FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2118461151> ?p ?o ?g. }

• W2118461151 endingPage "203" @default.
• W2118461151 startingPage "201" @default.
• W2118461151 abstract "HomeCirculation ResearchVol. 97, No. 3Targeting Arterial Chemoreceptor Over-Activity in Heart Failure With a Gas Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTargeting Arterial Chemoreceptor Over-Activity in Heart Failure With a Gas David J. Paterson David J. PatersonDavid J. Paterson From the University Laboratory of Physiology, Oxford, UK. Search for more papers by this author Originally published5 Aug 2005https://doi.org/10.1161/01.RES.0000177931.10616.cbCirculation Research. 2005;97:201–203With an aging population the prevalence of heart failure (HF) continues to rise. In the United States almost 5 million people experience HF, often with a poor prognosis resulting in 20% of patients dying within 1 year and ≈80% mortality within 8 years.1 Although the mechanisms underpinning cardiac failure are not firmly established, several converging events ranging from depressed contractility itself,2 diastolic dysfunction,3 failing energy stores,4 abnormal cell growth,3 and defective beta adrenergic signaling5 are implicated. Neurohumoral activation also appears to play a significant role in amplifying harmful substrate to trigger lethal ventricular arrhythmia which may account for ≈50% of all deaths that are sudden and unexpected.6 The precise role of abnormal neurohumoral signaling is still unclear but is thought to involve a synergistic activation of the sympathetic nervous system with the renin-angiotensin-aldosterone system7,8 and diminished parasympathetic activity.9 Emerging evidence now suggests that an aspect of impaired neurohumoral signaling in HF may arise from dysregulation of the arterial chemoreflex at the level of the carotid bodies by oxygen-free radicals.Stimulation of the carotid body (CB) arterial chemoreceptors provides an excitatory input to activate the sympathetic nervous system.10 Chronic HF causes a sustained activation of the sympathetic nervous system11 and is also associated with enhanced chemosensitivity in both clinical and experimental HF.12,13 The type I (glomus) cell of the CB is thought to be the primary chemoreceptor sensor. There is an extensive plexus of nitric oxide synthase (predominately nNOS) positive immunoreactivity and NADPH-diaphorase activity in the intrinsic neurons that innervate intraglomic arterioles, glomus cells, and intraglomal vascular endothelial cells,14,15 thereby providing a structure for potential autocrine and paracrine signaling by nitric oxide (NO). Physiologically, when NOS is inhibited during hypoxia16 or when the enzyme is knocked out,17 chemoreceptor afferent activity and ventilation increase. Hypoxia also decreases NOS activity suggesting that endogenous NO may act to inhibit chemoreceptor output.14 Moreover, decreased NO production is observed in the enhanced CB chemoreceptor response seen in HF.13In this issue of Circulation Research Li and colleagues18 from Schultz’s group in a series of challenging experiments show that gene transfer of adenovirus encoding nNOS (Ad.nNOS) into the CBs reversed enhanced chemoreceptor activity in rabbits with HF. They reported that nNOS expression and NO production was suppressed in the CBs in HF and that these animals had higher chemoreceptor activity compared with the sham-operated group. Targeting Ad.nNOS into the chemoreceptor increased expression of nNOS and NO bioavailability resulting in a reversal of the HF chemoreceptor phenotype. The beneficial effects of nNOS gene transfer were abolished by nNOS inhibition. In addition the inhibitor also enhanced chemoreceptor activity in the sham operated group supporting the idea that nNOS-derived NO has a tonic inhibitory action under normal conditions. NOS inhibition alone in the HF group failed to increase chemoreceptor activity without the presence of Ad.nNOS, indicating the removal of the tonic inhibitory influence in HF. Interestingly, Ad.nNOS also lowered basal renal sympathetic nerve activity (RSNA), peripheral chemoreflex sensitivity, and reduced RSNA and ventilatory responses to hypoxia. However, these reflex responses were not normalized to levels seen in the sham animals suggesting dysregulation at other autonomic sites not targeted by Ad.nNOS, because central sympathetic outflow is increased in HF.19Adenoviruses can give rise to promiscuous transfection. This is particularly important with gene transfer studies targeting NOS given the potential paracrine action of the gaseous messenger if the gene gets placed in cell types not normally involved in physiological function. NOS is a highly-conserved enzyme in the nervous system and is known to exert its action in a very site-specific manner relative to its target.20 The vector used by Li et al has previously been used with good effect in targeting both central21 and peripheral22 cardiac autonomic neurons with a high degree of specificity because of its CMV promoter.23,24 Nevertheless one cannot rule out a nonspecific autocrine and paracrine action that might be set up in cell types not directly involved in chemoreception (eg, type II cells). Most evidence supports the idea that the action of NO in the CB is predominately paracrine in nature and arises from intrinsic neurones, because there is no convincing data for the primary source of NOS residing in either type 1 or type II chemoreceptor cells.15How does gene transfer rescue the CB phenotype in HF and what mechanisms are involved? The glomus cell as the primary chemosensor releases excitatory neurotransmitter(s) resulting in depolarization of the carotid sinus afferent nerve.25 NO targets cGMP and non-GMP dependent pathways to modulate ion channels that regulate calcium entry. A decrease in excitatory neurotransmitters is brought about by a decrease in calcium-dependent exocytosis that can be influenced by a number of simultaneous events. Several pathways, outlined in the Figure, may explain the beneficial action of nNOS gene transfer on the physiology of the glomus cell in HF. First, NO can activate the calcium-gated-potassium channel (KCa2+) because of NO-cGMP dependent stimulation of PKG.26,27 This increases potassium channel conductance, in particular IK, that is blunted in HF rabbits.13,26 Activation of this channel leads to a more negative membrane potential and in turn results in decreased voltage activation of the L-type calcium channel (ICaL). Secondly, NO can also decrease the open time of ICaL via cGMP independent processes that probably act by nitrosylation of calcium channel proteins on the channel itself to inhibit the current.28 Thirdly, when these events are taken together there is a significant decrease in intracellular calcium-dependent transmitter release. Fourthly, what is the excitatory transmitter that NO modulates? The strongest candidates appear to be ATP and acetylcholine (Ach). Both are released from type I cells in response to hypoxia29–31 and excite the sinus nerve. Importantly, recent work shows Ach release can be significantly inhibited by L-arginine,29 the precursor for NOS, or NO donors over a wide range of oxygen tensions.32Download figureDownload PowerPointProposed mechanism for action of nNOS on carotid body. Inset shows integrative response.The present study is an important step in unraveling the complex link between the failing heart and nervous system. They have identified a potentially interesting target in the CB that warrants further investigation beyond the stage of physiological proof of principle. It remains to be seen how sustained nNOS gene expression (eg, lentiviral nNOS constructs) in the CB affects the progression of the HF model in the awake animal. Future studies will likely involve understanding more about the molecular and cellular basis for suppressed sinus nerve activity that is brought about by NO. How does NO interact with other gaseous messengers? For example, carbon monoxide uses heme-oxygenase-2 that is localized in the type 1 cell and causes an inhibitory action on sensory activity.14 The neural axis from the CBs to the brain may also be important because HF can modify central autonomic outflow. Is NO also a key messenger in sinus nerve efferent inhibition of the CB? Understanding the integrative response from the CB to the end organ response is clearly desirable to establish whether chemoreceptors should be viewed as a potential therapeutic target in heart failure.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.The author thanks Dr S. Golding for his assistance with the figure.FootnotesCorrespondence to David Paterson, University Laboratory of Physiology, Parks Rd, Oxford OX1 3PT, UK. E-mail [email protected] References 1 American Heart Association. Heart Disease and stroke statistics - 2003 Update. Dallas, Tex.: American Heart Association; 2002.Google Scholar2 Houser SR, Margulies KB. Is depressed myocyte contractility centrally involved in heart failure? Circ Res. 2003; 92: 350–358.LinkGoogle Scholar3 Kass DA, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004; 94: 1533–1542.LinkGoogle Scholar4 Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res. 2004; 95: 135–145.LinkGoogle Scholar5 Post SR, Hammond HK, Insel PA. Beta-adrenergic receptors and receptor signaling in heart failure. Annu Rev Pharmacol Toxicol. 1999; 39: 343–360.CrossrefMedlineGoogle Scholar6 Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res. 2004; 95: 754–763.LinkGoogle Scholar7 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.CrossrefMedlineGoogle Scholar8 Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001; 344: 1659–1667.CrossrefMedlineGoogle Scholar9 Nolan J, Flapan AD, Capewell S, MacDonald TM, Neilson JM, Ewing DJ. Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function. Br Heart J. 1992; 67: 482–485.CrossrefMedlineGoogle Scholar10 Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev. 1994; 74: 543–594.CrossrefMedlineGoogle Scholar11 Zucker IH, Wang W, Brandle M, Schultz HD, Patel KP. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis. 1995; 37: 397–414.CrossrefMedlineGoogle Scholar12 Chua TP, Clark AL, Amadi AA, Coats AJ. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1996; 27: 650–657.CrossrefMedlineGoogle Scholar13 Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol. 1999; 86: 1264–1272.CrossrefMedlineGoogle Scholar14 Prabhakar NR, Kumar GK, Chang CH, Agani FH, Haxhiu MA. Nitric oxide in the sensory function of the carotid body. Brain Res. 1993; 625: 16–22.CrossrefMedlineGoogle Scholar15 Wang ZZ, Bredt DS, Fidone SJ, Stensaas LJ. Neurons synthesizing nitric oxide innervate the mammalian carotid body. J Comp Neurol. 1993; 336: 419–432.CrossrefMedlineGoogle Scholar16 Valdes V, Mosqueira M, Rey S, Del Rio R, Iturriaga R. Inhibitory effects of NO on carotid body: contribution of neural and endothelial nitric oxide synthase isoforms. Am J Physiol Lung Cell Mol Physiol. 2003; 284: L57–L68.CrossrefMedlineGoogle Scholar17 Kline DD, Yang T, Huang PL, Prabhakar NR. Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase. J Physiol. 1998; 511: 273–287.CrossrefMedlineGoogle Scholar18 Li Y-L, Li Y-F, Liu D, Cornish KG, Patel KP, Zucker IH, Channon KM, Schultz HD. Gene transfer of nNOS to carotid body revereses enhanced chemoreceptor function in heart failure rabbits. Circ Res. 2005; 97: 260–267.LinkGoogle Scholar19 Zucker IH, Pliquett RU. Novel mechanisms of sympatho-excitation in chronic heart failure. Heart Fail Monit. 2002; 3: 2–7.MedlineGoogle Scholar20 Paton JF, Kasparov S, Paterson DJ. Nitric oxide and autonomic control of heart rate: a question of specificity. Trends Neurosci. 2002; 25: 626–631.CrossrefMedlineGoogle Scholar21 Li YF, Roy SK, Channon KM, Zucker IH, Patel KP. Effect of in vivo gene transfer of nNOS in the PVN on renal nerve discharge in rats. Am J Physiol Heart Circ Physiol. 2002; 282: H594–H601.CrossrefMedlineGoogle Scholar22 Mohan RM, Heaton DA, Danson EJ, Krishnan SP, Cai S, Channon KM, Paterson DJ. Neuronal nitric oxide synthase gene transfer promotes cardiac vagal gain of function. Circ Res. 2002; 91: 1089–1091.LinkGoogle Scholar23 Channon KM, Blazing MA, Shetty GA, Potts KE, George SE. Adenoviral gene transfer of nitric oxide synthase: high level expression in human vascular cells. Cardiovasc Res. 1996; 32: 962–972.CrossrefMedlineGoogle Scholar24 Mohan RM, Golding S, Heaton DA, Danson EJ, Paterson DJ. Targeting neuronal nitric oxide synthase with gene transfer to modulate cardiac autonomic function. Prog Biophys Mol Biol. 2004; 84: 321–344.CrossrefMedlineGoogle Scholar25 Peers C. Ionic channels in Type I carotid body cells. In: O’Regan RNP, McQueen DS, Paterson DJ, ed. Arterial Receptors Cell to System. New York: Plenum Press; 1994: 29–40.Google Scholar26 Li YL, Sun SY, Overholt JL, Prabhakar NR, Rozanski GJ, Zucker IH, Schultz HD. Attenuated outward potassium currents in carotid body glomus cells of heart failure rabbit: involvement of nitric oxide. J Physiol. 2004; 555: 219–229.CrossrefMedlineGoogle Scholar27 Silva JM, Lewis DL. Nitric oxide enhances Ca(2+)-dependent K(+) channel activity in rat carotid body cells. Pflugers Arch. 2002; 443: 671–675.CrossrefMedlineGoogle Scholar28 Summers BA, Overholt JL, Prabhakar NR. Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism. J Neurophysiol. 1999; 81: 1449–1457.CrossrefMedlineGoogle Scholar29 Fitzgerald RS, Shirahata M, Chang I, Balbir A. L-arginine’s effect on the hypoxia-induced release of acetylcholine from the in vitro cat carotid body. Respir Physiol Neurobiol. 2005; 147: 11–17.CrossrefMedlineGoogle Scholar30 Zhang M, Zhong H, Vollmer C, Nurse CA. Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors. J Physiol. 2000; 525: 143–158.CrossrefMedlineGoogle Scholar31 Rong W, Gourine AV, Cockayne DA, Xiang Z, Ford AP, Spyer KM, Burnstock G. Pivotal role of nucleotide P2X2 receptor subunit of the ATP-gated ion channel mediating ventilatory responses to hypoxia. J Neurosci. 2003; 23: 11315–11321.CrossrefMedlineGoogle Scholar32 Fitzgerald RS, Shirahata M, Chang I. The effect of a nitric oxide donor, sodium nitroprusside, on the release of acetylcholine from the in vitro cat carotid body. Neurosci Lett. In Press.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fitzgerald R (2011) The cardiovascular mighty mini-ruler, The Journal of Physiology, 10.1113/jphysiol.2010.203059, 589:3, (455-456), Online publication date: 1-Feb-2011. Fitzgerald R, Shirahata M, Balbir A and Grossman C (2007) Oxygen Sensing in the Carotid Body and Its Relation to Heart Failure, Antioxidants & Redox Signaling, 10.1089/ars.2007.1546, 9:6, (745-749), Online publication date: 1-Jun-2007. Fitzgerald R (2014) Carotid body: a new target for rescuing neural control of cardiorespiratory balance in disease, Frontiers in Physiology, 10.3389/fphys.2014.00304, 5 August 5, 2005Vol 97, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000177931.10616.cbPMID: 16081873 Originally publishedAugust 5, 2005 Keywordscarotid bodyheart failurenitric oxidegene transferPDF download Advertisement" @default.
• W2118461151 created "2016-06-24" @default.
• W2118461151 creator A5070224675 @default.
• W2118461151 date "2005-08-05" @default.
• W2118461151 modified "2023-09-25" @default.
• W2118461151 title "Targeting Arterial Chemoreceptor Over-Activity in Heart Failure With a Gas" @default.
• W2118461151 cites W180946569 @default.
• W2118461151 cites W1880484442 @default.
• W2118461151 cites W1923525643 @default.
• W2118461151 cites W1966146923 @default.
• W2118461151 cites W1987095470 @default.
• W2118461151 cites W1996713672 @default.
• W2118461151 cites W1999876593 @default.
• W2118461151 cites W2020358342 @default.
• W2118461151 cites W2028286745 @default.
• W2118461151 cites W2031755372 @default.
• W2118461151 cites W2032411573 @default.
• W2118461151 cites W2042525034 @default.
• W2118461151 cites W2050803577 @default.
• W2118461151 cites W2055117340 @default.
• W2118461151 cites W2072987045 @default.
• W2118461151 cites W2097783955 @default.
• W2118461151 cites W2102780353 @default.
• W2118461151 cites W2130770984 @default.
• W2118461151 cites W2140254921 @default.
• W2118461151 cites W2140664776 @default.
• W2118461151 cites W2142298463 @default.
• W2118461151 cites W2150272558 @default.
• W2118461151 cites W2158787215 @default.
• W2118461151 cites W2160806878 @default.
• W2118461151 cites W2161390320 @default.
• W2118461151 cites W2163092377 @default.
• W2118461151 cites W2167646683 @default.
• W2118461151 cites W2185485611 @default.
• W2118461151 cites W2255076808 @default.
• W2118461151 cites W2998034180 @default.
• W2118461151 doi "https://doi.org/10.1161/01.res.0000177931.10616.cb" @default.
• W2118461151 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16081873" @default.
• W2118461151 hasPublicationYear "2005" @default.
• W2118461151 type Work @default.
• W2118461151 sameAs 2118461151 @default.
• W2118461151 citedByCount "3" @default.
• W2118461151 countsByYear W21184611512014 @default.
• W2118461151 crossrefType "journal-article" @default.
• W2118461151 hasAuthorship W2118461151A5070224675 @default.
• W2118461151 hasBestOaLocation W21184611512 @default.
• W2118461151 hasConcept C103247709 @default.
• W2118461151 hasConcept C126322002 @default.
• W2118461151 hasConcept C164705383 @default.
• W2118461151 hasConcept C170493617 @default.
• W2118461151 hasConcept C2778198053 @default.
• W2118461151 hasConcept C71924100 @default.
• W2118461151 hasConceptScore W2118461151C103247709 @default.
• W2118461151 hasConceptScore W2118461151C126322002 @default.
• W2118461151 hasConceptScore W2118461151C164705383 @default.
• W2118461151 hasConceptScore W2118461151C170493617 @default.
• W2118461151 hasConceptScore W2118461151C2778198053 @default.
• W2118461151 hasConceptScore W2118461151C71924100 @default.
• W2118461151 hasIssue "3" @default.
• W2118461151 hasLocation W21184611511 @default.
• W2118461151 hasLocation W21184611512 @default.
• W2118461151 hasLocation W21184611513 @default.
• W2118461151 hasOpenAccess W2118461151 @default.
• W2118461151 hasPrimaryLocation W21184611511 @default.
• W2118461151 hasRelatedWork W1998556240 @default.
• W2118461151 hasRelatedWork W2012241433 @default.
• W2118461151 hasRelatedWork W2039995053 @default.
• W2118461151 hasRelatedWork W2076843464 @default.
• W2118461151 hasRelatedWork W2125804349 @default.
• W2118461151 hasRelatedWork W2304633692 @default.
• W2118461151 hasRelatedWork W2763805509 @default.
• W2118461151 hasRelatedWork W4244920391 @default.
• W2118461151 hasRelatedWork W4247718175 @default.
• W2118461151 hasRelatedWork W4313444034 @default.
• W2118461151 hasVolume "97" @default.
• W2118461151 isParatext "false" @default.
• W2118461151 isRetracted "false" @default.
• W2118461151 magId "2118461151" @default.
• W2118461151 workType "article" @default.