Heart Failure Reviews

, Volume 13, Issue 3, pp 273–284 | Cite as

New insights into the importance of aminopeptidase A in hypertension

  • Shigehiko Mizutani
  • Masakazu IshiiEmail author
  • Akira Hattori
  • Seiji Nomura
  • Yasushi Numaguchi
  • Masafumi Tsujimoto
  • Hiroshi Kobayshi
  • Toyoaki Murohara
  • John W. Wright


The renin-angiotensin system (RAS) plays an important role in the maintenance of normal blood pressure and the etiology of hypertension; however, minimal attention has been paid to the degradation of the effector peptide, angiotensin II (AngII). Since aminopeptidase A (APA)-deficient mice develop hypertension APA appears to be an essential enzyme in the control of blood pressure via degradation of AngII. The robust hypertension seen in the spontaneously hypertensive rat (SHR) is due to activation of the RAS, and an accompanying decrease in kidney APA. Changes in APA have also been measured during the activation of the RAS in the Goldblatt hypertension model and Dahl salt-sensitive (DSS) rat. The DSS rat shows an elevation in renal APA activity at the onset of hypertension suggesting a protective role against elevations in circulating AngII, followed by decreased APA activity with advancing hypertension. Changes seen in human maternal serum APA activity during preeclampsia are similar to changes measured in renal APA in the DSS rat model. APA activity is higher than during normal pregnancy at the onset of preeclampsia, and with advancing preeclampsia (severe preeclampsia) declines below that seen during normal pregnancy. Serum APA activity is also increased during hormone replacement therapy (HRT), perhaps in reaction to elevated levels of AngII. Thus, it appears important to consider the relationship among activation of the RAS, circulating levels of AngII, and the availability of APA in hypertensive disorders.


Angiotensin II Aminopeptidase A Hypertensive rats Preeclampsia Hormone replacement therapy 



Angiotensin-converting enzyme


Angiotensin-converting enzyme 2


Aminopeptidase A


Aminopeptidase N


Area postrema


AT1 receptor blocker


AT1 receptor


AT2 receptor


Angiotensin I


Angiotensin II


Angiotensin III


Angiotensin IV


Circumventricular organs


Dahl Salt-resistant


Dahl Salt-sensitive


Acute heart failure


Hormone replacement Therapy




Nucleus of the solitary tract


Organum vasculosum of the lamina terminalis


Paraventricular nucleus


Renin-angiotensin system


Subfornical organ


Spontaneously hypertensive rat


Supraoptic nucleus




Two-kidney one-clip



We are grateful to Dr. Motowo Nakajima (Director, New Business & Personal Care Group, Johnson & Johnson) for contributing valuable comments on earlier drafts of this manuscript.


  1. 1.
    Mangos GJ (2006) Cardiovascular disease following pre-eclampsia: understanding the mechanisms. J Hyperten 24:639–641Google Scholar
  2. 2.
    Basile JN, Chrysant S (2006) The importance of early antihypertensive efficacy: the role of angiotensin therapy. J Hum Hyperten 20:169–175CrossRefGoogle Scholar
  3. 3.
    de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472PubMedGoogle Scholar
  4. 4.
    Gard PR (2002) The role of angiotensin II in cognition and behaviour. Eur J Pharmacol 438:1–14PubMedCrossRefGoogle Scholar
  5. 5.
    McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, Oldfield BJ, Mendelsohn FAO, Chai SY (2003) The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol 35:901–918PubMedCrossRefGoogle Scholar
  6. 6.
    Thomas WG, Mendelsohn FAO (2003) Molecules in focus: angiotensin receptors: form and function and distribution. Int J Biochem Cell Biol 35:774–779PubMedCrossRefGoogle Scholar
  7. 7.
    Wright JW, Harding JW (2004) The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory. Prog Neurobiol 72:263–293PubMedCrossRefGoogle Scholar
  8. 8.
    de Gasparo M, Siragy HM (1999) The AT2 receptor: fact, fancy and fantasy. Regul Pept 81:11–24PubMedCrossRefGoogle Scholar
  9. 9.
    Speth RC, Thompson SM, Johns SJ (1995) Angiotensin II receptors: structural and functional considerations. In: Mukhopadhyay AK, Raizada MK (eds) Current concepts: tissue renin angiotensin systems as local regulators in reproductive and endocrine organs. Plenum Press, New York, pp 169–192Google Scholar
  10. 10.
    Johnston CI (1990) Biochemistry and pharmacology of the renin-angiotensin system. Drugs 39:21–31PubMedCrossRefGoogle Scholar
  11. 11.
    Chauvel EN, Llorens-Cortes C, Coric P, Wilk S, Roques BP, Fournie-Zaluski MC (1994) Differential inhibition of aminopeptidase A and aminopeptidase N by new-amino thiols. J Med Chem 37:2950–2957PubMedCrossRefGoogle Scholar
  12. 12.
    Mizutani S, Akiyama H, Kurauchi O, Taira H, Narita O, Tomoda Y (1985) In vitro degradation of angiotensin II (A-II) by human placental subcellular fractions, pregnancy sera and purified placental aminopeptidases. Acta Endocrinol 110:35–139Google Scholar
  13. 13.
    Rich DH, Moon BJ, Harbeson S (1984) Inhibition of aminopeptidases by amastatin and bestatin derivatives, effect of inhibitor structure on slow-binding processes. J Med Chem 27:417–422PubMedCrossRefGoogle Scholar
  14. 14.
    Wilk S, Healy DP (1993) Glutamyl aminopeptidase (aminopeptidase A), the BP-1/6C3 antigen. Adv Neuroimmunol 3:195–207CrossRefGoogle Scholar
  15. 15.
    Wright JW, Harding JW (1997) Important roles for angiotensin III and IV in the brain renin-angiotensin system. Brain Res Rev 25:96–124PubMedCrossRefGoogle Scholar
  16. 16.
    Sayeski PP, Ali MS, Semeniuk DJ, Doan TN, Bernstein KE (1998) Angiotensin II signal transduction pathways. Regul Pept 78:19–29PubMedCrossRefGoogle Scholar
  17. 17.
    Guo DF, Inagami T (1994) The genomic organization of the rat angiotensin II receptor AT1B. Biochim Biophys Acta 1218:91–94PubMedGoogle Scholar
  18. 18.
    Saavedra JM (1999) Emerging features of brain angiotensin receptors. Regul Pept 85:31–45PubMedCrossRefGoogle Scholar
  19. 19.
    Phillips MI, Sumners C (1998) Angiotensin II in central nervous system physiology. Regul Pept 78:1–11PubMedCrossRefGoogle Scholar
  20. 20.
    Wright JW, Harding JW (1992) Regulatory role of brain angiotensins in the control of physiological and behavioral responses. Brain Res Rev 17:227–262PubMedCrossRefGoogle Scholar
  21. 21.
    Culman J, Blume A, Gohlke P, Unger T (2002) The renin-angiotensin system in the brain: Possible therapeutic implications for AT1-receptor blockers. J Hum Hyper 16: S64–S70CrossRefGoogle Scholar
  22. 22.
    Muratami H (1996) Brain angiotensin and circulatory control. Clin Exp Pharmacol Physiol 23:458–464CrossRefGoogle Scholar
  23. 23.
    Phillips MI (1987) Functions of angiotensin in the central nervous system. Annu Rev Physiol 49:413–435PubMedCrossRefGoogle Scholar
  24. 24.
    Allen AM, Zhuo J, Mendelsohn FA (2001) AT1-receptors in the central nervous system. J Renin Angiotensin Aldosterone Syst 2(Suppl 1):S95–S101Google Scholar
  25. 25.
    Dampney RAL, Hirooka Y, Potts PD, Head GA (1996) Functions of angiotensin peptides in the rostral ventrolateral medulla. Clin Exp Pharmacol Physiol 3(Suppl):S105–S111Google Scholar
  26. 26.
    Head GA (1996) Role of AT1 receptors in the central control of sympathetic vasomotor function. Clin Exp Pharmacol Physiol 3(Suppl):S93–S98Google Scholar
  27. 27.
    Unger T, Becker H, Petty M, Demmert G, Schneider B, Ganten D, Lang RE (1985) Differential effects of central angiotensin II and substance P on sympathetic nerve activity in conscious rats. Implications for cardiovascular adaptation to behavioral responses. Circ Res 56:563–575PubMedGoogle Scholar
  28. 28.
    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 93:11968–11973PubMedCrossRefGoogle Scholar
  29. 29.
    Song L, Wilk S, Healy DP (1997) Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II-induced dipsogenic and pressor responses. Brain Res 744:1–6PubMedCrossRefGoogle Scholar
  30. 30.
    Wright JW, Tamura-Myers E, Wilson WL, Roques BP, Llorens-Cortes C, Speth RC, Harding JW (2002) Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats. Am J Physiol Regul Integr Comp Physiol 284:R725–R733PubMedGoogle Scholar
  31. 31.
    Inguimbert N, Coric P, Dhotel H, Bonnard E, LLorens-Cortes C, Mota N, Fournie-Zaluski MC, Roques BP (2005) Synthesis and in vitro activities of new non-peptidic APA inhibitors. J Pept Res 65:175–188PubMedCrossRefGoogle Scholar
  32. 32.
    Harding JW, Yoshida MS, Dilts RP, Woods TM, Wright JW (1986) Cerebroventricular and intravascular metabolism of 125I-angiotensins in rat. J Neurochem 46:1292–1297PubMedCrossRefGoogle Scholar
  33. 33.
    Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R (2000) Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 36:646–661PubMedGoogle Scholar
  34. 34.
    Long DA, Price KL, Herrera-Acosta J, Johnson RJ (2004) How does angiotensin II cause renal injury? Hypertension 43:722–723PubMedCrossRefGoogle Scholar
  35. 35.
    Cooper ME (2001) Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44:1957–1972PubMedCrossRefGoogle Scholar
  36. 36.
    Karalliedde J, Viberti G (2006) Evidence for renoprotection by blockage of the rennin-angiotensin-aldosterone system in hypertension and diabetes. J Hum Hyperten 20:239–253CrossRefGoogle Scholar
  37. 37.
    Yamada R, Mizutani S, Kurauchi O, Okano K, Imaizumi H, Narita O, Tomoda Y (1988) Purification and characterization of human placental aminopeptidase A. Enzyme 40:223–230PubMedGoogle Scholar
  38. 38.
    Healy DP, Song L (1999) Kidney aminopeptidase A and hypertension, part I spontaneously hypertensive rats. Hypertension 33:740–745PubMedGoogle Scholar
  39. 39.
    Raasch W, Johren O, Schwartz S, Gieselberg A, Dominiak P (2004) Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR. J Hypertens 22:611–618PubMedCrossRefGoogle Scholar
  40. 40.
    Mizutani S, Okano K, Hasegawa E, Sakura H, Oya M, Yamada M (1982) Human placental leucine aminopeptidase (P-LAP) as a hypotensive agent. Experientia 38:821–822PubMedCrossRefGoogle Scholar
  41. 41.
    Mizutani S, Furuhashi M, Imaizumi H, Ito Y, Kurauchi O, Tomoda Y (1987) Effects of human placental aminopeptidases in spontaneously hypertensive rats. Med Sci Res 15:1203–1204Google Scholar
  42. 42.
    Wolf G, Menzel S, Assmann KJM (1997) Aminopeptidase A: a key enzyme in the intrarenal degradation of angiotensin II. Exp Nephrol 5:364–369PubMedGoogle Scholar
  43. 43.
    Nakashima Y, Ohno Y, Itakura A, Takeuchi M, Mutata Y, Kuno N, Mizutani S (2002) Possible involvement of aminopeptidase A in hypertension in spontaneously hypertensive rats (SHRs) and change of refractoriness in response to angiotensin II in pregnant SHRs. J Hypertens 20:2233–2238PubMedCrossRefGoogle Scholar
  44. 44.
    Goto Y, Hattori A, Ishii Y, Mizutani S, Tsujimoto M (2006) Enzymatic properties of aminopeptidase A: Regulation of its enzymatic activity by calcium and angiotensin IV. J Biol Chem 281:23503–23513PubMedCrossRefGoogle Scholar
  45. 45.
    Bivol LM, Vagnes OB, Iversen BM (2005) The renal vascular response to ANG II injection is reduced in the nonclipped kidney of two-kidney, one-clip hypertension. Am J Physiol Renal Physiol 289:F393–F400PubMedCrossRefGoogle Scholar
  46. 46.
    Prieto I, Martinez JM, Hermoso F, Ramirez MJ, de Gasparo M, Vargas F, Alba F, Ramirez M (2001) Effect of valsartan on angiotensin II- and vasopressin-degrading activities in the kidney of normotensive and hypertensive rats. Horm Metab Res 33:559–563PubMedCrossRefGoogle Scholar
  47. 47.
    Prieto I, Hermoso F, Gaspara M, Vargas F, Alba F, Segarra AB, Banegas I, Ramirez M (2003) Angiotensinase activities in the kidney of renovascular hypertensive rats. Peptides 24:755–760PubMedCrossRefGoogle Scholar
  48. 48.
    Wolf G, Wenzel U, Assmann KJM, Stahl RAK (2000) Renal expression of aminopeptidase A in rats with two-kidney, one-clip hypertension. Nephrol Dial Transplant 15:1935–1942PubMedCrossRefGoogle Scholar
  49. 49.
    Wolf G, Thaiss F, Scherberich JE, Schoeppe W, Stahl RA (1990) Glomerular angiotensinase A in the rat: increase of enzyme activity following renal ablation. Kidney Int 38:862–868PubMedCrossRefGoogle Scholar
  50. 50.
    Hariyama Y, Itakura A, Okamura M, Ito M, Murata Y, Nagasaka T, Mizutani S (2002) Placental aminopeptidase A as a possible barrier of angiotensin II between mother and fetus. Placenta 21:621–627CrossRefGoogle Scholar
  51. 51.
    Ino K, Uehara C, Kikkawa F, Kajiyama H, Shibata K, Suzuki T, Khin EE, Ito M, Takeuchi M,Itakura A, Mizutani S (2003) Enhancement of aminopeptidase A expression during angiotensin II-induced choriocharcinoma cell proliferation through AT1 receptor involving protein kinase C-and mitogen-activated protein kinase-dependent signaling pathway. J Clin Endocrinol Metab 88:3973–3982PubMedCrossRefGoogle Scholar
  52. 52.
    Lin Q, Taniuchi I, Kitamura D, Wang J, Kearney JF, Watanabe T, Cooper MD (1998) T and B cell development in BP-1/6C3/aminopeptidase A-deficient mice. J Immunol 160:4681–4687PubMedGoogle Scholar
  53. 53.
    Mitsui T, Nomura S, Okada M, Ohno Y, Kobayashi H, Nakashima Y, Murata Y, Takeuchi M, Kuno N, Nagasaka T, O-Wang J, Cooper MD, Mizutani S (2003) Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice. Mol Med 9:57–62PubMedGoogle Scholar
  54. 54.
    Lavoie JL, Bianco RA, Sakai K, Keen HL, Ryan MJ, Sigmund CD (2004) Transgenic mice for studies of the renin-angiotensin system in hypertension. Acta Physiol Scand 181:571–577PubMedCrossRefGoogle Scholar
  55. 55.
    Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BLM, Inagami T (1995) Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 377:748–750PubMedCrossRefGoogle Scholar
  56. 56.
    Ouali R, Bethelon MC, Begeot M, Saez JM (1997) Angiotensin II receptor subtypes AT1 and AT2 are down-regulated by angiotensin II through AT1 receptor by different mechanisms. Endocrinology 138:725–733PubMedCrossRefGoogle Scholar
  57. 57.
    Kagami S, Border WA, Miller DE, Noble NA (1994) Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437PubMedCrossRefGoogle Scholar
  58. 58.
    Kobori H, Nishiyama A, Abe Y, Navar G (2003) Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension 41:592–597PubMedCrossRefGoogle Scholar
  59. 59.
    Nomura M, Nomura S, Mitsui T, Suzuki M, Kobayashi H, Ito T, Itakura A, Kikkawa F, Mizutani S (2005) Possible involvement of aminopeptidase A in hypertension and renal damage in Dahl salt-sensitive rats. Am J Hypertens 18:538–543PubMedCrossRefGoogle Scholar
  60. 60.
    Otsuka F, Yamauchi T, Kataoka H, Mimura Y, Ogura T, Makino H (1998) Effects of chronic inhibition of ACE and AT1 receptors on glomerular injury in Dahl salt-sensitive rats. Am J Physiol 274:R1797–R1806PubMedGoogle Scholar
  61. 61.
    Mizutani S, Tomoda Y (1996) Effects of placental proteases on maternal and fetal blood pressure in normal pregnancy and preeclampsia. Am J Hypertens 9:591–597PubMedCrossRefGoogle Scholar
  62. 62.
    Broughton-Pipkin F, Symonds EM (1977) Factors affecting angiotensin II concentrations in the human infant at birth. Clin Sci Molec Med 52:449–456Google Scholar
  63. 63.
    Safwat MA, Mizutani S, Hosam ST, Sayed MA, Itakura A, Neveen HA, Kuno N, Kurauchi O, Tomoda Y (1995) Changes of placental proteases, which degrade vasoactive peptidases, in maternal sera at the onset of preeclampsia. Med Sci Res 23:123–126Google Scholar
  64. 64.
    Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC (1973) A study of angiotensin II pressor responses throughout primigravid pregnancy. J Clin Invest 52:2682–2689PubMedCrossRefGoogle Scholar
  65. 65.
    Saito T, Ishida J, Takimoto-Ohnishi E, Takamine S, Shimizu T, Sugaya T, Kato H, Matsuoka T, Nangaku M, Kon Y, Sugiyama F, Yagami K-I, Fukamizu A (2004) An essential role for angiotensin II type 1a receptor in pregnancy-associated hypertension with intrauterine growth retardation. The FASEB J 18:388–390Google Scholar
  66. 66.
    Binder ND, Anderson DF (1992) Plasma renin activity responses to graded decreases in renal perfusion pressure in fetal and newborn lambs. Am J Physiol 262:R524–R529PubMedGoogle Scholar
  67. 67.
    Martinez JM, Prieto I, Ramirez MJ, de Gasparo M, Hermoso F, Arias JM, Alba F, Ramirez M (1998) Sex differences and age-related changes in human serum aminopeptidase A activity. Clin Chim Acta 274:53–61PubMedCrossRefGoogle Scholar
  68. 68.
    Baylis C, Engels K, Hymel A, Navar LG (1997) Plasma renin activity and metabolic rate of angiotensin II in the unstressed aging rat. Mech Aging Dev 97:163–172PubMedCrossRefGoogle Scholar
  69. 69.
    Ijima M, Nomura S, Okada M, Ikoma Y, Ito T, Mitsui T, Maeda O, Mizutani S (2002) Effects of age, hypertension and HRT on serum aminopeptidase A activity. Matutitas 43:215–221CrossRefGoogle Scholar
  70. 70.
    Ferris JB, Sullivan PA, Gonggrijp H, Cole M, O’sullivan DJ (1982) Plasma angiotensin II and aldosterone in unselected diabetic patients. Cli Endocrinol 17:261–269CrossRefGoogle Scholar
  71. 71.
    Duggan J, Kifeather S, O’Brien E, O’ Mallery K, Nussberger J (1992) Effects of aging and hypertension on plasma angiotensin II and platelet angiotensin II receptor density. Am J Hypertens 5:687–693PubMedGoogle Scholar
  72. 72.
    Hinojosa-Laborde C, Craig T, Zheng W, Ji H, Haywood JR, Sandberg K (2004) Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats. Hypertension 44:405–409PubMedCrossRefGoogle Scholar
  73. 73.
    Inoko M, Kihara Y, Moii I, Fujiwara H, Sasayama S (1994) Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats. Am J Physiol 267:H2471–H2482PubMedGoogle Scholar
  74. 74.
    Vaughan CJ, Delanty N (2000) Hypertensive emergencies. Lancet 356:411–417PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Shigehiko Mizutani
    • 1
  • Masakazu Ishii
    • 1
    Email author
  • Akira Hattori
    • 2
  • Seiji Nomura
    • 3
  • Yasushi Numaguchi
    • 1
  • Masafumi Tsujimoto
    • 2
  • Hiroshi Kobayshi
    • 5
  • Toyoaki Murohara
    • 4
  • John W. Wright
    • 6
  1. 1.Department of Medical Science of ProteasesNagoya University, Graduate School of MedicineNagoyaJapan
  2. 2.Laboratory of Cellular BiochemistryRIKEN (The Institute of Physical and Chemical Research)TsukubaJapan
  3. 3.Department of Obstetrics and GynecologyNagoya University, Graduate School of MedicineNagoyaJapan
  4. 4.Departments of Cardiology and Vascular SurgeryNagoya University, Graduate School of MedicineNagoyaJapan
  5. 5.Department of Obstetrics and GynecologyNara Medical UniversityKashiharaJapan
  6. 6.Departments of Psychology and Veterinary PhysiologyWashington State UniversityPullmanUSA

Personalised recommendations