Review
Angiotensin III: a central regulator of vasopressin release and blood pressure

https://doi.org/10.1016/S1043-2760(01)00381-2Get rights and content

Abstract

Among the main bioactive peptides of the brain renin–angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for type 1 and type 2 AngII receptors. Both peptides, injected intracerebroventricularly, cause similar increases in vasopressin release and blood pressure. Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarizes new insights into the predominant role of brain AngIII in the control of vasopressin release and blood pressure and underlines the fact that brain aminopeptidase A, the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension.

Section snippets

Identification of the in vivo metabolic pathways of brain AngII and AngIII

Among the enzymes potentially able to hydrolyse AngII and AngIII, two membrane-bound zinc metallopeptidases 13, 14, 15, aminopeptidase A (APA: EC 3.4.11.7) and aminopeptidase N (APN: EC 3.4.11.2), are particularly good candidates for this function. It is well established that, in vitro, purified APA hydrolyses the N-terminal Asp of AngII to generate AngIII (reviewed in Ref. 16), whereas purified APN hydrolyses the N-terminal Arg of AngIII to generate AngIV (Ref. 17).

Both APA and APN have been

Brain angiotensin III and vasopressin release

Vasopressin is released from the posterior pituitary into the blood by magnocellular neurones originating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN) 35. The stimulation of AVP release by AngII/III is thought to be one of the mechanisms by which AngII/III controls volume homeostasis under conditions of hypovolemia, by reducing renal water loss and increasing BP (Ref. 36).

It is now well established that AngII and AngIII, injected i.c.v. or directly into the SON or PVN,

Angiotensin III and central control of blood pressure

Several studies have tried to determine the respective roles of AngII and AngIII in the central control of BP. AngII and AngIII, injected separately i.c.v. into normotensive Wistar Kyoto (WKY) or SHR rats, cause similar dose-dependent pressor responses 24, 49, 50. This pressor response involves an increase in sympathetic nerve activity, synaptic inhibition of the baroreflex at the level of the nucleus of the tractus solitarius and the release of AVP (Ref. 11). In addition, the

Conclusion and perspectives

Brain AngIII, generated by APA, seems to be a major effector peptide of the central RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP. Therefore, the inhibition of central, but not peripheral, APA with specific and selective inhibitors leads to a decrease in BP. Thus, central APA might be an interesting candidate target for the treatment of hypertension, which justifies the development of potent and selective APA inhibitors that cross the blood–brain

Acknowledgements

We are grateful to P. Corvol and B.P. Roques for critical reading of the article. The text was edited by J. Sappa (Alex Edelman and Associates). This work was supported by the INSERM and CNRS Institutes.

References (64)

  • D.P Healy et al.

    Localization of immunoreactive glutamyl aminopeptidase in rat brain. II. Distribution and correlation with angiotensin II

    Brain Res.

    (1993)
  • S Zini

    Aminopeptidase A: distribution in rat brain nuclei and increased activity in spontaneously hypertensive rats

    Neuroscience

    (1997)
  • A.L Dewey

    Effects of aminopeptidase inhibition on the half-lives of [125I]angiotensins in the cerebroventricles of the rat

    Brain Res.

    (1988)
  • J.W Harding et al.

    The effects of aminopeptidase inhibitors amastatin and bestatin on angiotensin-evoked neuronal activity in rat brain

    Brain Res.

    (1987)
  • S Tieku et al.

    Inhibition of aminopeptidases N, A and W. A re-evaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme

    Biochem. Pharmacol.

    (1992)
  • V.K Hopsu

    Characterization of aminopeptidase B: substrate specificity and affector studies

    Arch. Biochem. Biophys.

    (1966)
  • S Cadel

    Aminopeptidase-B in the rat testes: isolation, functional properties and cellular localization in the seminiferous tubules

    Mol. Cell. Endocrinol.

    (1995)
  • L.P Renaud et al.

    Neurophysiology and neuropharmacology of hypothalamic magnocellular neurons secreting vasopressin and oxytocin

    Prog. Neurobiol.

    (1991)
  • S Hohle

    Angiotensin AT1 receptor-mediated vasopressin release and drinking are potentiated by an AT2 receptor antagonist

    Eur. J. Pharmacol.

    (1995)
  • D.C Hogarty

    The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin

    Brain Res.

    (1992)
  • H Meng

    Antisense oligonucleotide to AT1 receptor mRNA inhibits central angiotensin induced thirst and vasopressin

    Regul. Pept.

    (1994)
  • D Felix et al.

    Angiotensin receptive neurones in the subfornical organ. Structure–activity relations

    Brain Res.

    (1978)
  • J.W Harding et al.

    Angiotensin-sensitive neurons in the rat paraventricular nucleus: relative potencies of angiotensin II and angiotensin III

    Brain Res.

    (1987)
  • J.W Wright

    Intracerebroventricularly infused [d-Arg1]angiotensin III, is superior to [d-Asp1]angiotensin II, as a pressor agent in rats

    Brain Res.

    (1990)
  • C.M Batt

    Pressor responses to amastatin, bestatin and Plummer's inhibitors are suppressed by pretreatment with the angiotensin receptor antagonist sarthran

    Brain Res. Bull.

    (1988)
  • L Song

    Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II- induced dipsogenic and pressor responses

    Brain Res.

    (1997)
  • G Waksman

    In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain

    Eur. J. Pharmacol.

    (1985)
  • S Oparil

    The role of the central nervous system in hypertension

  • D.B Averill

    Role of area postrema in transgene hypertension

    Hypertension

    (1996)
  • R.L Davisson

    The brain renin–angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes

    Circ. Res.

    (1998)
  • A.M Allen

    Localization of angiotensin receptor binding sites in the rat brain

  • J.M Saavedra

    Brain and pituitary angiotensin

    Endocr. Rev.

    (1992)
  • Cited by (0)

    View full text