Elsevier

Regulatory Peptides

Volume 78, Issues 1–3, 30 November 1998, Pages 1-11
Regulatory Peptides

Brief review
Angiotensin II in central nervous system physiology1

https://doi.org/10.1016/S0167-0115(98)00122-0Get rights and content

Introduction

Exactly one hundred years ago Tiegerstedt and Bergman [1]demonstrated that injection of kidney extracts into rabbits elicited a pressor effect. They named the unknown pressor substance renin, and it was later shown to be a protease enzyme. From that time we can trace the slow realization that the product of renin activity has a major role in human physiology and cardiovascular disease. It took 40 years after the discovery of renin to elucidate that the active pressor substance was an octapeptide, angiotensin II (Ang II). Studies from labs in Argentina [2]and Cleveland [3]in 1940, independently named the same pressor substance “hypertensin” [2]and “angiotonin” [3]respectively, which became by agreement, “angiotensin”. It took more than a decade to work out the cascade of the renin–angiotensin system (RAS) 4, 5. By the 1960s the story seemed to be complete, at least for explaining the effects of Ang II on blood pressure and sodium balance [6]. The theory of renin–angiotensin formation involving the kidney, liver and lung became a practical one for the treatment of hypertension. In science, however, no field is an island, and experiments were suggesting a different view. Cross perfusion experiments in dogs showed that Ang II could stimulate the central nervous system producing an increase in peripheral blood pressure [7]. By the 1970s, when peptides in the gut were also being found in the brain, and receptor binding techniques had become available, a coincidence of research interest independently arrived at the same conclusion-that there was an endogenous RAS in the brain. Binding studies by Sirrett et al [8]demonstrated the presence of Ang II receptors in the brain, direct injection of Ang II into the rat brain produced drinking behavior [9]and indirect measurements showing the presence of renin in the brain [10], pointed to an independent brain renin–angiotensin system. Whereas other tissues could take up angiotensin directly from blood, only the brain was protected by the blood brain barrier (BBB). Therefore, finding evidence for a separate renin–angiotensin system, independent of blood borne Ang II, was more logical for the brain than for any other tissue. It took years of applying new techniques as they became available to provide the evidence. Such evidence eventually came from immunocytochemistry, direct measurements of Ang II by radioimmunoassay and Northern blotting of angiotensinogen (AGT) and renin mRNAs 10, 11, 12, 13, 14, 15, 16. As the idea of angiotensin formation in the brain was gradually accepted, the concept could be applied to other tissues. Ang II was not only an endocrine hormone in blood but a paracrine hormone in tissue (Fig. 1). The presence of a paracrine RAS has now been recognized in almost every tissue [17]. It is particularly significant in heart and blood vessel walls for atherosclerosis and heart failure [18]. Tissue RAS is probably equally important in the reproductive organs where it has a role in fertility [19].

The latest development in the angiotensin story came in 1989 with the characterization of Ang II receptor subtypes 20, 21. Purifying the Ang II receptor was a difficult challenge and one which was eventually overcome by expression cloning. First the Ang II type 1 (AT1) receptor 22, 23and then the Ang II type 2 (AT2) receptor 24, 25were cloned. Further cloning studies are required to reveal the identity of AT3, AT4 and AT1–7. Although the AT3 receptor does not appear to exist, there is evidence for an AT4 receptor, one which specifically responds to angiotensin II (4–8) [Ang IV] [26]. There is also evidence for a receptor to angiotensin (1–7) [27]. Both of these metabolites appear to have different physiological effects from the Ang II. In the rat, but not the human, the AT1 receptor has two subtypes, AT1A and AT1B [28]. The role of all these receptor subtypes and the intracellular signaling pathways that are modulated following their activation are major frontiers of angiotensin research 100 years after renin was discovered.

Section snippets

Structure and function: the CNS cardiovascular sites and pathways

Brain Ang II regulates fluid balance, sodium intake, thirst, blood pressure and possibly cognitive functions [29]. Ang II receptors are located in the nuclei and areas that correspond to the multi-synaptic pathways associated with the autonomic nervous system and what has become known as “cardiovascular pathways” (Fig. 2).

At the most anterior part of the CNS in the forebrain, is what may be considered the beginning of the autonomic nervous system. This includes the autonomic promotor neurons in

The brain renin–angiotensin system

Physiological evidence that the regulation of the brain RAS is independent of the circulating RAS, comes from a study showing that in rats chronically dialyzed for five days after bilateral nephrectomy, levels of brain Ang II are increased above control levels [49]. The study also revealed that K+ regulates the brain RAS. K+ is elevated after nephrectomy unless rats are on a low K+ diet. When K+ is elevated, the concentration of brain Ang II is increased. When K+ is reduced after nephrectomy by

Angiotensin receptors

Ang II acts at specific receptors within the brain to elicit behavioral and physiological changes such as increased water and sodium intake, increased BP, altered baroreflex modulation, increased secretion of AVP and altered secretion of reproductive hormones. The basis of these effects is the physiological role of Ang II as a neuropeptide with neurotransmitter and neuromodulator properties in the brain. The distribution of Ang II receptors in the brain has been demonstrated by receptor

Thirst

When Ang II is injected into the brain it rapidly stimulates drinking behavior [9]. The fact that this will happen even in animals that have no fluid deficit, indicates that Ang II normally triggers complex circuits that induce the sensation of thirst and the compelling behavioral drive to find water and drink. This seems to be a brain effect and not due to blood borne Ang II. In humans and in rats it is difficult to elicit drinking by infusion of Ang II into the blood unless exceptionally high

The brain RAS and hypertension hypothesis

There have been numerous studies on the spontaneously hypertensive rat (SHR) which indicate that their brain angiotensin system is more active and different from normotensive controls. The hypothesis was first proposed in experiments on the Okamoto strain of SHR [93]and independently by Ganten et al [94], based on similar experiments on the Smirk strain of SHR. Working together, both groups found a decrease in BP following the infusion of saralasin (Sar1Ala8 Ang II), the Ang II antagonist,

Summary

In summary, the prevailing concept is that brain Ang II increases blood pressure by activating AT1 receptors, and that these have a neuromodulating effect to increase the activity of autonomic nervous system. Pathways for Ang II stimulating thirst and blood pressure, increased vasopressin release and sympathetic activation have been outlined. Brain RAS synthesis, while incompletely understood, is active in the absence of a peripheral RAS. Angiotensin elicits specific receptor mediated signals

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References (116)

  • P Carrive et al.

    Viscerotropic organization of neurons subserving hypotensive reactions within the midbrain periaqueductal grey. A correlative functional and anatomical study

    Brain Res.

    (1991)
  • R.N Willette et al.

    Interdependence of rostral and caudal ventrolateral medullary areas in the control of blood pressure

    Brain Res.

    (1984)
  • L.P Reagan et al.

    Immunohistochemical mapping of angiotensin type 2 (AT2) receptors in rat brin

    Brain Res.

    (1994)
  • Y Ko et al.

    Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signaling system in vascular smooth muscle cells

    Eur. J. Pharmacol.

    (1992)
  • M.B Marrero et al.

    Angiotensin II signaling events mediates by tyrosine phosphorylation

    Cell Signaling

    (1996)
  • X.-C Huang et al.

    Mitogen-activated protein kinases in rat brain neuronal cultures are activated by angiotensin II type 1 receptors and inhibited by angiotensin II type 2 receptors

    J. Biol. Chem.

    (1996)
  • A.J Lokuta et al.

    Angiotensin II stimulates the release of phospholipid derived second messengers through multiple receptor subtypes in heart cells

    J. Biol. Chem.

    (1994)
  • R Gyurko et al.

    Angiotensin II receptor subtypes play opposite roles in regulating phosphatidylinositol hydrolysis in rat skin slices

    Biochem. and Biophys. Res. Comm. Vol.

    (1992)
  • S Hohle et al.

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

    Eur. J. Pharmacol.

    (1995)
  • M.A Millan et al.

    Developmental changes in brain angiotensin II receptors in the rat

    Peptides

    (1991)
  • M Horiuchi et al.

    Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apopotosis

    J. Biol. Chem.

    (1997)
  • J Pfister et al.

    Immunohistochemical demonstration of angiotensin II receptors in rat brain by use of an anti-idiotypic antibody

    Regul. Pept.

    (1993)
  • D.C Hogarty et al.

    Involvement of angiotensin receptor subtypes in osmotically induced release of vasopressin

    Brain Res.

    (1994)
  • C.A Bruner et al.

    Cerebroventricular infusion of angiotensin antagonist does not influence hypertensive response to blood-borne angiotensin II

    Brain Res.

    (1985)
  • R Tiegerstedt et al.

    Niere und Kreislauf

    Skand. Arch. Physiol.

    (1898)
  • M.J Munoz et al.

    Hypertensin: The substance causing renal hypertension

    Nature

    (1939)
  • I.H Page et al.

    A crystaline pressor substance (angiotonin) resulting from the action between renin and renin-activator

    J. Exp. Med.

    (1940)
  • L.T Skeggs et al.

    The preparation, purification and amino acid sequence of a polypeptide renin substrate

    J. Exp. Med.

    (1957)
  • D.F Elliott et al.

    Amino acid sequence in a hypertensin

    Nature

    (1956)
  • Gross F. Adrenocortical function and renal pressor mechanisms in hypertension. In: Bock KD, Cottier PT, editors....
  • R.K Bickerton et al.

    Evidence for a central mechanism in angiotensin induced hypertension

    Proc. Soc. Expt. Biol. Med.

    (1961)
  • N.E Sirrett et al.

    Distribution of angiotensin II receptors in rat brain

    Brain Res.

    (1977)
  • J.T Fitzsimons

    Thirst. Physiol. Rev.

    (1972)
  • Ganten D, Fuxe J, Phillips MI, Mann JFE. The brain isorenin angiotensin system: biochemistry, localization and possible...
  • M.I Phillips et al.

    Evidence for an endogenous brain renin angiotensin system

    Fed. Proc.

    (1979)
  • D Ganten et al.

    Angiotensin synthesis in the brain and increased turnover in hypertensive rats

    Science Washington D.C.

    (1983)
  • M.I Phillips et al.

    Angiotensin II in rat brain comigrates with authentic angiotensin II in HPLC

    Circ. Res.

    (1985)
  • K.R Lynch et al.

    Localization of angiotensinogen messenger RNA sequences in the rat brain

    Hypertension

    (1986)
  • V.J Dzau et al.

    Identification of renin and angiotensinogen messenger RNA sequences in rat brain

    Hypertension

    (1986)
  • M.I Phillips et al.

    Levels of angiotensin and molecular biology of the tissue renin-angiotensin systems

    Regul. Pept.

    (1992)
  • V.J Dzau

    Vascular renin-angiotensin: a possible autocrine or paracrine system in control of vascular function

    J. Cardiovasc. Pharmacol.

    (1984)
  • S Whitebread et al.

    Preliminary biochemical characterization of two angiotensin II receptor subtypes

    Biochem. Biophys. Res. Comm.

    (1989)
  • T.J Murphy et al.

    Isolation of a cDNA encoding the vascular type-1 angiotensin receptor

    Nature

    (1991)
  • A Moriguchi et al.

    Angiotensin II and angiotensin (1–7) augment the local release of vasopressin from the paraventricular nucleus (PVN) and the supraoptic nucleus (SON), Abstract #240

    Hypertension

    (1993)
  • M.I Phillips

    Functions of brain angiotensin

    Ann. Rev. Physiol.

    (1987)
  • Brody MJ, Faber JE, Mangiapane ML, Porter JP. The central nervous system and prevention of hypertension. In: deJong W,...
  • S.L Bealer et al.

    Anteroventral third ventricle lesions reduce antidiuretic responses to angiotensin II

    Am. J. Physiol.

    (1979)
  • A Tsukashima et al.

    Angiotensin II increases norepinephrine turnover in the anteroventral third ventricle of spontaneously hypertensive rats

    Hypertension

    (1996)
  • S.M Gardiner et al.

    Endogenous vasopressin and baroreflex mechanisms

    Brain Res. Rev.

    (1974)
  • P.E Sawchenko et al.

    The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat

    Brain Res.

    (1982)

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      Citation Excerpt :

      The renin-angiotensin system (RAS) is the main axis controlling systemic and local blood pressure. Angiotensin-converting enzyme (ACE) generates angiotensin II (AngII), which binds the angiotensin II type I receptor (AT1R), leading to desensitization of the baroreflex, which stimulates water uptake and vasopressin secretion.101 However, as antihypertension medications, ACE inhibitors and AT1R blockers have had adverse effects, such as reduction in glomerular filtration rate, hyperkalemia, angioedema, inflammation-related pain, hepatotoxicity, and hypotension.102,103

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