Abstract
Among the main bioactive peptides of the brain renin–angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.
Similar content being viewed by others
References
Smith DH (2002) Treatment of hypertension with an angiotensin II-receptor antagonist compared with an angiotensin-converting enzyme inhibitor: a review of clinical studies of telmisartan and enalapril. Clin Ther 24:1484–1501
Levine CB, Fahrbach KR, Frame D, Connelly JE, Estok RP, Stone LR, Ludensky V (2003) Effect of amlodipine on systolic blood pressure. Clin Ther 25:35–57
Corvol P, Plouin PF (2002) Angiotensin II receptor blockers: current status and future prospects. Drugs 62(Spec No 1):53–64
Israili ZH, Hall WD (1992) Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 117:234–242
Owen HG, Brecher ME (1994) Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion 34:891–894
Fried MR, Eastlund T, Christie B, Mullin GT, Key NS (1996) Hypotensive reactions to white cell-reduced plasma in a patient undergoing angiotensin-converting enzyme inhibitor therapy. Transfusion 36:900–903
Holm EA, Randlov A, Strandgaard S (1996) Brief report: acute renal failure after losartan treatment in a patient with bilateral renal artery stenosis. Blood Press 5:360–362
Saine DR, Ahrens ER (1996) Renal impairment associated with losartan. Ann Intern Med 124:775
Johansen TL, Kjaer A (2001) Reversible renal impairment induced by treatment with the angiotensin II receptor antagonist candesartan in a patient with bilateral renal artery stenosis. BMC Nephrol 2:1
Saunders EJ, Saunders JA (1990) Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin. Health Care Women Int 11:423–432
Radevski I, Skudicky D, Candy G, Sathekge S, Strugo V, Sareli P (1999) Antihypertensive monotherapy with nisoldipine CC is superior to enalapril in black patients with severe hypertension. Am J Hypertens 12:194–203
Oparil S, Chen YF, Berecek KH, Calhoun DA, Wyss JM (1995) The role of central nervous system in hypertension. In: Laragh LH, Brenner BM (eds) Hypertension: pathology. diagnosis and management. Raven Press, pp 713–740
Esler M (1995) Sympathetic nervous system: contribution to human hypertension and related cardiovascular diseases. J Cardiovasc Pharmacol 26(Suppl 2):S24–S28
Lohmeier TE (2001) The sympathetic nervous system and long-term blood pressure regulation. Am J Hypertens 14:147S–154S
Veerasingham SJ, Raizada MK (2003) Brain renin–angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 139:191–202
Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7:335–346
Ganten D, Hermann K, Bayer C, Unger T, Lang RE (1983) Angiotensin synthesis in the brain and increased turnover in hypertensive rats. Science 221:869–871
Reaux A, Nadia de MN, Zini S, Cadel S, Fournie-Zaluski MC, Roques BP, Corvol P, Llorens-Cortes C (1999) PC18, a specific aminopeptidase N inhibitor, induces vasopressin release by increasing the half-life of brain angiotensin III. Neuroendocrinology 69:370–376
Basso N, Ruiz P, Mangiarua E, Taquini AC (1981) Renin-like activity in the rat brain during the development of DOC-salt hypertension. Hypertension 3:II-7
Davisson RL, Yang G, Beltz TG, Cassell MD, Johnson AK, Sigmund CD (1998) The brain renin–angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes. Circ Res 83:1047–1058
Morimoto S, Cassell MD, Beltz TG, Johnson AK, Davisson RL, Sigmund CD (2001) Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter. Circ Res 89:365–372
Allen AM, Paxinos G, Song KF, Mendelhson FAO (1992) Localization of angiotensin receptor binding sites in the rat brain. In: Björklund A, Hökfelt T, Kuhar MJ (eds) Handbook of chemical neuroanatomy: neuropeptide receptors in the CNS, vol 11. Elsevier, New York, pp 1–37
Saavedra JM (1992) Brain and pituitary angiotensin. Endocr Rev 13:329–380
Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C (1997) Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Front Neuroendocrinol 18:383–439
Phillips MI (1987) Functions of angiotensin in the central nervous system. Annu Rev Physiol 49:413–435
Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE (1991) Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature 351:233–236
Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T (1993) Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 268:24543–24546
Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ (1993) Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem 268:24539–24542
Wright JW, Harding JW (1994) Brain angiotensin receptor subtypes in the control of physiological and behavioral responses. Neurosci Biobehav Rev 18:21–53
Caputo FA, Rowland NE, Fregly MJ (1992) Angiotensin-related intakes of water and NaCl in Fischer 344 and Sprague-Dawley rats. Am J Physiol 262:R382–R388
Wilson WL, Roques BP, Llorens-Cortes C, Speth RC, Harding JW, Wright JW (2005) Roles of brain angiotensins II and III in thirst and sodium appetite. Brain Res 1060:108–117
Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P, Llorens-Cortes C (1999) Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA 96:13415–13420
Fournie-Zaluski MC, Fassot C, Valentin B, Djordjijevic D, Reaux-Le GA, Corvol P, Roques BP, Llorens-Cortes C (2004) Brain renin–angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci USA 101:7775–7780
Malfroy B, Kado-Fong H, Gros C, Giros B, Schwartz JC, Hellmiss R (1989) Molecular cloning and amino acid sequence of rat kidney aminopeptidase M: a member of a super family of zinc-metallohydrolases. Biochem Biophys Res Commun 161:236–241
Wu Q, Lahti JM, Air GM, Burrows PD, Cooper MD (1990) Molecular cloning of the murine BP-1/6C3 antigen: a member of the zinc-dependent metallopeptidase family. Proc Natl Acad Sci USA 87:993–997
Vazeux G, Wang J, Corvol P, Llorens-Cortes C (1996) Identification of glutamate residues essential for catalytic activity and zinc coordination in aminopeptidase A. J Biol Chem 271:9069–9074
Khairallah PA, Bumpus FM, Page IH, Smeby RR (1963) Angiotensinase with a high degree of specificity in plasma and red cells. Science 140:672–674
Kugler P (1982) On angiotensin-degrading aminopeptidases in the rat kidney. Adv Anat Embryol Cell Biol 76:1–86
Bausback HH, Churchill L, Ward PE (1988) Angiotensin metabolism by cerebral microvascular aminopeptidase A. Biochem Pharmacol 37:155–160
Ahmad S, Ward PE (1990) Role of aminopeptidase activity in the regulation of the pressor activity of circulating angiotensins. J Pharmacol Exp Ther 252:643–650
Iturrioz X, Rozenfeld R, Michaud A, Corvol P, Llorens-Cortes C (2001) Study of asparagine 353 in aminopeptidase A: characterization of a novel motif (GXMEN) implicated in exopeptidase specificity of monozinc aminopeptidases. Biochemistry 40:14440–14448
Wilk S, Healy DP (1993) Glutamyl aminopeptidase (aminopeptidase A), the BP-1/6C3 antigen. Adv Neuroimmunol 3:195–207
Nagatsu I, Nagatsu T, Yamamoto T, Glenner GG, Mehl JW (1970) Purification of aminopeptidase A in human serum and degradation of angiotensin II by the purified enzyme. Biochim Biophys Acta 198:255–270
Ward PE, Benter IF, Dick L, Wilk S (1990) Metabolism of vasoactive peptides by plasma and purified renal aminopeptidase M. Biochem Pharmacol 40:1725–1732
Palmieri FE, Bausback HH, Ward PE (1989) Metabolism of vasoactive peptides by vascular endothelium and smooth muscle aminopeptidase M. Biochem Pharmacol 38:173–180
Hersh LB, Aboukhair N, Watson S (1987) Immunohistochemical localization of aminopeptidase M in rat brain and periphery: relationship of enzyme localization and enkephalin metabolism. Peptides 8:523–532
Healy DP, Wilk S (1993) Localization of immunoreactive glutamyl aminopeptidase in rat brain. II. Distribution and correlation with angiotensin II. Brain Res 606:295–303
Troyanovskaya M, Jayaraman G, Song L, Healy DP (2000) Aminopeptidase-A. I. CDNA cloning and expression and localization in rat tissues. Am J Physiol Regul Integr Comp Physiol 278:R413–R424
Zini S, Masdehors P, Lenkei Z, Fournie-Zaluski MC, Roques BP, Corvol P, Llorens-Cortes C (1997) Aminopeptidase A: distribution in rat brain nuclei and increased activity in spontaneously hypertensive rats. Neuroscience 78:1187–1193
Lind RW, Ganten D (1990) Angiotensin. Handbook of chemical neuroanatomy, vol 9, part II. Elsevier, pp 165–286
Harding JW, Yoshida MS, Dilts RP, Woods TM, Wright JW (1986) Cerebroventricular and intravascular metabolism of [125I]angiotensins in rat. J Neurochem 46:1292–1297
Abhold RH, Sullivan MJ, Wright JW, Harding JW (1987) Binding, degradation and pressor activity of angiotensins II and III after aminopeptidase inhibition with amastatin and bestatin. J Pharmacol Exp Ther 242:957–962
Harding JW, Felix D (1987) The effects of the aminopeptidase inhibitors amastatin and bestatin on angiotensin-evoked neuronal activity in rat brain. Brain Res 424:299–304
Dewey AL, Wright JW, Hanesworth JM, Harding JW (1988) Effects of aminopeptidase inhibition on the half-lives of [125I]angiotensins in the cerebroventricles of the rat. Brain Res 448:369–372
Tieku S, Hooper NM (1992) Inhibition of aminopeptidases N, A and W. A re-evaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme. Biochem Pharmacol 44:1725–1730
Checler F (1993) Neuropetide-degrading peptidases. In: Parvez SH, Naoi M, Nagatsu T, Parvez S (eds) Methods in neurotransmitter and neuropeptide research. Elsevier, Amsterdam, pp 375–418
Chauvel EN, Coric P, Llorens-Cortes C, Wilk S, Roques BP, Fournie-Zaluski MC (1994) Investigation of the active site of aminopeptidase A using a series of new thiol-containing inhibitors. J Med Chem 37:1339–1346
Fournie-Zaluski MC, Coric P, Turcaud S, Lucas E, Noble F, Maldonado R, Roques BP (1992) “Mixed inhibitor-prodrug” as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes. J Med Chem 35:2473–2481
Hopsu V, Makinen EO (1966) Two methods for the demonstration of noradrenaline-containing adrenal medullary cells. J Histochem Cytochem 14:434–435
Cadel S, Pierotti AR, Foulon T, Creminon C, Barre N, Segretain D, Cohen P (1995) Aminopeptidase-B in the rat testes: isolation, functional properties and cellular localization in the seminiferous tubules. Mol Cell Endocrinol 110:149–160
Zini S, Fournie-Zaluski MC, Chauvel E, Roques BP, Corvol P, Llorens-Cortes C (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 USA 93:11968–11973
Ross CA, Ruggiero DA, Park DH, Joh TH, Sved AF, Fernandez-Pardal J, Saavedra JM, Reis DJ (1984) Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J Neurosci 4:474–494
Brown DL, Guyenet PG (1985) Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats. Circ Res 56:359–369
Wright JW, Morseth SL, Abhold RH, Harding JW (1985) Pressor action and dipsogenicity induced by angiotensin II and III in rats. Am J Physiol 249:R514–R521
Wright JW, Jensen LL, Cushing LL, Harding JW (1989) Leucine aminopeptidase M-induced reductions in blood pressure in spontaneously hypertensive rats. Hypertension 13:910–915
Felix D, Schlegel W (1978) Angiotensin receptive neurones in the subfornical organ. Structure–activity relations. Brain Res 149:107–116
Harding JW, Jensen LL, Hanesworth JM, Roberts KA, Page TA, Wright JW (1992) Release of angiotensins in paraventricular nucleus of rat in response to physiological and chemical stimuli. Am J Physiol 262:F17–F23
Wright JW, Roberts KA, Cook VI, Murray CE, Sardinia MF, Harding JW (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
Batt CM, Klein EW, Harding JW, Wright JW (1988) Pressor responses to amastatin, bestatin and Plummer’s inhibitors are suppressed by pretreatment with the angiotensin receptor antagonist sarthran. Brain Res Bull 21:731–735
Morton JJ, Casals-Stenzel J, Lever AF, Millar JA, Riegger AJ, Tree M (1979) Inhibitors of the renin–angiotensin system in experimental hypertension, with a note on the measurement of angiotensin I, II and III during infusion of converting-enzyme inhibitor. Br J Clin Pharmacol 7(Suppl 2):233S–241S
Nishimura M, Ohtsuka K, Sakamoto M, Nanbu A, Takahashi H, Yoshimura M (1998) Roles of brain angiotensin II and C-type natriuretic peptide in deoxycorticosterone acetate-salt hypertension in rats. J Hypertens 16:1175–1185
Masuyama Y, Tsuda K, Kuchii M, Nishio I (1986) Peripheral neural mechanism of hypertension in rat models—peripheral sympathetic neurotransmission in hypertension. J Hypertens 4(Suppl 3):S189–S192
Song L, Wilk S, Healy DP (1997) Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II-induced dipsogenic and pressor responses. Brain Res 744:1–6
Wright JW, Tamura-Myers E, Wilson WL, Roques BP, Llorens-Cortes C, Speth RC, Harding JW (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–R733
Kokje RJ, Wilson WL, Brown TE, Karamyan VT, Wright JW, Speth RC (2007) Central pressor actions of aminopeptidase-resistant angiotensin II analogs: challenging the angiotensin III hypothesis. Hypertension 49:1328–1335
Reaux A, Fournie-Zaluski MC, Llorens-Cortes C (2001) Angiotensin III: a central regulator of vasopressin release and blood pressure. Trends Endocrinol Metab 12:157–162
Bakris G, Bursztyn M, Gavras I, Bresnahan M, Gavras H (1997) Role of vasopressin in essential hypertension: racial differences. J Hypertens 15:545–550
Albiston AL, Mustafa T, McDowall SG, Mendelsohn FA, Lee J, Chai SY (2003) AT4 receptor is insulin-regulated membrane aminopeptidase: potential mechanisms of memory enhancement. Trends Endocrinol Metab 14:72–77
Wright JW, Harding JW (2004) The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory. Prog Neurobiol 72:263–293
Ferrario CM (2006) Angiotensin-converting enzyme 2 and angiotensin-(1–7): an evolving story in cardiovascular regulation. Hypertension 47:515–521
Acknowledgments
We would like to thank all of our collaborators for the work on the brain RAS especially Pr B. Roques, Pr M.-C. Fournie-Zaluski and Dr N. Inguimbert who designed and synthesized specific and selective APA and APN inhibitors. This study was financially supported by grants from the Agence Nationale de la Recherche (“EMERGENCE ET MATURATION” n° ANR-05-EMPB-015-02) and Quantum Genomics Corp. and by the Institut National de la Santé et de la Recherche Médicale.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bodineau, L., Frugière, A., Marc, Y. et al. Aminopeptidase A inhibitors as centrally acting antihypertensive agents. Heart Fail Rev 13, 311–319 (2008). https://doi.org/10.1007/s10741-007-9077-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-007-9077-3