/HYPERTENSIONAHA.116.08922 Feng, 2015, ANG II-independent prorenin/(pro)renin receptor signaling pathways in the central nervous system, Am. J. Physiol. Heart Circ. Physiol., 309, H731, 10.1152/ajpheart.00526.2015 Huber, 2015, Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats, Am. J. Physiol. – Hear. Circ. Physiol., H880, 10.1152/ajpheart.00095.2015 Shinohara, 2016, Selective deletion of the brain-specific isoform of renin causes neurogenic hypertension, Hypertension, 68, 1385, 10.1161/HYPERTENSIONAHA.116.08242 Simpson, 1978, Subfornical organ: a dipsogenic site of action of angiotensin II, Science (80-.), 201, 379, 10.1126/science.663664 Bishop, 2000, Angiotensin II modulation of the arterial baroreflex: role of the area postrema, Clin. Exp. Pharmacol. Physiol., 27, 428, 10.1046/j.1440-1681.2000.03260.x Schelling, 1976, Impermeability of the blood-cerebrospinal fluid barrier for angiotensin II in rats, Clin. Sci. Mol. Med., 5, 399s Harding, 1988, Inability of [125I]Sar1, Ile8-angiotensin II to move between the blood and cerebrospinal fluid compartments, J. Neurochem., 50, 554, 10.1111/j.1471-4159.1988.tb02946.x Huber, 2001, Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression, Am. J. Physiol. Heart Circ. Physiol., 280, H1241, 10.1152/ajpheart.2001.280.3.H1241 Pires, 2013, The effects of hypertension on the cerebral circulation, Am. J. Physiol. Heart Circ. Physiol., 304, H1598, 10.1152/ajpheart.00490.2012 Biancardi, 2016, Compromised blood-brain barrier permeability: novel mechanism by which circulating angiotensin II signals to sympathoexcitatory centres during hypertension, J. Physiol., 594, 1591, 10.1113/JP271584 Stornetta, 1988, Astrocytes synthesize angiotensinogen in brain, Science, 242, 1444, 10.1126/science.3201232 Palkovits, 1995, Neurotransmitters and neuropeptides in the baroreceptor reflex arc: connections between the nucleus of the solitary tract and the ventrolateral medulla oblongata in the rat, Clin. Exp. Hypertens., 17, 101, 10.3109/10641969509087058 Aronsson, 1988, Evidence for the existence of angiotensinogen mRNA in magnocellular paraventricular hypothalamic neurons, Acta Physiol. Scand., 132, 585, 10.1111/j.1748-1716.1988.tb08370.x Baltatu, 2001, Alterations in blood pressure and heart rate variability in transgenic rats with low brain angiotensinogen, Hypertension, 37, 408, 10.1161/01.HYP.37.2.408 Müller, 2010, Stress sensitivity is increased in transgenic rats with low brain angiotensinogen, J. Endocrinol., 204, 85, 10.1677/JOE-09-0363 Schinke, 1999, Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen, Proc. Natl. Acad. Sci. U. S. A., 96, 3975, 10.1073/pnas.96.7.3975 Caligiorne, 2008, Baroreflex control of heart rate and renal sympathetic nerve activity in rats with low brain angiotensinogen, Neuropeptides, 42, 159, 10.1016/j.npep.2007.12.003 Wang, 2004, Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen, Circ. Res., 94, 843, 10.1161/01.RES.0000120864.21172.5A Baltatu, 2000, The brain renin-angiotensin system modulates angiotensin II-induced hypertension and cardiac hypertrophy, Hypertension, 35, 409, 10.1161/01.HYP.35.1.409 Ferreira, 2015, Differential control of vasomotion by angiotensins in the rostral ventrolateral medulla of hypertensive rats, Neuropeptides, 53, 11, 10.1016/j.npep.2015.09.002 Dampney, 1994, Functional organization of central pathways regulating the cardiovascular system, Physiol. Rev., 74, 323, 10.1152/physrev.1994.74.2.323 Chan, 1991, Responses of cardiovascular neurons in the rostral ventrolateral medulla of the normotensive Wistar Kyoto and spontaneously hypertensive rats to iontophoretic application of angiotensin II, Brain Res., 556, 145, 10.1016/0006-8993(91)90559-E Kumagai, 2012, Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure, Hypertens. Res., 35, 132, 10.1038/hr.2011.208 Matsuura, 2002, Rostral ventrolateral medulla neurons of neonatal Wistar-Kyoto and spontaneously hypertensive rats, Hypertension, 40, 560, 10.1161/01.HYP.0000032043.64223.87 Gutkind, 1988, Increased concentration of angiotensin II binding sites in selected brain areas of spontaneously hypertensive rats, J. Hypertens., 6, 79, 10.1097/00004872-198801000-00012 Gehlert, 1991, Autoradiographic localization of subtypes of angiotensin II antagonist binding in the rat brain, Neuroscience, 44, 501, 10.1016/0306-4522(91)90073-W Phillips, 2008, Brain renin angiotensin in disease, J. Mol. Med., 86, 715, 10.1007/s00109-008-0331-5 Phillips, 1987, Functions of angiotensin in the central nervous system, Annu. Rev. Physiol., 49, 413, 10.1146/annurev.ph.49.030187.002213 Culman, 1995, Angiotensin as neuromodulator/neurotransmitter in central control of body fluid and electrolyte homeostasis, Clin. Exper. Hypertens., 17, 281, 10.3109/10641969509087071 Lippoldt, 1995, The brain renin-angiotensin system: molecular mechanisms of cell to cell interactions, Clin. Exp. Hypertens., 17, 251, 10.3109/10641969509087069 Dupont, 2010, Brain angiotensin peptides regulate sympathetic tone and blood pressure, J. Hypertens., 28, 1599, 10.1097/HJH.0b013e32833af3b2 Dudley, 1990, Subclasses of angiotensin II binding sites and their functional significance, Mol. Pharmacol., 38, 370 Chiu, 1989, Identification of angiotensin II receptor subtypes, Biochem. Biophys. Res. Commun., 165, 196, 10.1016/0006-291X(89)91054-1 Averill, 1994, Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II and L-glutamate in rostral ventrolateral medulla, Brain Res., 665, 245, 10.1016/0006-8993(94)91344-7 Hirooka, 1997, Role of angiotensin II receptor subtypes in mediating the sympathoexcitatory effects of exogenous and endogenous angiotensin peptides in the rostral ventrolateral medulla of the rabbit, Brain Res., 772, 107, 10.1016/S0006-8993(97)00861-5 Landas, 1980, Visualization of specific angiotensin II binding sites in the brain by fluorescent microscopy, Science, 210, 791, 10.1126/science.6254147 Allen, 2000, Localization and function of angiotensin AT1 receptors, Am. J. Hypertens., 7061, 31, 10.1016/S0895-7061(99)00249-6 Cato, 2005, Angiotensin II excites paraventricular nucleus neurons that innervate the rostral ventrolateral medulla: an in vitro patch-clamp study in brain slices, J. Neurophysiol., 93, 403, 10.1152/jn.01055.2003 Song, 1991, Angiotensin II receptor subtypes in rat brain, Clin. Exp. Pharmacol. Physiol., 18, 93, 10.1111/j.1440-1681.1991.tb01414.x Aldred, 1993, Distribution of angiotensin II receptor subtypes in the rabbit brain, Regul. Pept., 44, 119, 10.1016/0167-0115(93)90235-Z Saavedra, 1986, Binding of angiotensin and atrial natriuretic peptide in brain of hypertensive rats, Nature, 320, 758, 10.1038/320758a0 Gehlert, 1986, Quantitative autoradiography of angiotensin II receptors in the SHR brain, Peptides, 7, 1021, 10.1016/0196-9781(86)90132-4 Yang, 1997, Localization of angiotensin II AT1 receptor-like immunoreactivity in catecholaminergic neurons of the rat medulla oblongata, Neuroscience, 81, 503, 10.1016/S0306-4522(97)00057-2 Hu, 2002, Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats, J. Appl. Physiol., 92, 2153, 10.1152/japplphysiol.00261.2001 Muratani, 1993, Ventrolateral medulla in spontaneously hypertensive rats: role of angiotensin II: Am, J. Physiol. − Regul. Integr. Comp. Physiol., 264, R388, 10.1152/ajpregu.1993.264.2.R388 Phillips, 1977, Lowering of hypertension by central saralasin in the absence of plasma renin, Nature, 270, 445, 10.1038/270445a0 Yang, 1992, Blocking hypothalamic AT1 receptors lowers blood pressure in salt-sensitive rats, Hypertension, 20, 755, 10.1161/01.HYP.20.6.755 Berecek, 1986, Alterations in renal vascular reactivity induced by chronic central administration of captopril in the spontaneously hypertensive rat, Clin.Exp. Hypertens. A, 8, 1081 Sweet, 1981, Relationship between Angiotensin I blockade and antihypertensive properties of single doses of MK-421 and captopril in spontanous and renal hypertensive rats, Eur. J. Pharmacol., 76, 167, 10.1016/0014-2999(81)90498-2 Takata, 1986, Brain renin angiotensin system contributes to the salt-induced enhancement of hypertension in SHR, Clin. Exp. Hypertens. A., 8, 1149 Ito, 2002, Ventrolateral medulla AT1 receptors support blood pressure in hypertensive rats, Hypertension, 40, 552, 10.1161/01.HYP.0000033812.99089.92 Allen, 2001, Blockade of angiotensin AT1-receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats reduces blood pressure and sympathetic nerve discharge, J. Renin-Angiotensin-Aldosterone Syst., 2, S120, 10.1177/14703203010020012101 Lohmeier, 2001, The sympathetic nervous system and long-term blood pressure regulation, Am. J. Hypertens., 14, 147S, 10.1016/S0895-7061(01)02082-9 Esler, 1995, Sympathetic nervous system: contribution to human hypertension and related cardiovascular diseases, J. Cardiovasc. Pharmacol., 26, S24, 10.1097/00005344-199512020-00004 Schlaich, 2004, Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation, Hypertension, 43, 169, 10.1161/01.HYP.0000103160.35395.9E Mancia, 1999, Sympathetic activation in the pathogenesis of hypertension and progression of organ damage, Hypertension, 34, 724, 10.1161/01.HYP.34.4.724 Morise, 2000, The potent role of increased sympathetic tone in pathogenesis of essential hypertension with neurovascular compression, J. Hum. Hypertens., 14, 807, 10.1038/sj.jhh.1001114 Culman, 2002, The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers, J. Hum. Hypertens., 16, S64, 10.1038/sj.jhh.1001442 Muratani, 1996, Brain angiotensin and circulatory control, Clin. Exp. Pharmacol. Physiol., 23, 458, 10.1111/j.1440-1681.1996.tb02761.x Dampney, 1996, Functions of angiotensin peptides in the rostral ventrolateral medulla, Clin. Exp. Pharmacol. Physiol., S105, 10.1111/j.1440-1681.1996.tb02822.x Dendorfer, 1998, Interactions between the renin-angiotensin system (RAS) and the sympathetic system, Basic Res. Cardiol., 93, 24, 10.1007/s003950050202 Dendorfer, 2002, Angiotensin II induces catecholamine release by direct ganglionic excitation, Hypertension, 40, 348, 10.1161/01.HYP.0000028001.65341.AA Dendorfer, 1999, Mechanisms of bradykinin-induced catecholamine release in pithed spontaneously hypertensive rats, Immunopharmacology, 44, 99, 10.1016/S0162-3109(99)00114-9 Raasch, 2001, Angiotensin converting enzyme inhibition improves cardiac neuronal uptake of noradrenaline in spontaneously hypertensive rats, J.Hypertens, 19, 1827, 10.1097/00004872-200110000-00017 Raasch, 2004, Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR, J. Hypertens., 22, 611, 10.1097/00004872-200403000-00025 Dendorfer, 2005, Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?, J. Hypertens., 23, 1861, 10.1097/01.hjh.0000179510.86265.63 Tagawa, 1999, AT(1) receptors mediate excitatory inputs to rostral ventrolateral medulla pressor neurons from hypothalamus, Hypertension, 34, 1301, 10.1161/01.HYP.34.6.1301 Sheriff, 2006, Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions, Am. J. Physiol. Regul. Integr. Comp. Physiol., 290, R733, 10.1152/ajpregu.00410.2005 Dampney, 2007, Cardiovascular effects of angiotensin II in the rostral ventrolateral medulla: the push-pull hypothesis, Curr. Hypertens. Rep., 9, 222, 10.1007/s11906-007-0040-4 Burson, 1994, Differential expression of angiotensin receptor 1A and 1 B in mouse, Am. J. Physiol., 267, E260 Llorens-Cortes, 1994, Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis, Hypertension, 24, 538, 10.1161/01.HYP.24.5.538 Gasc, 1994, Tissue-specific expression of type 1 angiotensin II receptor subtypes, An in situ hybridization study, Hypertension., 24, 531 Jöhren, 1995, AT1A, ATIB and AT2 angiotensin II receptor subtype gene expression in rat brain, Neuroreport, 6, 2549, 10.1097/00001756-199512150-00024 Jöhren, 1996, Expression of AT1A and AT1B angiotensin II receptor messenger RNA in forebrain of 2-wk-old rats, Am. J. Physiol., 271, E104 Aguilera, 1995, Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration, Neuroendocrinol, 7, 775, 10.1111/j.1365-2826.1995.tb00714.x Castren, 1988, Repeated stress increases the density of angiotensin II binding sites in rat paraventricular nucleus and subfornical organ, Endocrinology, 122, 370, 10.1210/endo-122-1-370 Armando, 2014, Peripheral administration of an angiotensin II AT1 receptor antagonist decreases the hypothalamic-Pituitary-Adrenal response to isolation stress, Endocrinology, 142, 3880, 10.1210/endo.142.9.8366 Leong, 2002, Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT1A, AT1 B and AT2 receptors, Neuroendocrinology, 75, 227, 10.1159/000054714 Rivier, 1983, Effect of angiotensin II on ACTH release in vivo: role of corticotropin-releasing factor, Regul. Pept., 7, 253, 10.1016/0167-0115(83)90018-6 Jezova, 1998, Brain angiotensin II modulates sympathoadrenal and hypothalamic pituitary adrenocortical activation during stress, J. Neuroendocrinol., 10, 67, 10.1046/j.1365-2826.1998.00182.x Sumitomo, 1991, Angiotensin II increases the corticotropin-releasing factor messenger ribonucleic acid level in the rat hypothalamus, Endocrinology, 128, 2248, 10.1210/endo-128-5-2248 Seltzer, 2004, Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats, Brain Res., 1028, 9, 10.1016/j.brainres.2004.06.079 Jöhren, 2003, Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY, Hypertension, 41, 984, 10.1161/01.HYP.0000062466.38314.B7 Nyklíček, 2005, A generalized physiological hyperreactivity to acute stressors in hypertensives, Biol. Psychol., 70, 44, 10.1016/j.biopsycho.2004.11.013 Filipovský, 1996, The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men, J. Hypertens., 14, 229, 10.1097/00004872-199602000-00012 Gold, 2005, Hypertension and hypothalamo-pituitary-adrenal axis hyperactivity affect frontal lobe integrity, J. Clin. Endocrinol. Metab., 90, 3262, 10.1210/jc.2004-2181 Al’Absi, 1994, Borderline hypertensives produce exaggerated adrenocortical responses to mental stress, Psychosom. Med., 56, 245, 10.1097/00006842-199405000-00011 Rozanski, 1999, Clinical Cardiology: New Frontiers Impact of Psychological Factors on the Pathogenesis of Cardiovascular Disease and Implications for Therapy, Circulation, 2192, 10.1161/01.CIR.99.16.2192 Raasch, 2006, Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats, Endocrinology, 147, 3539, 10.1210/en.2006-0198 Hirasawa, 1990, Role of central angiotensinergic mechanism in shaking stress-induced ACTH and catecholamine secretion, Brain Res., 533, 1, 10.1016/0006-8993(90)91787-H Buckner, 1986, Centrally administered inhibitors of the generation and action of angiotensin II do not attenuate the increase in ACTH secretion produced by ether stress in rats, Neuroendocrinology, 42, 97, 10.1159/000124257 Müller, 2007, Angiotensin II stimulates the reactivity of the pituitary-adrenal axis in leptin-resistant Zucker rats, thereby influencing the glucose utilization, AJP Endocrinol, Metab, 293, E802 Müller-Fielitz, 2013, Angiotensin II impairs glucose utilization in obese zucker rats by increasing HPA activity via an adrenal-dependent mechanism, Horm. Metab. Res., 45, 173 Dallman, 2004, Minireview: glucocorticoids – food intake, abdominal obesity, and wealthy nations in 2004, Endocrinology, 145, 2633, 10.1210/en.2004-0037 Pecoraro, 2004, Chronic stress promotes palatable feeding, which reduces signs of stress: feedforward and feedback effects of chronic stress, Endocrinology, 145, 3754, 10.1210/en.2004-0305 Dallman, 2003, Chronic stress and obesity: a new view of ‘comfort food, Proc. Natl. Acad. Sci., 100, 11696, 10.1073/pnas.1934666100 Kintscher, 2007, Irbesartan for the treatment of hypertension in patients with the metabolic syndrome: a sub analysis of the Treat to Target post authorization survey. Prospective observational, two armed study in 14,200 patients, Cardiovasc. Diabetol., 6, 12, 10.1186/1475-2840-6-12 Lawrence, 1996, Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius, Prog. Neurobiol., 48, 21, 10.1016/0301-0082(95)00034-8 Averill, 2000, Angiotensin peptides and baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata, in: brain Res, Bull, 51, 119 Baltatu, 2001, Alterations of the renin-angiotensin system at the RVLM of transgenic rats with low brain angiotensinogen, Am. J. Physiol. Regul. Integr. Comp. Physiol, 280, R428, 10.1152/ajpregu.2001.280.2.R428 Botelho, 1994, Plasma angiotensin(1–7) immunoreactivity is increased by salt load, water deprivation, and hemorrhage, Peptides, 15, 723, 10.1016/0196-9781(94)90103-1 Casto, 1985, Neuropeptide action in nucleus tractus solitarius: angiotensin specificity and hypertensive rats, Am. J. Physiol., 249, R341 Campagnole-Santos, 1988, Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii, Hypertension, 11, I167, 10.1161/01.HYP.11.2_Pt_2.I167 Paton, 2001, Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat, J. Physiol., 531, 445, 10.1111/j.1469-7793.2001.0445i.x Paton, 2008, Signalling across the blood brain barrier by angiotensin II: Novel implications for neurogenic hypertension, J. Mol. Med., 86, 705, 10.1007/s00109-008-0324-4 Paton, 2006, Detection of angiotensin II mediated nitric oxide release within the nucleus of the solitary tract using electron-paramagnetic resonance (EPR) spectroscopy, Auton. Neurosci. Basic Clin., 126–127, 193, 10.1016/j.autneu.2006.02.016 Waki, 2003, Chronic inhibition of endothelial nitric oxide synthase activity in nucleus tractus solitarii enhances baroreceptor reflex in conscious rats, J. Physiol., 546, 233, 10.1113/jphysiol.2002.030270 Waki, 2006, Endothelial NO synthase activity in nucleus tractus solitarii contributes to hypertension in spontaneously hypertensive rats, Hypertension, 48, 644, 10.1161/01.HYP.0000238200.46085.c6 Morimoto, 2001, Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter, Circ. Res., 89, 365, 10.1161/hh1601.094988 Monti, 2001, Glial angiotensinogen regulates brain angiotensin II receptors in transgenic rats TGR(ASrAOGEN), Am. J. Physiol. Regul. Integr. Comp. Physiol., 280, R233, 10.1152/ajpregu.2001.280.1.R233 Wright, 2013, The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases, Pflugers Arch. Eur. J. Physiol., 465, 133, 10.1007/s00424-012-1102-2 Engeli, 1999, Co-expression of renin-angiotensin system genes in human adipose tissue, J. Hypertens., 17, 555, 10.1097/00004872-199917040-00014 Engeli, 2005, Weight loss and the renin-angiotensin-aldosterone system, Hypertension, 45, 356, 10.1161/01.HYP.0000154361.47683.d3 Harte, 2005, Insulin-mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone, Circulation, 111, 1954, 10.1161/01.CIR.0000161954.17870.5D Cabassi, 2005, Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat, J. Clin. Endocrinol. Metab., 90, 2888, 10.1210/jc.2004-1995 Brink, 1996, Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism, J. Clin. Invest., 97, 2509, 10.1172/JCI118698 Cassis, 2004, Differential effects of local versus systemic angiotensin II in the regulation of leptin release from adipocytes, Endocrinology, 145, 169, 10.1210/en.2003-0767 de Kloet, 2011, Central angiotensin II has catabolic action at white and brown adipose tissue, Am. J. Physiol. Endocrinol. Metab., 301, E1081, 10.1152/ajpendo.00307.2011 de Kloet, 2013, Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity, J. Neurosci., 33, 4825, 10.1523/JNEUROSCI.3806-12.2013 M. Winkler, I. Stölting, S., Binder, M., Bader, W. Raasch, Development of obesity can be prevented in rats by chronic icv infusions of AngII but not by Ang(1–7), in revision. Schuchard, 2015, Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1–7)/Mas-dependent pathway, Br. J. Pharmacol., 172, 3764, 10.1111/bph.13172 Reaux-Le Goazigo, 2005, Role of angiotensin III in hypertension, Curr. Hypertens. Rep., 7, 128, 10.1007/s11906-005-0087-z Fournie-Zaluski, 2004, Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension, Proc. Natl. Acad. Sci. U. S. A., 101, 7775, 10.1073/pnas.0402312101 Reaux, 1999, PC18, a specific aminopeptidase N inhibitor, induces vasopressin release by increasing the half-life of brain Angiotensin III, Neuroendocrinology, 69, 370, 10.1159/000054439 Reaux, 1999, Aminopeptidase A inhibitors as potential central antihypertensive agents, Proc. Natl. Acad. Sci. U. S. A., 96, 13415, 10.1073/pnas.96.23.13415 Zini, 1996, Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release, Proc. Natl. Acad. Sci. U. S. A., 93, 11968, 10.1073/pnas.93.21.11968 Wright, 2003, Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats, Am. J. Physiol. Regul. Integr. Comp. Physiol., 284, R725, 10.1152/ajpregu.00326.2002 Reaux, 2001, Angiotensin III: a central regulator of vasopressin release and blood pressure, Trends Endocrinol. Metab, 12, 157, 10.1016/S1043-2760(01)00381-2 Blair-West, 2001, Possible contribution of brain angiotensin III to ingestive behaviors in baboons, Am. J. Physiol. Regul. Integr. Comp. Physiol., 281, R1633, 10.1152/ajpregu.2001.281.5.R1633 Song, 1997, Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II-induced dipsogenic and pressor responses, Brain Res., 744, 1, 10.1016/S0006-8993(96)00952-3 Bodineau, 2008, Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension, Hypertension, 51, 1318, 10.1161/HYPERTENSIONAHA.107.098772 Harding, 1987, Angiotensin-sensitive neurons in the rat paraventricular nucleus: relative potencies of angiotensin II and angiotensin III, Brain Res., 410, 130, 10.1016/S0006-8993(87)80033-1 Felix, 1978, Angiotensin receptive neurones in the subfornical organ structure-activity relations, Brain Res., 149, 107, 10.1016/0006-8993(78)90591-7 Harding, 1987, The effects of the aminopeptidase inhibitors amastatin and bestatin on angiotensin-evoked neuronal activity in rat brain, Brain Res., 424, 299, 10.1016/0006-8993(87)91474-0 Wright, 1997, Important roles for angiotensin III and IV in the brain renin- angiotensin system, Brain Res. Rev., 25, 96, 10.1016/S0165-0173(97)00019-2 Llorens-Cortes, 2002, Organisation and functional role of the brain angiotensin system, J. Renin. Angiotensin. Aldosterone. Syst., 3, S39, 10.3317/jraas.2002.029 Saavedra, 1992, Brain and pituitary angiotensin, Endocr. Rev., 13, 329, 10.1210/edrv-13-2-329 Ganong, 1993, Blood, pituitary, and brain renin-Angiotensin systems and regulation of secretion of anterior pituitary gland, Front. Neuroendocrinol., 14, 233, 10.1006/frne.1993.1008 Wright, 2012, Focus on brain angiotensin III and aminopeptidase a in the control of hypertension, Int. J. Hypertens., 2012 Papouchado, 1995, Angiotensin III modulates noradrenaline uptake and release in the rat hypothalamus, J. Auton. Pharmacol., 15, 1, 10.1111/j.1474-8673.1995.tb00342.x Wilson, 2005, Roles of brain angiotensins II and III in thirst and sodium appetite, Brain Res., 1060, 108, 10.1016/j.brainres.2005.08.032 Tseng, 1994, Cardiovascular effects of angiotensin III in brainstem nuclei of normotensive and hypertensive rats, J.Pharmacol.Exp.Ther, 268, 558 Fink, 1985, Hypertension during chronic peripheral and central infusion of angiotensin III, Am. J. Physiol., 249, E201 Kokje, 2007, Central pressor actions of aminopeptidase-resistant angiotensin II analogs: challenging the angiotensin III hypothesis, Hypertension, 49, 1328, 10.1161/HYPERTENSIONAHA.107.087130 Wright, 1996, Angiotensin III and IV activation of the brain AT1 receptor subtype in cardiovascular function, Peptides, 17, 1365, 10.1016/S0196-9781(96)00226-4 Zini, 1997, Aminopeptidase A: Distribution in rat brain nuclei and increased activity in spontaneously hypertensive rats, Neuroscience, 78, 1187, 10.1016/S0306-4522(96)00660-4 De Mota, 2008, Human brain aminopeptidase A: Biochemical properties and distribution in brain nuclei, J. Neurochem., 106, 416, 10.1111/j.1471-4159.2008.05402.x Gao, 2014, A new strategy for treating hypertension by blocking the activity of the brain renin–angiotensin system with aminopeptidase A inhibitors, Clin. Sci., 127, 135, 10.1042/CS20130396 Wang, 1993, Histidine residue in the zinc-binding motif of aminopeptidase A is critical for enzymatic activity, Proc. Natl. Acad. Sci. U. S. A., 90, 1222, 10.1073/pnas.90.4.1222 Vazeux, 1996, Identification of glutamate residues essential for catalytic activity and zinc coordination in aminopeptidase A, J. Biol. Chem., 271, 9069, 10.1074/jbc.271.15.9069 Vazeux, 1997, A tyrosine residue essential for catalytic activity in aminopeptidase A, Biochem. J., 327, 883, 10.1042/bj3270883 Vazeux, 1998, A glutamate residue contributes to the exopeptidase specificity in aminopeptidase A, Biochem. J., 334, 407, 10.1042/bj3340407 John Kenny, 1980, Proteins of the kidney microvillar membrane: topological considerations, Int. J. Biochem., 12, 215, 10.1016/0020-711X(80)90072-5 Wright, 1990, Intracerebroventricularly infused [d-Arg1]angiotensin III, is superior to [d-Asp1]angiotensin II, as a pressor agent in rats, Brain Res., 514, 5, 10.1016/0006-8993(90)90428-E Reaux, 2000, Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure, Biochem. Soc. Trans., 28, 435, 10.1042/bst0280435 Llorens-Cortes, 2008, The neuroendocrine view of the angiotensin and apelin systems, J. Neuroendocrinol., 20, 279, 10.1111/j.1365-2826.2007.01642.x Marc, 2012, Central antihypertensive effects of orally active aminopeptidase an inhibitors in spontaneously hypertensive rats, Hypertension, 60, 411, 10.1161/HYPERTENSIONAHA.112.190942 Balavoine, 2014, Randomised, double-blind, placebo-controlled, dose-escalating phase i study of qgc001, a centrally acting aminopeptidase an inhibitor prodrug, Clin. Pharmacokinet., 53, 385, 10.1007/s40262-013-0125-y Bader, 2013, ACE2, angiotensin-(1–7), and Mas: the other side of the coin, Pflugers Arch, Eur. J. Physiol., 465, 79, 10.1007/s00424-012-1120-0 http://www.quantum-genomics.com/www/en/science/qgc001-program/. Huang, 2013, Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction, Cardiovasc. Res., 97, 424, 10.1093/cvr/cvs420 Karnik, 2015, Angiotensin receptors: interpreters of pathophysiological angiotensinergic stimuli, Pharmacol. Rev., 67, 754, 10.1124/pr.114.010454 Albiston, 2001, Evidence that the angiotensin IV (AT4) receptor is the enzyme insulin-regulated aminopeptidase, J. Biol. Chem., 276, 48623, 10.1074/jbc.C100512200 Wright, 2015, The development of small molecule angiotensin IV analogs to treat Alzheimer’s and Parkinson’s diseases, Prog. Neurobiol., 125, 26, 10.1016/j.pneurobio.2014.11.004 Li, 1997, Comparative vasoconstrictor effects of angiotensin-ii angiotensin-iii, and angiotensin IV in human isolated saphenous- vein, J. Cardiovasc. Pharmacol., 29, 451, 10.1097/00005344-199704000-00004 Yang, 2008, Brain and peripheral angiotensin II type 1 receptors mediate renal vasoconstrictor and blood pressure responses to angiotensin IV in the rat, J. Hypertens., 26, 998, 10.1097/HJH.0b013e3282f5ed58 Lochard, 2004, Chronic production of angiotensin IV in the brain leads to hypertension that is reversible with an angiotensin II AT1 receptor antagonist, Circ. Res., 94, 1451, 10.1161/01.RES.0000130654.56599.40 Benoist, 2014, The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system, J. Pharmacol. Exp. Ther., 351, 390, 10.1124/jpet.114.218735 Chappell, 1989, Identification of Angiotensin-(1–7) in Rat Brain – Evidence for differential processing of angiotensin peptides, J. Biol. Chem., 264, 16518, 10.1016/S0021-9258(19)84737-3 Metzger, 1995, Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues, FEBS Lett., 357, 27, 10.1016/0014-5793(94)01292-9 Xu, 2008, Endothelial dysfunction and elevated blood pressure in Mas gene-deleted mice, Hypertension, 51, 574, 10.1161/HYPERTENSIONAHA.107.102764 Du, 2013, The effects of angiotensin II and angiotensin-(1–7) in the rostral ventrolateral medulla of rats on stress-Induced hypertension, PLoS One., 8, 1, 10.1371/journal.pone.0070976 Li, 2013, Angiotensin-(1–7) in the rostral ventrolateral medulla modulates enhanced cardiac sympathetic afferent reflex and sympathetic activation in renovascular hypertensive rats, Hypertension, 61, 820, 10.1161/HYPERTENSIONAHA.111.00191 Becker, 2007, Immunofluorescence localization of the receptor Mas in cardiovascular-related areas of the rat brain, Am. J. Physiol. Heart Circ. Physiol., 293, H1416, 10.1152/ajpheart.00141.2007 Freund, 2012, Immunohistochemical localization of the angiotensin-(1–7) receptor Mas in the murine forebrain, Cell Tissue Res., 348, 29, 10.1007/s00441-012-1354-3 Doobay, 2007, Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system, Am. J. Physiol. Regul. Integr. Comp. Physiol., 292, R373, 10.1152/ajpregu.00292.2006 Santos, 1994, Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors, Brain Res. Bull., 35, 293, 10.1016/0361-9230(94)90104-X Fontes, 2016, Brain angiotensin-(1–7)/Mas axis: a new target to reduce the cardiovascular risk to emotional stress, Neuropeptides, 56, 9, 10.1016/j.npep.2015.10.003 Gironacci, 2014, Protective axis of the renin–angiotensin system in the brain, Clin. Sci., 127, 295, 10.1042/CS20130450 Ferreira, 2008, Hemodynamic effect produced by microinjection of angiotensins at the caudal ventrolateral medulla of spontaneously hypertensive rats, Neuroscience, 151, 1208, 10.1016/j.neuroscience.2007.11.042 Chaves, 2000, Modulation of the baroreflex control of heart rate by angiotensin-(1–7) at the nucleus tractus solitarii of normotensive and spontaneously hypertensive rats, J. Hypertens., 18, 1841, 10.1097/00004872-200018120-00019 Campagnole-Santos, 1989, Cardiovascular effects of angiotensin-(1–7) injected into the dorsal medulla of rats, Am. J. Physiol. – Hear. Circ. Physiol., 257, H324, 10.1152/ajpheart.1989.257.1.H324 Campagnole-Santos, 1992, Differential baroreceptor reflex modulation by centrally infused angiotensin peptides, Am. J. Physiol., 263, R89 Santos, 2014, Angiotensin-(1–7), Hypertension, 63, 1138, 10.1161/HYPERTENSIONAHA.113.01274 Britto, 1997, Role of angiotensin-(1–7) in the modulation of the baroreflex in renovascular hypertensive rats, Hypertension, 30, 549, 10.1161/01.HYP.30.3.549 Heringer-Walther, 2001, Baroreflex improvement in SHR after ACE inhibition involves angiotensin-(1–7), Hypertension, 37, 1309, 10.1161/01.HYP.37.5.1309 Oliveira, 1996, Changes in the baroreflex control of heart rate produced by central infusion of selective angiotensin antagonists in hypertensive rats, Hypertension, 27, 1284, 10.1161/01.HYP.27.6.1284 Diz, 2011, Angiotensin peptides and central autonomic regulation, Curr. Opin. Pharmacol., 11, 131, 10.1016/j.coph.2011.02.001 Sakima, 2005, Impaired heart rate baroreflex in older rats: role of endogenous angiotensin-(1–7) at the nucleus tractus solitarii, Hypertension, 46, 333, 10.1161/01.HYP.0000178157.70142.33 Stegbauer, 2004, Angiotensin-(1–7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats, Cardiovasc. Res., 61, 352, 10.1016/j.cardiores.2003.11.017 Gironacci, 2004, Angiotensin-(1–7) inhibits the angiotensin II-enhanced norepinephrine release in coarcted hypertensive rats, Regul. Pept., 118, 45, 10.1016/j.regpep.2003.10.026 Gironacci, 2004, Angiotensin-(1–7) inhibitory mechanism of norepinephrine release in hypertensive rats, Hypertension, 44, 783, 10.1161/01.HYP.0000143850.73831.9d Gironacci, 2000, Angiotensin-(1–7) does not affect norepinephrine neuronal uptake or catabolism in rat hypothalamus and atria, Cell. Mol. Neurobiol., 20, 773, 10.1023/A:1007063111479 Gironacci, 2000, Angiotensin-(1–7) reduces norepinephrine release through a nitric oxide mechanism in rat hypothalamus, Hypertension, 35, 1248, 10.1161/01.HYP.35.6.1248 Lopez Verrilli, 2009, Angiotensin-(1–7) through AT2 receptors mediates tyrosine hydroxylase degradation via the ubiquitin-proteasome pathway, J. Neurochem., 109, 326, 10.1111/j.1471-4159.2009.05912.x Alzamora, 2002, Hypotensive effect of ANG II and ANG-(1–7) at the caudal ventrolateral medulla involves different mechanisms, Am. J. Physiol. Regul. Integr. Comp. Physiol, 283, R1187, 10.1152/ajpregu.00580.2001 Sun, 2012, Angiotensin II and angiotensin-(1–7) in paraventricular nucleus modulate cardiac sympathetic afferent reflex in Renovascular hypertensive rats, PLoS One., 7, 10.1371/journal.pone.0052557 Da Silva, 2011, Chronic infusion of angiotensin receptor antagonists in the hypothalamic paraventricular nucleus prevents hypertension in a rat model of sleep apnea, Brain Res., 1368, 231, 10.1016/j.brainres.2010.10.087 Zhou, 2010, Angiotensin-(1–7) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats, Pflugers Arch, Eur. J. Physiol., 459, 681, 10.1007/s00424-010-0793-5 Li, 2015, Angiotensin-(1–7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats, J. Am. Soc. Hypertens., 9, 865, 10.1016/j.jash.2015.08.005 Li, 2012, Superoxide anions modulate the effects of angiotensin-(1–7) in the rostral ventrolateral medulla on cardiac sympathetic afferent reflex and sympathetic activity in rats, Neuroscience, 223, 388, 10.1016/j.neuroscience.2012.07.048 Guimaraes, 2012, Chronic infusion of angiotensin- (1–7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats, Am J Physiol Hear. Circ Physiol., 303, H393, 10.1152/ajpheart.00075.2012 Jiang, 2013, Angiotensin-(1–7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats, Pharmacol. Res., 67, 84, 10.1016/j.phrs.2012.10.014 Senanayake, 1994, Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats, Peptides, 15, 919, 10.1016/0196-9781(94)90051-5 Diz, 2008, Angiotensin-(1–7) and baroreflex function in nucleus tractus solitarii of (mRen2)27 transgenic rats, J. Cardiovasc. Pharmacol., 51, 542, 10.1097/FJC.0b013e3181734a54 Kangussu, 2015, Activation of angiotensin-(1–7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats, Neuropharmacology, 97, 58, 10.1016/j.neuropharm.2015.04.036 De Moura, 2010, Altered cardiovascular reflexes responses in conscious Angiotensin-(1–7) receptor Mas-knockout mice, Peptides, 31, 1934, 10.1016/j.peptides.2010.06.030 Nautiyal, 2012, Central angiotensin-(1–7) improves vagal function independent of blood pressure in hypertensive (mRen2)27 rats, Hypertension, 60, 1257, 10.1161/HYPERTENSIONAHA.112.196782 Feng, 2010, Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension, Circ. Res., 106, 373, 10.1161/CIRCRESAHA.109.208645 Xiao, 2011, Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure, Hypertension, 58, 1057, 10.1161/HYPERTENSIONAHA.111.176636 Xia, 2013, Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension, Circ. Res., 113, 1087, 10.1161/CIRCRESAHA.113.301811 Wang, 2014, Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats, AJP Hear, Circ. Physiol., 307, H182, 10.1152/ajpheart.00518.2013 Yamazato, 2007, Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats, Hypertension, 49, 926, 10.1161/01.HYP.0000259942.38108.20 Yamazato, 2011, Gene transfer of angiotensin-converting enzyme 2 in the nucleus tractus solitarius improves baroreceptor heart rate reflex in spontaneously hypertensive rats, J. Renin. Angiotensin. Aldosterone. Syst., 12, 456, 10.1177/1470320311412809 Silva-Barcellos, 2001, Long-lasting cardiovascular effects of liposome-entrapped angiotensin-(1–7) at the rostral ventrolateral medulla, Hypertension, 38, 1266, 10.1161/hy1201.096056 Sampaio, 2003, Systemic and regional hemodynamic effects of angiotensin-(1–7) in rats, Am. J. Physiol. Heart Circ. Physiol., 284, H1985, 10.1152/ajpheart.01145.2002 Lu, 2008, Effects of intracerebroventricular infusion of angiotensin-(1–7) on bradykinin formation and the kinin receptor expression after focal cerebral ischemia-reperfusion in rats, Brain Res., 1219, 127, 10.1016/j.brainres.2008.04.057 Zhang, 2008, Central administration of angiotensin-(1–7) stimulates nitric oxide release and upregulates the endothelial nitric oxide synthase expression following focal cerebral ischemia/reperfusion in rats, Neuropeptides, 42, 593, 10.1016/j.npep.2008.09.005 Igase, 2005, Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1–7) expression in the aorta of spontaneously hypertensive rats, AJP Hear, Circ. Physiol., 289, H1013, 10.1152/ajpheart.00068.2005 Ishiyama, 2004, Upregulation of angiotensin-Converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors, Hypertension, 43, 970, 10.1161/01.HYP.0000124667.34652.1a Blanke, 2015, Effect of angiotensin(1–7) on heart function in an experimental rat model of obesity, Front. Physiol., 6, 1, 10.3389/fphys.2015.00392 Winkler, 2016, The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats, Br. J. Pharmacol., 173, 1602, 10.1111/bph.13461 Nagata, 2006, Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system, Biochem. Biophys. Res. Commun., 350, 1026, 10.1016/j.bbrc.2006.09.146 Ahmad, 2014, Angiotensin-(1–12): A chymase-mediated cellular angiotensin II substrate, Curr. Hypertens. Rep., 16, 1, 10.1007/s11906-014-0429-9 Arnold, 2010, Angiotensin-(1–12) requires angiotensin converting enzyme and AT1 receptors for cardiovascular actions within the solitary tract nucleus, Am J Physiol Hear. Circ Physiol., 299, H763, 10.1152/ajpheart.00345.2010 Isa, 2009, Chronic immunoneutralization of brain angiotensin-(1–12) lowers blood pressure in transgenic (mRen2)27 hypertensive rats, Am. J. Physiol. Regul. Integr. Comp. Physiol, 297, R111, 10.1152/ajpregu.90588.2008 Arakawa, 2011, The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II, Am J Physiol Hear. Circ Physiol., 300, H951, 10.1152/ajpheart.01144.2010 Chitravanshi, 2012, Cardiovascular actions of angiotensin-(1–12) in the hypothalamic paraventricular nucleus of the rat are mediated via angiotensin II, Exp. Physiol., 97, 1001, 10.1113/expphysiol.2011.062471 Arakawa, 2013, Angiotensin-(1–12) in the rostral ventrolateral medullary pressor area of the rat elicits sympathoexcitatory responses, Exp. Physiol., 98, 94, 10.1113/expphysiol.2012.067116 Kawabe, 2014, Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat, Am J Physiol Hear. Circ Physiol., 306, H438, 10.1152/ajpheart.00628.2013 Chitravanshi, 2011, Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat, Am. J. Physiol. Heart Circ. Physiol., 300, H230, 10.1152/ajpheart.00861.2010 Paula, 1999, Potentiation of the hypotensive effect of bradykinin by angiotensin-(1–7)-related peptides, Peptides, 20, 493, 10.1016/S0196-9781(99)00031-5 Handa, 2000, Metabolism alters the selectivity of angiotensin-(1–7) receptor ligands for angiotensin receptors, J. Am. Soc. Nephrol., 11, 1377, 10.1681/ASN.V1181377 Etelvino, 2014, New components of the renin-angiotensin system: alamandine and the mas-related G protein-coupled receptor D, Curr. Hypertens. Rep., 16, 10, 10.1007/s11906-014-0433-0 Avula, 2013, Expression and distribution patterns of mas-related gene receptor subtypes A-H in the mouse intestine: inflammation-induced changes, Histochem. Cell Biol., 139, 639, 10.1007/s00418-013-1086-9 Bader, 2012, New therapeutic pathways in the RAS, J. Renin-Angiotensin-Aldosterone Syst., 13, 505, 10.1177/1470320312466519 Passos-Silva, 2015, Angiotensins as therapeutic targets beyond heart disease, Trends Pharmacol. Sci., 36, 310, 10.1016/j.tips.2015.03.001 Lautner, 2013, Discovery and characterization of alamandine: a novel component of the renin-angiotensin system, Circ. Res., 112, 1104, 10.1161/CIRCRESAHA.113.301077 Villela, 2014, Alamandine: a new member of the angiotensin family, Curr. Opin. Nephrol. Hypertens., 23, 130, 10.1097/01.mnh.0000441052.44406.92 Hrenak, 2016, Angiotensin A/Alamandine/MrgD axis: another clue to understanding cardiovascular pathophysiology, Int. J. Mol. Sci., 17, 10.3390/ijms17071098 Jankowski, 2007, Mass-spectrometric identification of a novel angiotensin peptide in human plasma, Arterioscler. Thromb. Vasc. Biol., 27, 297, 10.1161/01.ATV.0000253889.09765.5f Campbell, 1977, (Des-Asp 1) angiotensin I: a study of its pressor and steroidogenic activities in conscious rats, Endocr. Rev, 100, 46, 10.1210/endo-100-1-46 Mogi, 2012, Roles of brain angiotensin II in cognitive function and dementia, Int. J. Hypertens., 2012, 10.1155/2012/169649 Villapol, 2015, Neuroprotective effects of angiotensin receptor blockers, Am. J. Hypertens., 28, 289, 10.1093/ajh/hpu197 Wright, 2013, A role for the brain RAS in Alzheimer’s and Parkinson’s diseases, Front. Endocrinol., 4, 158, 10.3389/fendo.2013.00158 Saavedra, 2012, Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders, Clin. Sci., 123, 567, 10.1042/CS20120078 Kehoe, 2017, Angiotensin-III is increased in alzheimer’s disease in association with amyloid-β and tau pathology, J. Alzheimer’s Dis., 58, 203, 10.3233/JAD-161265 Santos, 2006, Pharmacological effects of AVE 0991, a nonpeptide angiotensin-(1–7) receptor agonist, Cardiovasc. Drug Rev., 24, 239, 10.1111/j.1527-3466.2006.00239.x Paulis, 2015, New developments in the pharmacological treatment of hypertension: dead-End or a glimmer at the horizon?, Curr. Hypertens. Rep., 17, 10.1007/s11906-015-0557-x Healy, 1985, Angiotensinogen levels in the brain and cerebrospinal fluid of the genetically hypertensive rat, Hypertension, 7, 752, 10.1161/01.HYP.7.5.752 Imai, 1968, Plasma renin and angiotensinogen levels in pathological states associated with oedema, arch. diss, Childh, 43, 475 Wysocki, 2015, Plasma and kidney angiotensin peptides: importance of the aminopeptidase A/Angiotensin III axis, Am. J. Hypertens., 28, 1418, 10.1093/ajh/hpv054 Miners, 2009, Angiotensin-converting enzyme levels and activity in Alzheimer’s disease: differences in brain and CSF ACE and association with ACE1 genotypes, Am. J. Transl. Res., 1, 163 Cambien, 1994, Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction, Circulation, 90, 669, 10.1161/01.CIR.90.2.669 Piedfer, 2011, Aminopeptidase-N/CD13 is a potential proapoptotic target in human myeloid tumor cells, FASEB J., 25, 2831, 10.1096/fj.11-181396 Gabrilovac, 2011, Expression, regulation and functional activities of aminopeptidase N (EC 3.4.11.2; APN; CD13) on murine macrophage J774 cell line, Immunobiology, 216, 132, 10.1016/j.imbio.2010.06.005 Hensbergen van, 2002, Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid 1, Clin. Cancer Res., 8, 3747 Cheng, 2015, Effects of female sex hormones on expression of the Ang-(1–7)/Mas-R/nNOS pathways in rat brain, Can. J. Physiol. Pharmacol., 998, 993, 10.1139/cjpp-2015-0087 Jalil, 2003, Levels of plasma angiotensin-(1–7) in patients with hypertension who have the angiotensin-I-converting enzyme deletion/deletion genotype, Am. J. Cardiol., 92, 749, 10.1016/S0002-9149(03)00847-6 Ferreira, 2007, Angiotensin-(3–7) pressor effect at the rostral ventrolateral medulla, Regul. Pept., 141, 168, 10.1016/j.regpep.2006.12.031