Brain Angiotensin II
2002; Lippincott Williams & Wilkins; Volume: 90; Issue: 5 Linguagem: Inglês
10.1161/01.res.0000014287.96335.21
ISSN1524-4571
Autores Tópico(s)Hormonal Regulation and Hypertension
ResumoHomeCirculation ResearchVol. 90, No. 5Brain Angiotensin II Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBrain Angiotensin IINew Insights Into Its Role in Sympathetic Regulation Irving H. Zucker Irving H. ZuckerIrving H. Zucker From the Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebr. Originally published22 Mar 2002https://doi.org/10.1161/01.RES.0000014287.96335.21Circulation Research. 2002;90:503–505Since its discovery, the renin-angiotensin II system (RAS) has intrigued physiologists and clinicians.1 Angiotensin II (Ang II), an ancient peptide, evolved to carry out a variety of biological functions, in order to meet the needs of diverse organisms. The negative feedback nature of the RAS enables it to participate in hemodynamic, endocrine, neural, behavioral, and excretory functions. It is truly a peptide to which the survival of most species is closely linked.Over the past 20 years, blockade of the RAS has become a prime target for pharmacotherapy in a variety of diseases. Either blockade of Ang I conversion to Ang II or blockade of the Ang II type 1 receptor (AT1) has been used to treat hypertension and heart failure.2–4 Administration of these agents are effective in ameliorating disease and enhancing survival, even in patients without augmented levels of circulating Ang II. This observation has led investigato0rs to focus on the tissue RAS as a mechanism by which organ function is both controlled and, in disease states, impaired. Although the kidney is the only organ that stores renin in granular form, the components of the RAS have been found in tissues from several other organs. These include the heart, liver, lung, and brain.5–7 The regulation of the RAS system in the brain is especially intriguing because Ang II can act as both a neurotransmitter and a vasoconstrictor.It has been known for some time that the brain expresses the genes that code for angiotensinogen, renin, converting enzyme, and all of the subtypes of the AT1 and AT2 receptors.8–10 The actions of Ang II in the central nervous system include promotion of thirst behavior and salt appetite,11 the regulation of vasopressin secretion,12,13 the regulation of sympathetic outflow, and modulation of the sensitivity of the arterial baroreflex, as well as many other important cardiovascular reflexes14 (Figure). The modulation of sympathetic outflow is a critical regulatory action of central Ang II because both chronic heart failure and some forms of hypertension are characterized by sympathoexcitation. The precise nature by which the brain RAS participates in the regulation of sympathetic outflow is still not completely understood. A major step forward in our understanding of the role of the RAS in blood pressure regulation has come from the study of Lazartigues et al15 reported in this issue of Circulation Research. These investigators developed a new and novel transgenic mouse that selectively overexpresses brain AT1a receptors. To develop this model, they took advantage of splicing the gene for the AT1a receptor with that of the neuron-specific enolase (NSE). The resulting animals (NSE-AT1) overexpressed the AT1a receptor in neurons in a wide variety of brain areas but not in glial cells or peripheral tissues (except for the adrenal medulla). Interestingly, these animals had normal resting arterial blood pressure, a finding not predicted based on other experiments in which arterial pressure was lowered in hypertensive animals by blockade or genetic manipulation of the central RAS.16 Although the arterial pressure of the NSE-AT1 was normal, these animals responded with an exaggerated increase in arterial pressure after central administration of Ang II. These two observations are important because they strongly suggest that overexpression of AT1a receptors in normal animals does not alter arterial pressure and, most likely, sympathetic outflow. These data also relate to the issue of baroreflex resetting, which has been shown to be influenced by nonpressor doses of Ang II.17 In order to minimize decreases in baroreflex sensitivity after an increase in arterial pressure, the baroreflex operating point may shift closer to the elevated pressure. The study by Lazartigues et al15 adds support for the notion that central AT1 receptors may participate in the resetting process. Download figureDownload PowerPointThe RAS in the brain has been shown to modulate both sympathoinhibitory and sympathoexcitatory reflexes. In addition to an intrinsic RAS, circulating Ang II may gain access to the brain through areas with weak or no blood brain barriers. Ang II via stimulation of the AT1 receptor in the brain may reduce arterial baroreflex and cardiopulmonary reflex sensitivity and contribute to baroreflex resetting. At the same time, Ang II augments excitatory reflexes. Both of these actions of central Ang II may lead to increases in sympathetic outflow in such disease states as heart failure and hypertension.The role of Ang II in the sympathoexcitatory process of disease states such as chronic heart failure has been an active area of investigation. For instance, it has been shown that central and peripheral administration of the AT1 receptor antagonist losartan enhances baroreflex sensitivity, which may contribute to sympathoinhibition.18–20 In addition, it appears that central Ang II participates in the sympathoexcitatory process of the heart failure state by virtue of sensitization of reflexes that are sympathoexcitatory in nature, such as the cardiac sympathetic afferent reflex.21,22 This reflex too can be normalized by blockade of the AT1 receptor in the brain or more specifically in discrete regions of the central nervous system such as the paraventricular nucleus.23The genetic manipulation of the AT1 receptor offers a unique opportunity to develop new therapeutic strategies in the treatment of hypertension, heart failure, and other states characterized by sympathoexcitation. The strategy described in the article of Lazartigues et al15 is but one possibility. Another method to implicate overexpression or hyperactivity of the AT1 receptor in disease states is the use of antisense 0oligonucleotide administration to reduce transcription of the mRNA for the AT1 receptor in both hypertension and heart failure.16,24–26 These studies point to a potential pivotal role of the AT1 receptor in the mechanism of the sympathoexcitation in these disease states. Finally, overexpression of the renin gene has proved to be an important model to implicate the brain RAS in the pathogenesis of hypertension.10,27 Hopefully, it will be possible to construct target-specific overexpression in order to identify specific sites in the regulation of Ang II–mediated responses.Although the observations relating to the manipulation of the central RAS suggest that Ang II and the AT1 receptors may be important in blood pressure regulation, there is also a large amount of evidence showing that these elements operate in concert with other endocrine and paracrine factors. For instance, nitric oxide (NO) may modulate the action of Ang II and expression of AT1 receptors in various sites.28–30 Blockade of NO synthase (NOS) increased sympathetic nerve activity in conscious animals only after increasing plasma (and most likely brain) levels of Ang II.29 In fact, central infusion of Ang II has been shown to decrease nNOS gene expression in the brainstem.31 Therefore, one could envision the use of the NSE-AT1 model as a tool to investigate the role of other substances produced in the central nervous system that are modulated by Ang II, such as NOS.In summary, there are now several transgenic and knockout rodent models in which the brain RAS has been manipulated. Indeed, in a recent report from the laboratory of one of the coauthors of the article by Lazartigues et al,15 the human renin gene was overexpressed in the mouse.9 These models will undoubtedly be important for a comprehensive understanding of the role played by, and the regulation of, Ang II in the brain. The application of integrative physiology to these models will help to mesh this novel molecular biology with pathology to better treat patients with sympathoexcitatory syndromes.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Irving H. Zucker, PhD, Dept of Physiology and Biophysics, University of Nebraska Medical Center, 984575 Nebraska Medical Center, Omaha, NE 68198-4575. E-mail [email protected] References 1 Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001; 38: 1246–1249.CrossrefMedlineGoogle Scholar2 McInnes GT. 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Endocrinology. 1998; 128: 204–210.Google Scholar13 Sun M-K, Reis DJ. Intracisternally applied angiotensin II does not excite reticulospinal vasomotor neurons in anesthetized rats. Eur J Pharmacol. 1996; 304: 63–71.CrossrefMedlineGoogle Scholar14 Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992; 262: E763–E778.CrossrefMedlineGoogle Scholar15 Lazartigues E, Dunlay SM, Loihl AK, Sinnayah P, Lang JA, Espelund JJ, Sigmund CD, Davisson RL. Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice. Circ Res. 2002; 90: 617–624.LinkGoogle Scholar16 Meng H, Wielb D, Gyurko R, Phillips MI. Antisense oligonucleotide to AT1 receptor mRNA inhibits central angiotensin induced thirst and vasopressin. Regul Pept. 1994; 54: 543–551.CrossrefMedlineGoogle Scholar17 Brooks VL. Chronic infusion of angiotensin II resets baroreflex control of heart rate by an arterial pressure-independent mechanism. Hypertension. 1995; 26: 420–424.CrossrefMedlineGoogle Scholar18 DiBona GF, Jones SY, Brooks VL. Ang II receptor blockade and arterial baroreflex regulation of renal nerve activity in cardiac failure. Am J Physiol. 1995; 269: R1189–R1196.CrossrefMedlineGoogle Scholar19 Liu J-L, Murakami H, Sanderford M, Bishop VS, Zucker IH. ANG II and baroreflex function in rabbits with CHF and lesions of the area postrema. Am J Physiol. 1999; 277: H342–H350.CrossrefMedlineGoogle Scholar20 Murakami H, Liu J-L, Zucker IH. Blockade of AT1 receptors enhances baroreflex control of heart rate in conscious rabbits with heart failure. Am J Physiol. 1996; 271: R303–R309.MedlineGoogle Scholar21 Ma R, Zucker IH, Wang W. Central gain of the cardiac sympathetic afferent reflex in dogs with heart failure. Am J Physiol. 1997; 273: H2664–H2671.CrossrefMedlineGoogle Scholar22 Ma R, Schultz HD, Wang W. Chronic central infusion of Ang II potentiates cardiac sympathetic afferent reflex in dogs. Am J Physiol. 1999; 277: H15–H22.CrossrefMedlineGoogle Scholar23 Zhu G-Q, Patel KP, Zucker IH, Wang W. Microinjection of Ang II into the paraventricular nucleus enhances cardiac sympathetic afferent reflex in rats. Am J Physiol Heart Circ Physiol. In press.Google Scholar24 Diz DI, Westwood B, Averill DB. AT1 antisense distinguishes receptors mediating angiotensin II actions in solitary tract nucleus. Hypertension. 2001; 37: 1292–1297.CrossrefMedlineGoogle Scholar25 Ambühl P, Gyurko R, Phillips MI. A decrease in angiotensin receptor binding in rat brain nuclei by antisense oligonucleotides to the angiotensin AT1 receptor. Regul Pept. 1995. 59: 171–182.CrossrefMedlineGoogle Scholar26 Wang W, Zhu G-Q, Patel KP, Zucker IH. AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with heart failure. FASEB J. In press.Google Scholar27 Nishioka T, Callahan MF, Li P, Ferrario CM, Ganten D, Morris M. Increased central angiotensin and osmotic responses in the Ren-2 transgenic rat. Hypertension. 1999; 33: 385–388.CrossrefMedlineGoogle Scholar28 Ichiki T, Usui M, Kato M, Funakoshi Y, Ito K, Egashira K, Takeshita A. Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension. 1998; 31: 342–348.CrossrefMedlineGoogle Scholar29 Liu J-L, Murakami H, Zucker IH. Angiotensin II–nitric oxide interaction on sympathetic outflow in conscious rabbits. Circ Res. 1998; 82: 496–502.CrossrefMedlineGoogle Scholar30 Paton JFR, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S. 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Sumners C and Richards E (2004) Angiotensin Receptor Signaling in the Brain: Ionic Currents and Neuronal Activity Angiotensin Vol. II, 10.1007/978-3-642-18497-0_8, (141-161), . March 22, 2002Vol 90, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000014287.96335.21PMID: 11909812 Originally publishedMarch 22, 2002 Keywordsautonomic outflowtransgenic animalreninangiotensin IItype 1 receptorsPDF download Advertisement
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