TiPS - September
1992 [Vol. 131
23 Yellen, G., Jurman, M. E., Abramson, T. and MacKinnon, R. (1991) Science 251, 93%941 24 Hartmann, H. et al. (1991) Science 251, 942-944 25 Kavanaugh, M. P. et al. (1991) J, Biol. Chem. 266,7583-7587 26 Stiihmer, W. et al. (1989) EMBO J. 8, 3235-3244 27 Stocker, M. et al. (1991) Proc. R. Sot. Lond. Ser. B 245,101-107
28 Moczydlowski, E., Lucchese, K. and Ravindram, A. (1988) J. Membrane Biol. 105,95-111 29 Miller, C. (1988) Neuron 1,1003-1006 30 Bontemps, F., Roumestand, C., Gilquin, B., Menez, A. and Toma, F. (1991) Science 254,1521-1523 31 MacKinnon, R. and Miller, C. (1989) Science 245,1382-1385 32 MacKinnon, R., Heginbotham, L. and Abramson, T. (1990) Neuron 5,767-771
Angiotensin receptor subtypes in the brain U. Muscha Steckelings, Serge P. Bottari and Thomas Unger Development of specific angiotensin 11 receptor ligands has recently provided evidence for the existence of two angiotensin 11 receptor subtypes, termed AT, and AT2, which differ in their signal transduction mechanisms and in the effects they mediate. In brain, both receptor subtypes are present. Most of the known central actions of angiotensin 11, for example the regulation of blood pressure and of electrolyte and water balance, seem to be mediated by the AT, receptor, while the role of the AT2 receptor is still an enigma. This review by Thomas Unger and colleagues summarizes the current knowledge and latest hypotheses in this rapidly developing field. The octapeptide angiotensin II is a potent effector hormone of the renin-angiotensin system. It exerts a wi’de range of physiological effects on the cardiovascular, renal and endocrine systems, and the peripheral and central nervous syslems’. Angiotensin II formed in the circulation acts on receptor sites in brain areas lacking a blood-brain barrier. Angiotensin II being part of an intrinsic reninangiotensin system within the brain may also act as a neuromodulator or neurotransmitter within a number of anatomically discrete brain structures and pathways.
Angiotensin II receptor subtypes Indirect evidence has accumulated over many years for the existence of different subtypes of angiotensin II binding sites*. Pharmacological evidence for two specific sites has only recently been found, following the development of highly selective angiotensin II receptor ligands such as losartan (DuP753), CGP42112A and PD123177 (Refs 3-5). RecepU. Muscha Steckelings is Research Fellow and T. Unger is Professor in the Department of Pharmacology, Universityof Heidelberg, FRG, and S. P. Bottari is in Cardiovascular Research, Ciba-Geigy ltd, Basel, Switzerland.
tars with highest affinity for losartan (Ki = 10-50 nM) and the lowest affinity for CGP42112A (Ki > 0.5 PM) and PD123177 (Ki > 10 PM), are referred to as ATI. Conversely, binding sites displaying highest affinity for CGl’42112A (Ki < 1 nM) and PD123177 (Ki = l&100 nM) and lowest affinity for losartan (Ki > 1 PM), are referred to as AT2 (Ref. 6). Sulphydryl reducing agents such as dithiothreitol and glutathione are also able to distinguish the two subtypes. These two compounds inhibit the binding of angiotensin II to ATI receptors, whereas they enhance the binding affinity of angiotensin II for AT2 sites317. In peripheral tissues, AT1 and AT2 subtypes seem to mediate the biological actions of angiotensin II via different signal transduction pathways. AT, receptors interact with G proteins, inhibiting adenylyl cyclase activity and stimulating phospholipases C, A2 and D. This, in turn, causes a decrease in cellular CAMP, and a stimulation of both inositol 1,4,5trisphosphate (IP3) and diacylglycerol generation as well as prostaglandin synthesis”“. In contrast, AT2 receptors do not interact with G proteins”, ruling
33 Dreyer, F. (1990) Rev. Physiol. Biochem. Phannacof. 115,9&136 34 Block, A. R., Donegan, C. M., Denny, B. J. and Dolly, J. 0. (1988) Biochemistry 27,6814-6820 35 Rehm, H. and Lazdunski, M. (19813) Proc. Nat1 Acad. Sci. USA 85,491%923 36 Kirsch, G. E. et al. (1992) Neuron 8, 499-505 37 Hurst, R. S. et aI. (1991) Mol. Phurmncol. 40,572-576
out a connection to any of the signalling pathways described for the AT, receptor. In fact, two studies recently showed that stimulation of the AT2 receptor leads to a decrease of cGMP levels”r13. This decrease may be caused by an inhibition of particulate guanylyl cyclase following the stimulation of a phosphotyrosine phosphatase”. In the brain, it is not clear whether angiotensin II receptors are coupled to the same signaI transduction mechanisms as in the periphery. For example, the results on the effect of angiotensin II binding on IP3 generation are still controversial. In primary glial cell cultures angiotensin II, as in peripheral tissues, leads to stimulation of phosphatidylinositol hydrolysis14. However, in in vitro experiments on cerebral cortex and a combined preparation of hypothalamus, thalamus, septum and midbrain of Sprague-Dawley rats, angiotensin II inhibited IP3 generationl’, and in neuronal cell cultures it had no significant effect on phosphatidylinositol hydrolysi9. Recent data also report coupling of a subgroup of central AT2 receptors to G proteins”. These receptors were localized in the ventral thalamic and medial geniculate nuclei and in the locus coeruleus, while AT2 receptors in the inferior olive were not coupled to G proteins. More data point to the existence of additional angiotensin II receptor subtypes. For example, the affinities of losartan, CGlWll2A and PD123177 for angiotensin II binding sites on amphibian (Xenopus laevis) cardiac membranes differ markedly from their affinities for binding sites in Furthermammalian tissues’s. more, in most areas of the rat brain, angiotensin II and [Sar’, Ile8]angiotensin II have a tenfold lower affinity for ‘AT1 receptors’
TiPS - September
366 TfiE
1.~~lization of angiotensinII bindingsitesin the ratbrainin sixdifferentstudies Reference numberof study 20*
21
2>1
2>1
22
23
1 1 1 1 1 1
1
24
25
1 1 1 1
1
1 1
1 1
1>>2 1>>2 1>2
2 2 2 2=-l 2 1 1 : 2 2 2 2>1 1
2
2:l
2 2 2 1 1 1
: 2 1 1 2
I 2 2
1 and2 2 2 1 1 2
2 2
1 1 2 1 : 2
1 2
VI& studyusadWistarrats;all othersusedSprague-Dawleyrats. 1 = AT, bindinge 2 = AT, bindingsite;1>2 = moreAT, thanAT, sites;etc.
than in peripheral tissuestgzo suggesting there may be subclasses of ATI receptors. Finally, in rat hypothalamus, angiotensin II binding sites have been identified that did not competitively bind losartan, indicating the existence of at least one central subtype of angiotensin II binding site that is neither an AT1 nor an AT2 binding siteM. LocaZization of binding sifes in bmin A number of reports have been published describing the distribution of angiotensin II receptor subtypes in brain, using either quantitative autoradiography or competitive radioligand binding techzuqueszGz. In these studies, angiotensin II receptors were characterized by displacement of the parent peptide with the selective angiotensin II receptor ligands. The distribution of AT, and AT2 sites within the brain was almost identical in all studies. AT1 receptors were localized mainly in target sites involved in regulation of blood pressure, drinking, salt appetite and vasopressin for-
mation and release, whereas the distribution of AT2 binding sites in adult rats did not provide definitive clues to their function (see Table I and Fig. 1). Interestingly, the distribution of receptor subtypes in the brain differs with species and age. Song et al. demonstrated differences between the distribution of angiotensin II receptor subtypes in Sprague-Dawley rats and human brain (Song, K. et al., unpublished). In human brain, but not in rat brain, angiotensin II receptors are expressed in the basal ganglia and the molecular layer of the cerebellum, with the AT1 receptor predominating in the basal ganglia and the AT2 binding site predominating in the molecular layer of the cerebellum. In humans, AT1 receptors are expressed in the locus coeruleus and the subthalamic nucleus, while in rat, AT, binding sites are expressed at these two sites. The slightly different distribution of angiotensin II receptor subtypes obtained from studies using either Sprague-DawleyZ1-25 or Wistarro rats may be due not to the
1992 [Vol. 131
different rat strains but to the different techniques used. Tsutsumi and Saavedra have demonstrated differences in the distribution of angiotensin II receptors in adult (&week-old) rats compared to young (2-weekold) or fetal rats24,26. In most areas of the adult rat brain, the distribution and density of AT1 receptors are comparable to those present in young and fetal rats. Conversely, the distribution and number of AT2 binding sites changes during development. Their concentration is always much lower in adult animals. Indeed, in some brain areas AT2 binding sites are expressed only in young and fetal rats, and are undetectable in adult rats. Central actions of angiotensin II Stimulation of angiotensin II receptors in the brain evokes coordinated autonomic, many endocrine and behavioura! responses. These responses include an increase in blood pressure and water intake, stimulation of natriuresis and salt appetite, secretion of vasopressin, oxytocin, adrenocorticotropic hormone and other pituitary hormones, and an interaction with brain catecholaminesl. Peripheral angiotensin II receptors mediate the same effects on cardiovascular and fluid regulation with only one exception: while central angiotensin II causes the induction of natriuresis, stimulation of angiotensin II receptors in the periphery leads to renal Na+ retention*r. In rat brain, structures related to the known central actions of angiotensin 11 (e.g. organum vasculosum laminae terminalis, subfomical organ, preoptic medial nucleus, area postrema, nucleus of the solitary tract) mainly or exclusively contain AT1 receptors (see Fig. l), suggesting that this receptor subtype is responsible for mediating these effects2s25. The following lines of evidence support the hypothesis that the known central actions of angiotensin II are mediated by the AT1 receptor: Blood pressure regulation Intracerebroventricular injection of angiotensin II leads to an increase in blood pressure in the conscious rat. This augmentation of blood pressure is completely suppressed
TiPS - September 1992 [Vol. 131
367
nucleusof vagus
eminence
F&x 1. Schematic diagramof a longitudinal sectionof the ratbrain showing angiotensin It binding sites. $5 AT, binding sites only; l AT, binding sites onty; n AT, and AT, binding sites. IC, inferior colliculus; NTS, nucleus of the solitary tract; OVLT, organum vasculosum laminae terminalis; SC, superior colticulus; SCN, suprachiasmaticnucteus.
by pretreatment with the AT1 receptor ligand losartan, suggesting that the ATi receptor mediates the increase in blood pressure produced by angiotensin II (Ref. 28). Regulation of water intake Pretreatment with i.c.v. losartan abolishes angiotensin II-induced drinking, indicating that the AT1 receptor is involved in the mediation of this response. Drinking after water deprivation is significantly attenuated by i.c.v. injection of losartan or atropine, indicating that it is regulated both by endogenous angiotensin II and the cholinergic nervous system28~2g. Release of vasopressin from the hypothalamus Catecholamines play a critical role in expression of the central actions of angiotensin II, such as drinking and increased blood pressure1,30. In viva studies also suggest the involvement of a hypothalamic catecholaminergic pathway in the release of vasopressin from hypothalamic nuclei, including the paraventricular nucleus and supraoptic the nucleus31~32. Recent in viva experiments have shown that stimulation of periventricular angiotensin II receptors causes a dose-dependent release of catecholamines in the paraventricular nucleus and the supraoptic nucleus (Ref. 33 and Qadri, F. et al., unpublished). The
release of catecholamines in the paraventricular nucleus was temporally correlated with an increase in blood pressure. Both effects were abolished by i.c.v. pretreatment with losartan, indicating their dependence on AT1 receptor stimulation. In addition, release following vasopressin angiotensin II receptor stimulation could also be reduced by microinjection of alor araadrenoceptor antagonists prazosin or idazoxan, respectively, into the paraventricular nucleus and the supraoptic nucleus, confirming the hypothesis that a catecholaminergic hypothalamic pathway is involved in angiotensin IIinduced vasopressin release. These findings are contradicted by a report from Schiavone et al., indicating that angiotensin IIinduced vasopressin release from hypothalamo-neurohypophysial explants is mediated primarily via the AT2 receptor (Schiavone, M. T. et al., unpublished). Natriuresis Angiotensin II, by renal injection, causes natriuresis2’. Since this induced natriuresis can be blocked by i.c.v. pretreatment with losartan, this effect appears to be mediated by periventricular AT1 recepto#.
i.c.v.
The central actions of angiotensin II mediated by the AT2 still enigmatic. receptor are Jaiswal et al. reported that the AT2 receptor in human astrocytes
mediates synthesis of PGIa, whereas PGEa synthesis is mediated by the ATi receptors5. However, more recent studies suggest a role for this receptor subtype in differentiation and developmental processes. This hypothesis is mainly based on the observation that in the brain of fetal and young rats the number of ATa binding sites is much higher than in adult rats. The highest density of ATa binding sites in fetal and young rats is found in areas related to visual function and control of motor activity, in sensory areas, and in selected structures of the limbic system, suggesting that they may be involved in control and learning of motor activity. A role in learning processes is also supported by a study claiming that the AT2 receptor mediates a cognitive enhancing action of angiotensin II (Ref. 36). Apart from these observations in certain brain areas, similar results were obtained from autoradiographic studies of the rat anterior cerebral artery, where the number of ATs binding sites was much higher in young than in adult rats, suggesting that the AT2 binding sites may also be involved in cerebrovascular developments’. q
cl
cl
Recent development of specific angiotensin II receptor ligands has allowed the identification of at least two different angiotensin II receptor subtypes, which mediate their actions through different signal transduction mechanisms. Binding of angiotensin II to ATi receptors decreases cellular cAMP levels and stimulates both generation of IP3 and prostaglandin synthesis. Binding of angiotensin II to AT, receptors leads to a decrease in cellular cGMP concenprobably caused by trations, stimulation of a phosphotyrosine phosphatase. AT, receptors are localized mainly in brain areas responsible for mediating the cardiovascular- and fluid-regulating actions of angiotensin II, and their involvement in these actions is corroborated by functional studies. It is still unknown which actions of angiotensin II are mediated by AT2 receptors. From the distribution of AT2 binding’ sites in adult and young animals it has
TiPS - September 1992 fVol.13f
333 been suggested that they may play a role in differentiation and development.
Refkxences 1 Unger, T., Badoer, E., Ganten, D., Lang, R. E. and Ret@, R. (1988) CircdafiO~77 (SuppI. 1). 40-54 2 Kkn&as~,. G. (1987)Am. J. Phytiot.=,
32 Leibowitt, S. F., Eidelman, D., Suh, J. S., Diaz, S. and Sladek, C. D. (1990) Exn. Neural. 110.298-305 33 Stidler, T., Veltmar, A., Qadri, F. and Unger, T. (1992) Brain Res. 569,117-122 34 Rohmeiss, P., Nagy, E. and Unger, T. (1991) 1. Hyperfens. 9 (Suppl. 6). 480 35 Jaiswal, N., Tallant, A., Diz, D. I., Khosla, M. C. and Ferrario, C. M. (1991) Hypertension 17,1115--1120 36 Barnes, N. M., Costa&B., Kelly. M. E.,
Murphy, D. A. and Naylor, R. J. (1991) NeuroReport 2,351-3.53 37 Tsutsumi, K. and Saavedra, J. M. (1991) Am. 1. Pkysiol. 261, H667-H670
New editions
drugs across various mucosae and digestive tract membranes.
CGP42112Ar nicotinie acid-Tyr-(N”benzoylcarbonyl-Arg)Lys-His-Pro-Be-OH PD123177: I-(4-amino-3_methylphenyl)methyl-S-diphenyl-acetyl-4,5.6,7tetrahydro-lH-imidazo[4,.5-clpyridine-6carboxyhc acid
F&-F7
3 Whitebread, S.. Me& M., Kamber. B. and de Gaspam, M. (1989) &o&m. Biopbys.Res. Commun. 163,2&T-291 4 Q&I, A. T. et al. (1989) Biockem. Biopkys. Res. Commnm. 165,196-203 5 Chang. R. S. L. and Lotti, V. J- (1989) MOE PkamtucoL 37.347-351 6 Btunp~, F. M. et nl. (1991)Hypertension 17.720-722 7 ~&sumi. K. and Saavedra, J. M. (1991) Cell. Mol. Neurobiol. Il. 295299 8 Lassegue,B.. Alexander, R. W.. Uark, M. and Crien~ K. K. (1991) Biochem. J. 276s19-22 9 Jar& S.. Cantau, B. and Jakobs, K. H. (1991) J_ B&i. Chem. 2!56,2603-2606 10 Pfeikhifter~ J. (1990) Eur. J. Pharmocol. 184,201-203 11 FWtarL S. I’. et al. (1991) Eur. 1. PhatYiza~t. 207.157-163 12 Sumners, C, W., Zelezna, B. and Raizada, M. K, (1991) Proc. Nat! Acad. Sci. USA 88.7367-7S7l 13 Bottari. S. P. et af. (1992) Biockem. Riophys. Res. Commun. 183,206-211 14 Smith T. I.... Yamamma, H. I. and Lee, L. (1986)Life Sci_39,1675-X84 15 Tarnura, C. S. and Speth, R. (1990) Neurockem. Int, 17,475-479 16 Sumne~~, C. Myers, L M., Kalberg, C. 1. and Raizada, M. K. (1990) Pmg. N#~~oi_ 34,355-385 I? Tsutsumi. K. and Saavedra. 1. M. (1992) Mol. Pha&ocol. 41,290-297. ’ 18 Ji,tt. !%ndbexg,K. and Catt, K. J.(1991) Mol. Pkanaacol. 39,120-w 19 Chang, R. S. L, Chen,T. D., Faust, K. A. and Lo&i. V. J. (1990) Biochem. Biopkys. Res. Convnun. 17l.813-817 20 Obermiiiier, N. et al. (1991) Neurosci. z&t. 132.11-15 21 Leung, K. H., Smith, R. D., Tiiermans, P. B. M. W. M. and Chiu, A. T. (19!X) Newosti. Left 123.95-98 22 Rowe, B. P.. Grove, K. L., Saylor, D. L. and Speth, R C. (1991) Regul. Pep. 33,
fang,
PharmacoJogie - des Concepts Fondamentaux aux Applications Therapeutiquw. Deuxieme edition
Principles of Biochemical Toxicology. Second edition
by Michel Schorderet and colleagues, Editions Slatfcine, 1992. SFr28.00 (952 pages) ISBN 2 05 100910 4
by John A. Timbre& Taylor & Francis, 2992. f19.95 f415 pages) 1S~N 0 85066 832 8 pbk
comprehensive textbook This draws on the collective expertise of 92 authors under the overah direction of Michel Schorderet. The information is arranged in 11 sections based on the principal systems and in-depth organ accounts of antiparasitic, antimicrobial and antitumour therapies. The treatment is detailed, weJl but rather heterogeneously illustrated, and thoroughly documented with a useful ‘to know more’ bibliography for every chapter. AR in all, a most valuable basic reference work that, although aimed principally at a francophone readership, should also prove useful for those who, like this reviewer, are rather less competent in French.
This edition is considerably larger than the first, containing new figures, more examples and additional information, but retains the original format of a wide-ranging introduction to toxicology.
J. R. FOZARD
23 Song, L, Allen, A. M., Paxinos, G. and Mendelsohn. F. A. 0. (1991) Clin. Exp. Pkarrnacol. Pkysiol. 18,93% 24 Tsutsumi. K. and Saavedra, J. M. (1991) Am. I. Pkusiol. 261. R209R216 25 Gehiert, ‘D_R,, Gackenheimer, S. L., Reel, J. K., Lin, H-S. and Steinberg, M. I. (1990) Eur. I. Pharmucol. 187,123-126 26 Tsutsumi, K., Viswanathan, M., Stroemberg, C and Saavedra, J. M. (1991) Eur. J. Pha~a~ol. 1%,89-92 27 Unger, T. ef ni. (1989) Brnik Res. 486,
Novel Drug Delivery Systems. Second edition by Yie W. Chen, Marcel Dekker, 1992. $150.00 in USA and Canada, $172.50 elsewhere (vii + 797 pages) ISBN 0 8247 8520 7
AR chapters have been extensively rewritten and updated, for example 33-3s that on regulatory considerations 28 Wong, P. C. et ni. (1990) Hypertension 15, in controlled drug delivery has 823-334 been expanded to incorporate 29 Stauss, H. and Unger, T. (1991) NuunyngOred. Arch. Pha~uco~. 343 (SuppI.), new guidelines used in the regulatory approval process. New 30 Badoer,E., Wuerth, H., Qadri, F., Itoi, chapters have been added on K. and Unger, T. (1988) Eur. 1. issues associated with systemic Pkarmacol. 154,105-108 delivery of peptide/protein drugs, 31 Benetos, A., Gavras, I. and Gavras, H. (1986)BruinRes. 38,322-326 and rate-con~lled delivery of
Annual Review of Neuroscience, Volume 15 edited by W. Ma~~~~ Cowan, Eric M. Shooter, Charles F. Sfevens and Richard F. Thompson, Annual Reviews, 1992. $44.00 in USA, $49.00 elsewhere (vii + 454 pages) ISBN 0 8243 2415 3 Chapters include: The biosynthesis of neuropeptides: peptide (xamidation, Betty A. Eipper, Doris A. Staffers and Richard E. Mains; Adrenergic receptors as models for G protein-coupled receptors, Brian Kobilka; Guanylyl cyclaselinked receptors, Peter S. T. Yuen and l?avid L. Garbers; The role of the amygdaJa in fear and anxiety, Michael Davis.
TiFS Office/Elsevier Trends Journals REFURBllSHMENT From mid-August until midNovember please communicate with the TiPS office by mail or FAX, in preference to the telephone. Your help during this time is greatly appreciated.
1992 [Vol. 131
23 Yellen, G., Jurman, M. E., Abramson, T. and MacKinnon, R. (1991) Science 251, 93%941 24 Hartmann, H. et al. (1991) Science 251, 942-944 25 Kavanaugh, M. P. et al. (1991) J, Biol. Chem. 266,7583-7587 26 Stiihmer, W. et al. (1989) EMBO J. 8, 3235-3244 27 Stocker, M. et al. (1991) Proc. R. Sot. Lond. Ser. B 245,101-107
28 Moczydlowski, E., Lucchese, K. and Ravindram, A. (1988) J. Membrane Biol. 105,95-111 29 Miller, C. (1988) Neuron 1,1003-1006 30 Bontemps, F., Roumestand, C., Gilquin, B., Menez, A. and Toma, F. (1991) Science 254,1521-1523 31 MacKinnon, R. and Miller, C. (1989) Science 245,1382-1385 32 MacKinnon, R., Heginbotham, L. and Abramson, T. (1990) Neuron 5,767-771
Angiotensin receptor subtypes in the brain U. Muscha Steckelings, Serge P. Bottari and Thomas Unger Development of specific angiotensin 11 receptor ligands has recently provided evidence for the existence of two angiotensin 11 receptor subtypes, termed AT, and AT2, which differ in their signal transduction mechanisms and in the effects they mediate. In brain, both receptor subtypes are present. Most of the known central actions of angiotensin 11, for example the regulation of blood pressure and of electrolyte and water balance, seem to be mediated by the AT, receptor, while the role of the AT2 receptor is still an enigma. This review by Thomas Unger and colleagues summarizes the current knowledge and latest hypotheses in this rapidly developing field. The octapeptide angiotensin II is a potent effector hormone of the renin-angiotensin system. It exerts a wi’de range of physiological effects on the cardiovascular, renal and endocrine systems, and the peripheral and central nervous syslems’. Angiotensin II formed in the circulation acts on receptor sites in brain areas lacking a blood-brain barrier. Angiotensin II being part of an intrinsic reninangiotensin system within the brain may also act as a neuromodulator or neurotransmitter within a number of anatomically discrete brain structures and pathways.
Angiotensin II receptor subtypes Indirect evidence has accumulated over many years for the existence of different subtypes of angiotensin II binding sites*. Pharmacological evidence for two specific sites has only recently been found, following the development of highly selective angiotensin II receptor ligands such as losartan (DuP753), CGP42112A and PD123177 (Refs 3-5). RecepU. Muscha Steckelings is Research Fellow and T. Unger is Professor in the Department of Pharmacology, Universityof Heidelberg, FRG, and S. P. Bottari is in Cardiovascular Research, Ciba-Geigy ltd, Basel, Switzerland.
tars with highest affinity for losartan (Ki = 10-50 nM) and the lowest affinity for CGP42112A (Ki > 0.5 PM) and PD123177 (Ki > 10 PM), are referred to as ATI. Conversely, binding sites displaying highest affinity for CGl’42112A (Ki < 1 nM) and PD123177 (Ki = l&100 nM) and lowest affinity for losartan (Ki > 1 PM), are referred to as AT2 (Ref. 6). Sulphydryl reducing agents such as dithiothreitol and glutathione are also able to distinguish the two subtypes. These two compounds inhibit the binding of angiotensin II to ATI receptors, whereas they enhance the binding affinity of angiotensin II for AT2 sites317. In peripheral tissues, AT1 and AT2 subtypes seem to mediate the biological actions of angiotensin II via different signal transduction pathways. AT, receptors interact with G proteins, inhibiting adenylyl cyclase activity and stimulating phospholipases C, A2 and D. This, in turn, causes a decrease in cellular CAMP, and a stimulation of both inositol 1,4,5trisphosphate (IP3) and diacylglycerol generation as well as prostaglandin synthesis”“. In contrast, AT2 receptors do not interact with G proteins”, ruling
33 Dreyer, F. (1990) Rev. Physiol. Biochem. Phannacof. 115,9&136 34 Block, A. R., Donegan, C. M., Denny, B. J. and Dolly, J. 0. (1988) Biochemistry 27,6814-6820 35 Rehm, H. and Lazdunski, M. (19813) Proc. Nat1 Acad. Sci. USA 85,491%923 36 Kirsch, G. E. et al. (1992) Neuron 8, 499-505 37 Hurst, R. S. et aI. (1991) Mol. Phurmncol. 40,572-576
out a connection to any of the signalling pathways described for the AT, receptor. In fact, two studies recently showed that stimulation of the AT2 receptor leads to a decrease of cGMP levels”r13. This decrease may be caused by an inhibition of particulate guanylyl cyclase following the stimulation of a phosphotyrosine phosphatase”. In the brain, it is not clear whether angiotensin II receptors are coupled to the same signaI transduction mechanisms as in the periphery. For example, the results on the effect of angiotensin II binding on IP3 generation are still controversial. In primary glial cell cultures angiotensin II, as in peripheral tissues, leads to stimulation of phosphatidylinositol hydrolysis14. However, in in vitro experiments on cerebral cortex and a combined preparation of hypothalamus, thalamus, septum and midbrain of Sprague-Dawley rats, angiotensin II inhibited IP3 generationl’, and in neuronal cell cultures it had no significant effect on phosphatidylinositol hydrolysi9. Recent data also report coupling of a subgroup of central AT2 receptors to G proteins”. These receptors were localized in the ventral thalamic and medial geniculate nuclei and in the locus coeruleus, while AT2 receptors in the inferior olive were not coupled to G proteins. More data point to the existence of additional angiotensin II receptor subtypes. For example, the affinities of losartan, CGlWll2A and PD123177 for angiotensin II binding sites on amphibian (Xenopus laevis) cardiac membranes differ markedly from their affinities for binding sites in Furthermammalian tissues’s. more, in most areas of the rat brain, angiotensin II and [Sar’, Ile8]angiotensin II have a tenfold lower affinity for ‘AT1 receptors’
TiPS - September
366 TfiE
1.~~lization of angiotensinII bindingsitesin the ratbrainin sixdifferentstudies Reference numberof study 20*
21
2>1
2>1
22
23
1 1 1 1 1 1
1
24
25
1 1 1 1
1
1 1
1 1
1>>2 1>>2 1>2
2 2 2 2=-l 2 1 1 : 2 2 2 2>1 1
2
2:l
2 2 2 1 1 1
: 2 1 1 2
I 2 2
1 and2 2 2 1 1 2
2 2
1 1 2 1 : 2
1 2
VI& studyusadWistarrats;all othersusedSprague-Dawleyrats. 1 = AT, bindinge 2 = AT, bindingsite;1>2 = moreAT, thanAT, sites;etc.
than in peripheral tissuestgzo suggesting there may be subclasses of ATI receptors. Finally, in rat hypothalamus, angiotensin II binding sites have been identified that did not competitively bind losartan, indicating the existence of at least one central subtype of angiotensin II binding site that is neither an AT1 nor an AT2 binding siteM. LocaZization of binding sifes in bmin A number of reports have been published describing the distribution of angiotensin II receptor subtypes in brain, using either quantitative autoradiography or competitive radioligand binding techzuqueszGz. In these studies, angiotensin II receptors were characterized by displacement of the parent peptide with the selective angiotensin II receptor ligands. The distribution of AT, and AT2 sites within the brain was almost identical in all studies. AT1 receptors were localized mainly in target sites involved in regulation of blood pressure, drinking, salt appetite and vasopressin for-
mation and release, whereas the distribution of AT2 binding sites in adult rats did not provide definitive clues to their function (see Table I and Fig. 1). Interestingly, the distribution of receptor subtypes in the brain differs with species and age. Song et al. demonstrated differences between the distribution of angiotensin II receptor subtypes in Sprague-Dawley rats and human brain (Song, K. et al., unpublished). In human brain, but not in rat brain, angiotensin II receptors are expressed in the basal ganglia and the molecular layer of the cerebellum, with the AT1 receptor predominating in the basal ganglia and the AT2 binding site predominating in the molecular layer of the cerebellum. In humans, AT1 receptors are expressed in the locus coeruleus and the subthalamic nucleus, while in rat, AT, binding sites are expressed at these two sites. The slightly different distribution of angiotensin II receptor subtypes obtained from studies using either Sprague-DawleyZ1-25 or Wistarro rats may be due not to the
1992 [Vol. 131
different rat strains but to the different techniques used. Tsutsumi and Saavedra have demonstrated differences in the distribution of angiotensin II receptors in adult (&week-old) rats compared to young (2-weekold) or fetal rats24,26. In most areas of the adult rat brain, the distribution and density of AT1 receptors are comparable to those present in young and fetal rats. Conversely, the distribution and number of AT2 binding sites changes during development. Their concentration is always much lower in adult animals. Indeed, in some brain areas AT2 binding sites are expressed only in young and fetal rats, and are undetectable in adult rats. Central actions of angiotensin II Stimulation of angiotensin II receptors in the brain evokes coordinated autonomic, many endocrine and behavioura! responses. These responses include an increase in blood pressure and water intake, stimulation of natriuresis and salt appetite, secretion of vasopressin, oxytocin, adrenocorticotropic hormone and other pituitary hormones, and an interaction with brain catecholaminesl. Peripheral angiotensin II receptors mediate the same effects on cardiovascular and fluid regulation with only one exception: while central angiotensin II causes the induction of natriuresis, stimulation of angiotensin II receptors in the periphery leads to renal Na+ retention*r. In rat brain, structures related to the known central actions of angiotensin 11 (e.g. organum vasculosum laminae terminalis, subfomical organ, preoptic medial nucleus, area postrema, nucleus of the solitary tract) mainly or exclusively contain AT1 receptors (see Fig. l), suggesting that this receptor subtype is responsible for mediating these effects2s25. The following lines of evidence support the hypothesis that the known central actions of angiotensin II are mediated by the AT1 receptor: Blood pressure regulation Intracerebroventricular injection of angiotensin II leads to an increase in blood pressure in the conscious rat. This augmentation of blood pressure is completely suppressed
TiPS - September 1992 [Vol. 131
367
nucleusof vagus
eminence
F&x 1. Schematic diagramof a longitudinal sectionof the ratbrain showing angiotensin It binding sites. $5 AT, binding sites only; l AT, binding sites onty; n AT, and AT, binding sites. IC, inferior colliculus; NTS, nucleus of the solitary tract; OVLT, organum vasculosum laminae terminalis; SC, superior colticulus; SCN, suprachiasmaticnucteus.
by pretreatment with the AT1 receptor ligand losartan, suggesting that the ATi receptor mediates the increase in blood pressure produced by angiotensin II (Ref. 28). Regulation of water intake Pretreatment with i.c.v. losartan abolishes angiotensin II-induced drinking, indicating that the AT1 receptor is involved in the mediation of this response. Drinking after water deprivation is significantly attenuated by i.c.v. injection of losartan or atropine, indicating that it is regulated both by endogenous angiotensin II and the cholinergic nervous system28~2g. Release of vasopressin from the hypothalamus Catecholamines play a critical role in expression of the central actions of angiotensin II, such as drinking and increased blood pressure1,30. In viva studies also suggest the involvement of a hypothalamic catecholaminergic pathway in the release of vasopressin from hypothalamic nuclei, including the paraventricular nucleus and supraoptic the nucleus31~32. Recent in viva experiments have shown that stimulation of periventricular angiotensin II receptors causes a dose-dependent release of catecholamines in the paraventricular nucleus and the supraoptic nucleus (Ref. 33 and Qadri, F. et al., unpublished). The
release of catecholamines in the paraventricular nucleus was temporally correlated with an increase in blood pressure. Both effects were abolished by i.c.v. pretreatment with losartan, indicating their dependence on AT1 receptor stimulation. In addition, release following vasopressin angiotensin II receptor stimulation could also be reduced by microinjection of alor araadrenoceptor antagonists prazosin or idazoxan, respectively, into the paraventricular nucleus and the supraoptic nucleus, confirming the hypothesis that a catecholaminergic hypothalamic pathway is involved in angiotensin IIinduced vasopressin release. These findings are contradicted by a report from Schiavone et al., indicating that angiotensin IIinduced vasopressin release from hypothalamo-neurohypophysial explants is mediated primarily via the AT2 receptor (Schiavone, M. T. et al., unpublished). Natriuresis Angiotensin II, by renal injection, causes natriuresis2’. Since this induced natriuresis can be blocked by i.c.v. pretreatment with losartan, this effect appears to be mediated by periventricular AT1 recepto#.
i.c.v.
The central actions of angiotensin II mediated by the AT2 still enigmatic. receptor are Jaiswal et al. reported that the AT2 receptor in human astrocytes
mediates synthesis of PGIa, whereas PGEa synthesis is mediated by the ATi receptors5. However, more recent studies suggest a role for this receptor subtype in differentiation and developmental processes. This hypothesis is mainly based on the observation that in the brain of fetal and young rats the number of ATa binding sites is much higher than in adult rats. The highest density of ATa binding sites in fetal and young rats is found in areas related to visual function and control of motor activity, in sensory areas, and in selected structures of the limbic system, suggesting that they may be involved in control and learning of motor activity. A role in learning processes is also supported by a study claiming that the AT2 receptor mediates a cognitive enhancing action of angiotensin II (Ref. 36). Apart from these observations in certain brain areas, similar results were obtained from autoradiographic studies of the rat anterior cerebral artery, where the number of ATs binding sites was much higher in young than in adult rats, suggesting that the AT2 binding sites may also be involved in cerebrovascular developments’. q
cl
cl
Recent development of specific angiotensin II receptor ligands has allowed the identification of at least two different angiotensin II receptor subtypes, which mediate their actions through different signal transduction mechanisms. Binding of angiotensin II to ATi receptors decreases cellular cAMP levels and stimulates both generation of IP3 and prostaglandin synthesis. Binding of angiotensin II to AT, receptors leads to a decrease in cellular cGMP concenprobably caused by trations, stimulation of a phosphotyrosine phosphatase. AT, receptors are localized mainly in brain areas responsible for mediating the cardiovascular- and fluid-regulating actions of angiotensin II, and their involvement in these actions is corroborated by functional studies. It is still unknown which actions of angiotensin II are mediated by AT2 receptors. From the distribution of AT2 binding’ sites in adult and young animals it has
TiPS - September 1992 fVol.13f
333 been suggested that they may play a role in differentiation and development.
Refkxences 1 Unger, T., Badoer, E., Ganten, D., Lang, R. E. and Ret@, R. (1988) CircdafiO~77 (SuppI. 1). 40-54 2 Kkn&as~,. G. (1987)Am. J. Phytiot.=,
32 Leibowitt, S. F., Eidelman, D., Suh, J. S., Diaz, S. and Sladek, C. D. (1990) Exn. Neural. 110.298-305 33 Stidler, T., Veltmar, A., Qadri, F. and Unger, T. (1992) Brain Res. 569,117-122 34 Rohmeiss, P., Nagy, E. and Unger, T. (1991) 1. Hyperfens. 9 (Suppl. 6). 480 35 Jaiswal, N., Tallant, A., Diz, D. I., Khosla, M. C. and Ferrario, C. M. (1991) Hypertension 17,1115--1120 36 Barnes, N. M., Costa&B., Kelly. M. E.,
Murphy, D. A. and Naylor, R. J. (1991) NeuroReport 2,351-3.53 37 Tsutsumi, K. and Saavedra, J. M. (1991) Am. 1. Pkysiol. 261, H667-H670
New editions
drugs across various mucosae and digestive tract membranes.
CGP42112Ar nicotinie acid-Tyr-(N”benzoylcarbonyl-Arg)Lys-His-Pro-Be-OH PD123177: I-(4-amino-3_methylphenyl)methyl-S-diphenyl-acetyl-4,5.6,7tetrahydro-lH-imidazo[4,.5-clpyridine-6carboxyhc acid
F&-F7
3 Whitebread, S.. Me& M., Kamber. B. and de Gaspam, M. (1989) &o&m. Biopbys.Res. Commun. 163,2&T-291 4 Q&I, A. T. et al. (1989) Biockem. Biopkys. Res. Commnm. 165,196-203 5 Chang. R. S. L. and Lotti, V. J- (1989) MOE PkamtucoL 37.347-351 6 Btunp~, F. M. et nl. (1991)Hypertension 17.720-722 7 ~&sumi. K. and Saavedra, J. M. (1991) Cell. Mol. Neurobiol. Il. 295299 8 Lassegue,B.. Alexander, R. W.. Uark, M. and Crien~ K. K. (1991) Biochem. J. 276s19-22 9 Jar& S.. Cantau, B. and Jakobs, K. H. (1991) J_ B&i. Chem. 2!56,2603-2606 10 Pfeikhifter~ J. (1990) Eur. J. Pharmocol. 184,201-203 11 FWtarL S. I’. et al. (1991) Eur. 1. PhatYiza~t. 207.157-163 12 Sumners, C, W., Zelezna, B. and Raizada, M. K, (1991) Proc. Nat! Acad. Sci. USA 88.7367-7S7l 13 Bottari. S. P. et af. (1992) Biockem. Riophys. Res. Commun. 183,206-211 14 Smith T. I.... Yamamma, H. I. and Lee, L. (1986)Life Sci_39,1675-X84 15 Tarnura, C. S. and Speth, R. (1990) Neurockem. Int, 17,475-479 16 Sumne~~, C. Myers, L M., Kalberg, C. 1. and Raizada, M. K. (1990) Pmg. N#~~oi_ 34,355-385 I? Tsutsumi. K. and Saavedra. 1. M. (1992) Mol. Pha&ocol. 41,290-297. ’ 18 Ji,tt. !%ndbexg,K. and Catt, K. J.(1991) Mol. Pkanaacol. 39,120-w 19 Chang, R. S. L, Chen,T. D., Faust, K. A. and Lo&i. V. J. (1990) Biochem. Biopkys. Res. Convnun. 17l.813-817 20 Obermiiiier, N. et al. (1991) Neurosci. z&t. 132.11-15 21 Leung, K. H., Smith, R. D., Tiiermans, P. B. M. W. M. and Chiu, A. T. (19!X) Newosti. Left 123.95-98 22 Rowe, B. P.. Grove, K. L., Saylor, D. L. and Speth, R C. (1991) Regul. Pep. 33,
fang,
PharmacoJogie - des Concepts Fondamentaux aux Applications Therapeutiquw. Deuxieme edition
Principles of Biochemical Toxicology. Second edition
by Michel Schorderet and colleagues, Editions Slatfcine, 1992. SFr28.00 (952 pages) ISBN 2 05 100910 4
by John A. Timbre& Taylor & Francis, 2992. f19.95 f415 pages) 1S~N 0 85066 832 8 pbk
comprehensive textbook This draws on the collective expertise of 92 authors under the overah direction of Michel Schorderet. The information is arranged in 11 sections based on the principal systems and in-depth organ accounts of antiparasitic, antimicrobial and antitumour therapies. The treatment is detailed, weJl but rather heterogeneously illustrated, and thoroughly documented with a useful ‘to know more’ bibliography for every chapter. AR in all, a most valuable basic reference work that, although aimed principally at a francophone readership, should also prove useful for those who, like this reviewer, are rather less competent in French.
This edition is considerably larger than the first, containing new figures, more examples and additional information, but retains the original format of a wide-ranging introduction to toxicology.
J. R. FOZARD
23 Song, L, Allen, A. M., Paxinos, G. and Mendelsohn. F. A. 0. (1991) Clin. Exp. Pkarrnacol. Pkysiol. 18,93% 24 Tsutsumi. K. and Saavedra, J. M. (1991) Am. I. Pkusiol. 261. R209R216 25 Gehiert, ‘D_R,, Gackenheimer, S. L., Reel, J. K., Lin, H-S. and Steinberg, M. I. (1990) Eur. I. Pharmucol. 187,123-126 26 Tsutsumi, K., Viswanathan, M., Stroemberg, C and Saavedra, J. M. (1991) Eur. J. Pha~a~ol. 1%,89-92 27 Unger, T. ef ni. (1989) Brnik Res. 486,
Novel Drug Delivery Systems. Second edition by Yie W. Chen, Marcel Dekker, 1992. $150.00 in USA and Canada, $172.50 elsewhere (vii + 797 pages) ISBN 0 8247 8520 7
AR chapters have been extensively rewritten and updated, for example 33-3s that on regulatory considerations 28 Wong, P. C. et ni. (1990) Hypertension 15, in controlled drug delivery has 823-334 been expanded to incorporate 29 Stauss, H. and Unger, T. (1991) NuunyngOred. Arch. Pha~uco~. 343 (SuppI.), new guidelines used in the regulatory approval process. New 30 Badoer,E., Wuerth, H., Qadri, F., Itoi, chapters have been added on K. and Unger, T. (1988) Eur. 1. issues associated with systemic Pkarmacol. 154,105-108 delivery of peptide/protein drugs, 31 Benetos, A., Gavras, I. and Gavras, H. (1986)BruinRes. 38,322-326 and rate-con~lled delivery of
Annual Review of Neuroscience, Volume 15 edited by W. Ma~~~~ Cowan, Eric M. Shooter, Charles F. Sfevens and Richard F. Thompson, Annual Reviews, 1992. $44.00 in USA, $49.00 elsewhere (vii + 454 pages) ISBN 0 8243 2415 3 Chapters include: The biosynthesis of neuropeptides: peptide (xamidation, Betty A. Eipper, Doris A. Staffers and Richard E. Mains; Adrenergic receptors as models for G protein-coupled receptors, Brian Kobilka; Guanylyl cyclaselinked receptors, Peter S. T. Yuen and l?avid L. Garbers; The role of the amygdaJa in fear and anxiety, Michael Davis.
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