doi: 10.1161/01.RES.0000014287.96335.21
© 2002 American Heart Association, Inc.
Editorials |
Brain Angiotensin II
New Insights Into Its Role in Sympathetic Regulation
From the Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebr.
Correspondence 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 izucker{at}unmc.edu
Key Words: renin • angiotensin II • autonomic outflow • transgenic animal • type 1 receptors
Since 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.
|
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.23
The 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.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Basso N, Terragno NA. History about the discovery of the renin-angiotensin system. Hypertension. 2001; 38: 1246–1249.
2. McInnes GT. Clinical potential: angiotensin converting enzyme inhibitor or angiotensin II antagonist? J Hypertens. 2001; 19 (suppl 1): S61–S67.
3. Dickstein K. The role of losartan in the management of patients with heart failure. Clin Ther. 2001; 23: 1456–1477.[CrossRef][Medline] [Order article via Infotrieve]
4.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
5. Danser AHJ, Schalekamp MADH. Is there an internal cardiac renin-angiotensin system? Heart. 1996; 6 (suppl 3): 28–32.
6. Ye VZ, Duggan KA. Vasoactive intestinal peptide down-regulates the intrahepatic renin-angiotensin system in the anaesthetized rat. Clin Sci. 2000; 99: 201–206.[Medline] [Order article via Infotrieve]
7. Phillips MI, Speakman EA, Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept. 1993; 43: 1–20.[CrossRef][Medline] [Order article via Infotrieve]
8. Aldred GP, Chai SY, Song K, Zhuo J, MacGregor DP, Mendelsohn FAO. Distribution of angiotensin II receptor subtypes in the rabbit brain. Regul Pept. 1993; 44: 119–130.[CrossRef][Medline] [Order article via Infotrieve]
9.
Morimoto S, Cassell MD, Sigmund CD. The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene. Circ Res. 2002; 90: 80–86.
10. Lippoldt A, Paul M, Fuxe K, Ganten D. The brain renin-angiotensin system: molecular mechanisms of cell to cell interactions. Clin Exp Hypertens. 1995; 17: 251–266.[CrossRef][Medline] [Order article via Infotrieve]
11. Weisinger RS, Blair-West JR, Denton DA, Tarjan E. Role of brain angiotensin II in thirst and sodium appetite of sheep. Am J Physiol. 1997; 273: R187–R196.[Medline] [Order article via Infotrieve]
12. Matsukawa S, Keil LC, Reid IA. Role of endogenous angiotensin II in the control of vasopressin secretion during hypervolemia and hypotension in conscious rabbits. Endocrinology. 1998; 128: 204–210.
13. 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.[CrossRef][Medline] [Order article via Infotrieve]
14. Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol. 1992; 262: E763–E778.[Medline] [Order article via Infotrieve]
15.
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.
16. 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.[CrossRef][Medline] [Order article via Infotrieve]
17.
Brooks VL. Chronic infusion of angiotensin II resets baroreflex control of heart rate by an arterial pressure-independent mechanism. Hypertension. 1995; 26: 420–424.
18. 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.[Medline] [Order article via Infotrieve]
19. 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.[Medline] [Order article via Infotrieve]
20. 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.[Medline] [Order article via Infotrieve]
21. 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.[Medline] [Order article via Infotrieve]
22. 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.[Medline] [Order article via Infotrieve]
23. 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.
24.
Diz DI, Westwood B, Averill DB. AT1 antisense distinguishes receptors mediating angiotensin II actions in solitary tract nucleus. Hypertension. 2001; 37: 1292–1297.
25. 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.[CrossRef][Medline] [Order article via Infotrieve]
26. 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.
27.
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.
28.
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.
29.
Liu J-L, Murakami H, Zucker IH. Angiotensin II–nitric oxide interaction on sympathetic outflow in conscious rabbits. Circ Res. 1998; 82: 496–502.
30.
Paton JFR, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S. Adenoviral vector demonstrates that angiotensin II–induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol. 2001; 531: 445–458.
31. Calapai G, Marciano MC, Constantino G, Russo A, Corica F, Sautebin L, De Rosa M, Caputi AP. Effects of water deprivation and angiotensin II intracerebroventricular administration on brain nitric oxide synthase activity. Eur J Pharmacol. 1998; 360: 147–154.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J. S. Floras Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J. Am. Coll. Cardiol., July 28, 2009; 54(5): 375 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Stewart, A. J. Ocon, D. Clarke, I. Taneja, and M. S. Medow Defects in Cutaneous Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7) Production in Postural Tachycardia Syndrome Hypertension, May 1, 2009; 53(5): 767 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Stewart, I. Taneja, J. Glover, and M. S. Medow Angiotensin II type 1 receptor blockade corrects cutaneous nitric oxide deficit in postural tachycardia syndrome Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H466 - H473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Stewart, M. S. Medow, C. T. Minson, and I. Taneja Cutaneous neuronal nitric oxide is specifically decreased in postural tachycardia syndrome Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2161 - H2167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Weiss, M. D. Y. Liu, and J. Huang Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Physiological basis for a causal relationship of obstructive sleep apnoea to hypertension Exp Physiol, January 1, 2007; 92(1): 21 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nishikino, T. Matsunaga, K. Yasuda, T. Adachi, T. Moritani, G. Tsujimoto, K. Tsuda, and N. Aoki Genetic Variation in the Renin-Angiotensin System and Autonomic Nervous System Function in Young Healthy Japanese Subjects J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4676 - 4681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Campos, R. Iliescu, M. A. P. Fontes, W.-P. Schlegel, M. Bader, and O. C. Baltatu Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2371 - H2376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wang, J. Anrather, M. J. Glass, M. J. Tarsitano, P. Zhou, K. A. Frys, V. M. Pickel, and C. Iadecola Nox2, Ca2+, and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius Hypertension, September 1, 2006; 48(3): 482 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, L. F. Joaquim, V. M. Farah, R. B. Wichi, R. Fazan Jr., H. C. Salgado, and M. Morris Cardiovascular autonomic control in mice lacking angiotensin AT1a receptors Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2005; 288(4): R1071 - R1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Sun, X. Wang, C. E. Wood, and J. R. Cade Genetic AT1A receptor deficiency attenuates cold-induced hypertension Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R433 - R439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sakai, M. W. Chapleau, S. Morimoto, M. D. Cassell, and C. D. Sigmund Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II Physiol Genomics, December 15, 2004; 20(1): 66 - 72. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||