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• W4289792279 abstract "HomeCirculation ResearchVol. 131, No. 4Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCalcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow Kaushik P. Patel and Hong Zheng Kaushik P. PatelKaushik P. Patel Correspondence to: Kaushik P. Patel, PhD, A. Ross McIntyre Professor of Physiology, Department of Cellular & Integrative Physiology, University of Nebraska Medical Center. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4500-0819 Department of Integrative and Cellular Physiology, University of Nebraska Medical Center, Omaha (K.P.P.). Search for more papers by this author and Hong ZhengHong Zheng https://orcid.org/0000-0002-1660-3573 Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion (H.Z.). Search for more papers by this author Originally published4 Aug 2022https://doi.org/10.1161/CIRCRESAHA.122.321581Circulation Research. 2022;131:361–363This article is a commentary on the followingCalcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic OutflowHypertension is a multifaceted disease that includes activation of the sympathetic nervous system as a major contributing component. The etiology for the activation of the sympathetic nervous system during hypertension has been an area of intense focus for many years, with no clear or comprehensive resolution to the precise central neurotransmitter mechanisms involved. In light of the fact that sympatho-excitation has been shown to be integral for the etiology of essential hypertension,1 begs the question, is there a specific central neurotransmitter pathway that is critically involved in the hyper-sympathetically driven hypertension?Article, see p 345The paraventricular nucleus (PVN) of the hypothalamus is the most rostral of the 5 major central nervous system sites that directly dictates sympathetic outflow. The preautonomic neurons originating in the dorsal and lateral parvocellular portion of the PVN project to rostral ventrolateral medulla (RVLM), and intermediolateral columns of the spinal cord with specific dense innervation to the heart and the kidneys.2 The PVN has a heavy projection to the RVLM with 7-fold greater numbers of PVN neurons projecting to the RVLM than those to the spinal cord. It has been demonstrated that the activity of PVN-RVLM neurons is temporally correlated with renal sympathetic nerve activity (SNA) activation. As a result of these anatomic features, PVN specifically mediates sympathetic outflow to the heart and the kidneys with a single synapse in the intermediolateral columns, thus making it an ideal candidate for regulation of arterial blood pressure. Stimulation of PVN elicits increased discharge of several sympathetic nerves, including renal, lumbar, and adrenal. Functional studies have also implicated an important role for the PVN in cardiovascular regulation.3 Previous studies have indicated increased activation of the PVN in various forms of hypertension.4,5 Lesions of the PVN inhibits the development of DOCA/salt hypertension,6 and purely neurogenic hypertension produced by lesions of the aortic depressor nerves in rats.5 In spontaneously hypertensive rats, PVN lesions lower arterial pressure,4 but the underlying neurotransmitter mechanisms were not identified. More recently, specific manipulations of glutamatergic neurons in the PVN have been shown to induce neurogenic hypertension and abrogate the increase in arterial pressure in DOCA-salt hypertension.7 Interestingly, Xu et al8 have demonstrated that the spontaneous activity of PVN-RVLM neurons is enhanced during congestive heart failure, another condition with enhanced SNA.In the PVN, many neurotransmitters converge/interact to influence its neural activity and thus its effect on overall sympathetic outflow.2 As a major excitatory neurotransmitter in the brain, glutamate has been known to modulate sympathetic nervous system in several brain areas, including the hypothalamus and the RVLM. Both NMDA and AMPA receptors, the 2 major ionotropic glutamate receptors, exist in the PVN and preautonomic neurons and may be involved in mediating glutamate-induced excitatory action in the PVN. Microinjection of NMDA into the PVN significantly increases renal SNA.9 Glutamatergic tone drives neurons within the PVN that are generally inhibited by GABA. Furthermore, the expression of NMDA receptor subunit NR1 is increased as well as increase in renal SNA response to NMDA microinjected into the PVN in rats with congestive heart failure,10 suggesting an enhanced glutamatergic tone in the PVN may contribute to sympathetic activation in congestive heart failure. However, the specific mechanism for activating preautonomic neurons within the PVN is less well understood. It is interesting to note that pretreatment with memantine, an NMDA receptor antagonist, in congestive heart failure appears to be cardioprotective, perhaps by alleviating the centrally mediated sympatho-excitation from the PVN.11Calcineurin is a Ca2+/calmodulin-dependent serine/threonine protein phosphatase, also referred to as protein phosphatase 3. It is best known for its role in the immune response. When antigen interacts with T-cell, it increases calcium and activates calcineurin. Calcineurin inhibitors (CNIs) are potent immunosuppressive drugs that prevent rejection after transplantation and used in autoimmune disease. However, CNIs-induced hypertension is among the most common and prominent side effects after organ transplantation. The primary cause of hypertension is believed to reside in the nervous system with increased SNA12 and enhanced renal sodium transport.13 In the kidney, increased SNA and abnormal sodium regulation are believed to be involved in the pathogenesis of CNIs-induced hypertension and nephrotoxicity. In the central nervous system, CNIs have been shown to modulate glutaminergic neurotransmission in neurons through a presynaptic mechanism.14 Inhibition of calcineurin activity has been shown to significantly increase the amplitude of evoked NMDAR-EPSCs through protein phosphorylation controlled by calcineurin, specifically in the PVN. Inhibition of calcineurin activity has been shown to abolish inward rectification of AMPAR-EPSCs of spinally projecting PVN neurons in spontaneously hypertensive rats.15 It has also been reported that calcineurin inhibition increases GluR2 phosphorylation in the striatum.In light of the previous literature showing that CNI causes increase in arterial pressure acutely, Zhou et al16 in this issue of Circulation Research postulated that prolonged treatment with CNIs causes an increase in sympatho-excitation and hypertension by potentiating synaptic NMDA receptor activity, specifically within the PVN. They observed a gradual and significant increase in arterial pressure following systemic administration of CNIs for 2 weeks, which lasted even after treatment was terminated. Concurrent with CNIs treatment, there was a decrease in the level of calcineurin activity within the PVN and circumventricular organs but not in the RVLM. The authors claim that this was good evidence that CNIs crosses the blood-brain barrier and inhibits calcineurin activity in the brain, specifically in the forebrain. Selective administration of AMPA and NMDA receptor antagonists within the PVN demonstrated an enhanced glutamatergic tone in rats chronically treated with CNIs, which dictate renal SNA.Perforated whole-cell recording of spontaneously firing spinally projecting PVN neurons in slice preparation was used to assess AMPA and NMDA receptor-mediated activation of preautonomic neurons in the PVN. Chronic CNIs treatment enhanced AMPA and NMDA receptor-mediated activation of preautonomic neurons in the PVN. By measuring miniature excitatory currents, they assessed the spontaneous quantal release of glutamate and concluded that CNIs treatment resulted in greater glutamate release. Post-synaptic activity was also assessed, and it was concluded that there were greater effects of AMPA and NMDA on preautonomic neurons in the PVN in rats treated with CNIs. These in vitro electrophysiological studies suggested an enhanced activation of preautonomic neurons in the PVN of rats treated with CNIs. Immunoprecipitation assays were utilized to determine the phosphorylation levels of synaptic NMDARs in synaptosomes isolated from the PVN tissue to identify a link between calcineurin and trafficking of NMDA receptor in CNIs-induced hypertension. They concluded that CNIs enhanced the incorporation of NMDA receptors in postsynaptic clefts allowing enhanced activation of preautonomic neurons in the PVN. The overall conclusion was that endogenous calcineurin in the PVN is a negative regulator of sympathetic outflow (Figure).Download figureDownload PowerPointFigure. Schematic diagram shows the activation of preautonomic neuronal activation in the paraventricular nucleus (PVN) by glutamate via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors causing an increase in renal sympathetic nerve activity (RSNA), cardiac sympathetic nerve activity (CSNA) and sympathetic activity (SNA) to vasculature resulting in hypertension. Calcineurin inhibition (CNI) prevents the negative regulation of glutamatergic receptors resulting in the activation of preautonomic neurons in the PVN. The left panel shows NMDA receptor and neuronal nitric oxide synthase (nNOS) positive cells in the parvocellular portion of the PVN that typically represent the preautonomic neurons. Ca++ indicates calcium ions; Na+, sodium ions; and V, ventricle. (Templates used from www.BioRender.com).These are important findings that provide a mechanism for the action of CNIs during hypertension. However, there are limitations of this study, some of which are acknowledged by the authors. Prolonged treatment of CNIs in the brain may have effects on other sites that are also important in the generation of sympathetic activity, such as the circumventricular organs in the forebrain and the RVLM in the brain stem. It is well known that numerous neurotransmitters/modulators mechanisms within the PVN are involved in the regulation of the sympathetic outflow and cardiovascular function, including the nitric oxide mechanisms, angiotensin II, and cytokines, etc.2,9 The exclusive focus on the glutamatergic mechanism may also be a limitation. Further investigations of the interactions among these various neurotransmitter substances and glutamatergic system would be important and remains to be examined. Technically, the slice preparation with identified neurons is a difficult experimental preparation (disconnected from normal inputs and outputs) that should be kept in mind when evaluating integrational nature of these pathways. In addition to the above, one should consider alterations in the RVLM, a major relay site for sympathetic outflow in the brain stem as a factor in alterations in SNA during hypertension. Finally, the detailed molecular mechanism underlying the phosphorylation of the inotropic glutamatergic neurons with calcineurin and their molecular mechanisms remains to be examined.Overall, the present study could help explain why many forms of hypertension may be related to an altered glutamatergic activity within the PVN (Figure). The results demonstrate that prolonged activation of the glutamatergic tone within the PVN would result in an enhanced sympathetic outflow, possibly related to disease states such as hypertension and heart failure. The activations are either directly or indirectly mediated by the PVN or areas that are relaying that information to the PVN. Various conditions that exasperate this specific glutamatergic pathway within the PVN would result in exaggerated sympatho-excitation, such as that observed with chronic CNIs treatment demonstrated in this study. Recurrent periods of over-excitation in the PVN could contribute to chronic over-activation of this nucleus and thus enhance sympathetic drive leading to the worsening situation in hypertension and heart failure. With the efficacy of memantine, a clinically used NMDA receptor antagonist to effectively attenuate CNIs-induced hypertension in rats, suggests that the translational and therapeutic implications of this work are clearly important. This study provided much food for thought and set the stage for additional studies in cardiovascular diseases with centrally mediated enhanced sympathetic tone.Article InformationSources of FundingThis work was supported by National Institutes of Health Grants R01-DK-114663, R01-DK-129311 (to K.P. Patel and H. Zheng), P01-HL-62222 and endowed McIntyre Professorship to K.P. Patel.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Kaushik P. Patel, PhD, A. Ross McIntyre Professor of Physiology, Department of Cellular & Integrative Physiology, University of Nebraska Medical Center. Email kpatel@unmc.eduReferences1. Esler M, Rumantir M, Wiesner G, Kaye D, Hastings J, Lambert G. Sympathetic nervous system and insulin resistance: from obesity to diabetes.Am J Hypertens. 2001; 14:304S–309S. doi: 10.1016/s0895-7061(01)02236-1CrossrefMedlineGoogle Scholar2. Swanson LW, Sawchenko PE. Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms.Neuroendocrinology. 1980; 31:410–417. doi: 10.1159/000123111CrossrefMedlineGoogle Scholar3. Patel KP. Role of paraventricular nucleus in mediating sympathetic outflow in heart failure.Heart Fail Rev. 2000; 5:73–86. doi: 10.1023/A:1009850224802CrossrefMedlineGoogle Scholar4. Ciriello J, Kline RL, Zhang TX, Caverson MM. Lesions of the paraventricular nucleus alter the development of spontaneous hypertension in the rat.Brain Res. 1984; 310:355–359. doi: 10.1016/0006-8993(84)90159-8CrossrefMedlineGoogle Scholar5. Zhang TX, Ciriello J. Effect of paraventricular nucleus lesions on arterial pressure and heart rate after aortic baroreceptor denervation in the rat.Brain Res. 1985; 341:101–109. doi: 10.1016/0006-8993(85)91477-5CrossrefMedlineGoogle Scholar6. Nakata T, Takeda K, Itho H, Hirata M, Kawasaki S, Hayashi J, Oguro M, Sasaki S, Nakagawa M. Paraventricular nucleus lesions attenuate the development of hypertension in DOCA/salt-treated rats.Am J Hypertens. 1989; 2:625–630. doi: 10.1093/ajh/2.8.625CrossrefMedlineGoogle Scholar7. Basting T, Xu J, Mukerjee S, Epling J, Fuchs R, Sriramula S, Lazartigues E. Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension.J Physiol. 2018; 596:6235–6248. doi: 10.1113/JP276229CrossrefMedlineGoogle Scholar8. Xu B, Zheng H, Patel KP. Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure.Am J Physiol Heart Circ Physiol. 2012; 302:H1700–H1711. doi: 10.1152/ajpheart.00722.2011CrossrefMedlineGoogle Scholar9. Li YF, Mayhan WG, Patel KP. NMDA-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide.Am J Physiol Heart Circ Physiol. 2001; 281:H2328–H2336. doi: 10.1152/ajpheart.2001.281.6.H2328CrossrefMedlineGoogle Scholar10. Li YF, Cornish KG, Patel KP. Alteration of NMDA NR1 receptors within the paraventricular nucleus of hypothalamus in rats with heart failure.Circ Res. 2003; 93:990–997. doi: 10.1161/01.RES.0000102865.60437.55LinkGoogle Scholar11. Abbaszadeh S, Javidmehr A, Askari B, Janssen PML, Soraya H. Memantine, an NMDA receptor antagonist, attenuates cardiac remodeling, lipid peroxidation and neutrophil recruitment in heart failure: a cardioprotective agent?Biomed Pharmacother. 2018; 108:1237–1243. doi: 10.1016/j.biopha.2018.09.153CrossrefMedlineGoogle Scholar12. Klein IH, Abrahams AC, van Ede T, Oey PL, Ligtenberg G, Blankestijn PJ. Differential effects of acute and sustained cyclosporine and tacrolimus on sympathetic nerve activity.J Hypertens. 2010; 28:1928–1934. doi: 10.1097/HJH.0b013e32833c20ebCrossrefMedlineGoogle Scholar13. Hoorn EJ, Walsh SB, McCormick JA, Fürstenberg A, Yang CL, Roeschel T, Paliege A, Howie AJ, Conley J, Bachmann S, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension.Nat Med. 2011; 17:1304–1309. doi: 10.1038/nm.2497CrossrefMedlineGoogle Scholar14. Victor RG, Thomas GD, Marban E, O’Rourke B. Presynaptic modulation of cortical synaptic activity by calcineurin.Proc Natl Acad Sci U S A. 1995; 92:6269–6273. doi: 10.1073/pnas.92.14.6269CrossrefMedlineGoogle Scholar15. Li DP, Byan HS, Pan HL. Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension.J Neurosci. 2012; 32:372–380. doi: 10.1523/JNEUROSCI.3222-11.2012CrossrefMedlineGoogle Scholar16. Zhou JJ, Shao J-Y, Chen S-R, Pan H-L. Calcineurin controls hypothalamic NMDA receptor activity and sympathetic outflow.Circ Res. 2022; 131:345–360. doi: 10.1161/CIRCRESAHA.122.320976LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCalcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic OutflowJing-Jing Zhou, et al. Circulation Research. 2022;131:345-360 August 5, 2022Vol 131, Issue 4 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.122.321581PMID: 35926008 Originally publishedAugust 4, 2022 PDF download Advertisement" @default.
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