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The Adrenergic System of the Myocardium

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The Cardiovascular Adrenergic System

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Abstract

The adrenergic nervous system is a crucial regulator of cardiovascular homeostasis, both in physiological and pathological conditions. It fine-tunes heart rate, cardiac contractility, vascular constriction/relaxation as well as atrioventricular conduction. The actions of the adrenergic nervous system are mediated by catecholamine binding to the different adrenergic receptor (AR) subtypes. The ARs belong to the superfamily of G-protein-coupled receptors. To date, a total of three types and nine subtypes of ARs have been identified and classified into α1-AR (α1A, α1B, α1D), α2-AR (α2A, α2B, α2C), and β-AR (β1, β2, β3). All ARs primarily signal through heterotrimeric G proteins. Importantly, signaling through these receptors is finely regulated, and receptor activation also triggers regulatory processes that are responsible for receptor dysfunctional signaling in several cardiovascular diseases, including chronic heart failure (HF). The present chapter discusses the role of the adrenergic nervous system in cardiac physiology and in the pathophysiological model of HF, the mechanisms of regulation of sympathetic activity, and how they are dysfunctional in HF, the molecular alterations in heart physiology that occur in HF.

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References

  1. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54:1747–62.

    Article  CAS  PubMed  Google Scholar 

  2. Barrese V, Taglialatela M. New advances in beta-blocker therapy in heart failure. Front Physiol. 2013;4:323.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lymperopoulos A. Physiology and pharmacology of the cardiovascular adrenergic system. Front in Physiol. 2013;4:240.

    Article  Google Scholar 

  4. Granneman JG. The putative beta4-adrenergic receptor is a novel state of the beta1-adrenergic receptor. Am J Physiol Endocrinol Metab. 2001;280:E199–202.

    CAS  PubMed  Google Scholar 

  5. Brodde OE. Beta-adrenoceptors in cardiac disease. Pharmacol Ther. 1993;60:405–30.

    Article  CAS  PubMed  Google Scholar 

  6. Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 1. N Engl J Med. 1986;314:290–9.

    Article  CAS  PubMed  Google Scholar 

  7. Skeberdis VA, Gendviliene V, Zablockaite D, et al. beta3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2 + current. J Clin Invest. 2008;118:3219–27.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Shannon R, Chaudhry M. Effect of alpha1-adrenergic receptors in cardiac pathophysiology. Am Heart J. 2006;152:842–50.

    Article  CAS  PubMed  Google Scholar 

  9. Philipp M, Hein L. Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol Ther. 2004;101:65–74.

    Article  CAS  PubMed  Google Scholar 

  10. Hein L, Altman JD, Kobilka BK. Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature. 1999;402:181–4.

    Article  CAS  PubMed  Google Scholar 

  11. Johnson JA, Liggett SB. Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther. 2011;89:366–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Shin J, Johnson JA. Beta-blocker pharmacogenetics in heart failure. Heart Fail Rev. 2010;15:187–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Small KM, Forbes SL, Rahman FF, Bridges KM, Liggett SB. A four amino acid deletion polymorphism in the third intracellular loop of the human alpha 2 C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem. 2000;275:23059–64.

    Article  CAS  PubMed  Google Scholar 

  14. Rengo G, Perrone-Filardi P, Femminella GD, et al. Targeting the beta-adrenergic receptor system through G-protein-coupled receptor kinase 2: a new paradigm for therapy and prognostic evaluation in heart failure: from bench to bedside. Circ Heart Fail. 2012;5:385–91.

    Article  CAS  PubMed  Google Scholar 

  15. Ferrara N, Komici K, Corbi G, et al. beta-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol. 2014;4:396.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Morisco C, Zebrowski D, Condorelli G, Tsichlis P, Vatner SF, Sadoshima J. The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes. J Biol Chem. 2000;275:14466–75.

    Article  CAS  PubMed  Google Scholar 

  17. Hall RA, Premont RT, Chow CW, et al. The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H + exchange. Nature. 1998;392:626–30.

    Article  CAS  PubMed  Google Scholar 

  18. Xiao RP, Ji X, Lakatta EG. Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharm. 1995;47:322–9.

    CAS  Google Scholar 

  19. Dorn GW 2nd, Tepe NM, Lorenz JN, Koch WJ, Liggett SB. Low- and high-level transgenic expression of beta2-adrenergic receptors differentially affect cardiac hypertrophy and function in Galphaq-overexpressing mice. Proc Natl Acad Sci U S A. 1999;96:6400–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Liggett SB, Tepe NM, Lorenz JN, et al. Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. 2000;101:1707–14.

    Article  CAS  PubMed  Google Scholar 

  21. Salazar NC, Vallejos X, Siryk A, et al. GRK2 blockade with betaARKct is essential for cardiac beta2-adrenergic receptor signaling towards increased contractility. Cell Comm Signal. 2013;11:64.

    Article  CAS  Google Scholar 

  22. De Lucia C, Femminella GD, Gambino G, et al. Adrenal adrenoceptors in heart failure. Front Physiol. 2014;5:246.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Bathgate-Siryk A, Dabul S, Pandya K, et al. Negative impact of beta-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension. 2014;63:404–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Rengo G, Lymperopoulos A, Leosco D, Koch WJ. GRK2 as a novel gene therapy target in heart failure. J Mol Cell Cardiol. 2011;50:785–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Femminella GD, Rengo G, Pagano G, et al. beta-adrenergic receptors and G protein-coupled receptor kinase-2 in Alzheimer’s disease: a new paradigm for prognosis and therapy? J Alzheimer’s Dis. 2013;34:341–7.

    CAS  Google Scholar 

  26. Rengo G, Lymperopoulos A, Koch WJ. Future g protein-coupled receptor targets for treatment of heart failure. Curr Treat Opt Cardiovasc Med. 2009;11:328–38.

    Article  Google Scholar 

  27. Lymperopoulos A, Rengo G, Koch WJ. GRK2 inhibition in heart failure: something old, something new. Curr Pharm Des. 2012;18:186–91.

    Article  CAS  PubMed  Google Scholar 

  28. Rengo F, Leosco D, Iacovoni A, et al. Epidemiology and risk factors for heart failure in the elderly. Italian Heart J. 2004;5(Suppl 10):9–16.

    Google Scholar 

  29. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 2013;113:739–53.

    Article  CAS  PubMed  Google Scholar 

  30. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol. 1982;49:1659–66.

    Article  CAS  PubMed  Google Scholar 

  31. Lymperopoulos A, Rengo G, Zincarelli C, Kim J, Soltys S, Koch WJ. An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo. Proc Natl Acad Sci U S A. 2009;106:5825–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res. 1994;75:105–13.

    Article  CAS  PubMed  Google Scholar 

  33. Lymperopoulos A, Rengo G, Zincarelli C, Kim J, Koch WJ. Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels. J Am Coll Cardiol. 2011;57:356–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Kingwell BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation. 1994;90:234–40.

    Article  CAS  PubMed  Google Scholar 

  35. Link JM, Caldwell JH. Diagnostic and prognostic imaging of the cardiac sympathetic nervous system. Nat Clin Pract Cardiovasc Med. 2008;5(Suppl 2):79–86.

    Article  Google Scholar 

  36. Paolillo S, Rengo G, Pagano G, et al. Impact of diabetes on cardiac sympathetic innervation in patients with heart failure: a 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study. Diab Care. 2013;36:2395–401.

    Article  CAS  Google Scholar 

  37. Watson AM, Hood SG, May CN. Mechanisms of sympathetic activation in heart failure. Clin Exper Pharmacol Physiol. 2006;33:1269–74.

    Article  CAS  Google Scholar 

  38. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205–11.

    Article  CAS  PubMed  Google Scholar 

  39. Engelhardt S, Bohm M, Erdmann E, Lohse MJ. Analysis of beta-adrenergic receptor mRNA levels in human ventricular biopsy specimens by quantitative polymerase chain reactions: progressive reduction of beta 1-adrenergic receptor mRNA in heart failure. J Am Coll Cardiol. 1996;27:146–54.

    Article  CAS  PubMed  Google Scholar 

  40. Perrino C, Naga Prasad SV, Patel M, Wolf MJ, Rockman HA. Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol. 2005;45:1862–70.

    Article  CAS  PubMed  Google Scholar 

  41. Noma T, Lemaire A, Naga Prasad SV, et al. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest. 2007;117:2445–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation. 1993;87:454–63.

    Article  CAS  PubMed  Google Scholar 

  43. Rockman HA, Koch WJ, Milano CA, Lefkowitz RJ. Myocardial beta-adrenergic receptor signaling in vivo: insights from transgenic mice. J Mol Med. 1996;74:489–95.

    Article  CAS  PubMed  Google Scholar 

  44. Iaccarino G, Barbato E, Cipolletta E, et al. Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. Eur Heart J. 2005;26:1752–8.

    Article  CAS  PubMed  Google Scholar 

  45. Rengo G, Galasso G, Femminella GD, et al. Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure. Eur J Prev Cardiol. 2014;21:4–11.

    Article  PubMed  Google Scholar 

  46. Rengo G, Lymperopoulos A, Zincarelli C, et al. Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation. 2009;119:89–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Rengo G, Cannavo A, Liccardo D, et al. Vascular endothelial growth factor blockade prevents the beneficial effects of betablocker therapy on cardiac function, angiogenesis and remodeling in heart Failure. Circ Heart Fail. 2013;6:1259–67.

    Article  CAS  PubMed  Google Scholar 

  48. Rengo G, Zincarelli C, Femminella GD, et al. Myocardial beta(2) -adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure. Br J Pharmacol. 2012;166:2348–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Morimoto A, Hasegawa H, Cheng HJ, Little WC, Cheng CP. Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure. Am J Physiol Heart Circ Physiol. 2004;286:2425–33.

    Article  Google Scholar 

  50. Huang Y, Wright CD, Merkwan CL, et al. An alpha1A-adrenergic-extracellular signal-regulated kinase survival signaling pathway in cardiac myocytes. Circulation. 2007;115:763–72.

    Article  CAS  PubMed  Google Scholar 

  51. Leimbach WN Jr, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986;73:913–9.

    Article  PubMed  Google Scholar 

  52. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819–23.

    Article  CAS  PubMed  Google Scholar 

  53. Zucker IH, Xiao L, Haack KK. The central renin-angiotensin system and sympathetic nerve activity in chronic heart failure. Clin Sci. 2014;126:695–706.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Lymperopoulos A, Rengo G, Koch WJ. Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. Tr Mol Med. 2007;13:503–11.

    Article  CAS  Google Scholar 

  55. Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med. 2007;13:315–23.

    Article  CAS  PubMed  Google Scholar 

  56. Haase M, Willenberg HS, Bornstein SR. Update on the corticomedullary interaction in the adrenal gland. Endocr Dev. 2011;20:28–37.

    CAS  PubMed  Google Scholar 

  57. Brede M, Wiesmann F, Jahns R, et al. Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure. Circulation. 2002;106:2491–6.

    Article  CAS  PubMed  Google Scholar 

  58. Brum PC, Kosek J, Patterson A, Bernstein D, Kobilka B. Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice. Am J Physiol Heart Circ Physiol. 2002;283:1838–45.

    Article  Google Scholar 

  59. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB. Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. N Engl J Med. 2002;347:1135–42.

    Article  CAS  PubMed  Google Scholar 

  60. Davis HM, Johnson JA. Heart failure pharmacogenetics: past, present, and future. Curr Cardiol Rep. 2011;13:175–84.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Bristow MR, Murphy GA, Krause-Steinrauf H, et al. An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure. Circ Heart Fail. 2010;3:21–28.

    Article  CAS  PubMed  Google Scholar 

  62. Lymperopoulos A, Rengo G, Zincarelli C, Soltys S, Koch WJ. Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity. Mol Ther. 2008;16:302–7.

    Article  CAS  PubMed  Google Scholar 

  63. Schneider J, Lother A, Hein L, Gilsbach R. Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis. Basic Res Cardiol. 2011;106:591–602.

    Article  CAS  PubMed  Google Scholar 

  64. Lymperopoulos A, Rengo G, Gao E, Ebert SN, Dorn GW 2nd, Koch WJ. Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction. J Biol Chem. 2010;285:16378–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Rengo G, Lymperopoulos A, Zincarelli C, et al. Blockade of beta-adrenoceptors restores the GRK2-mediated adrenal alpha(2) -adrenoceptor-catecholamine production axis in heart failure. Br J Pharmacol. 2012;166:2430–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Rengo G, Leosco D, Zincarelli C, et al. Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure. Am J Physiol Heart Circ Physiol. 2010;298:2032–8.

    Article  Google Scholar 

  67. Thal DM, Homan KT, Chen J, et al. Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem Biol. 2012;7:1830–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy

    Grazia Daniela Femminella, Claudio de Lucia, Gennaro Pagano, Klara Komici & Nicola Ferrara

  2. Center for Translational Medicine, Department of Pharmacology, Temple University Philadelphia, Philadelphia, PA, USA

    Alessandro Cannavo

  3. Department of Neuroscience, University of Naples “Federico II”, Naples, Italy

    Vincenzo Barrese

  4. Division of Cardiology, “Salvatore Maugeri” Foundation—IRCCS—Institute of Telese Terme, Telese Terme, BN, Italy

    Nicola Ferrara & Giuseppe Rengo

Authors
  1. Grazia Daniela Femminella
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  2. Claudio de Lucia
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  3. Gennaro Pagano
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  4. Klara Komici
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  5. Alessandro Cannavo
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  6. Vincenzo Barrese
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  7. Nicola Ferrara
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  8. Giuseppe Rengo
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Correspondence to Giuseppe Rengo .

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Editors and Affiliations

  1. Dept. of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, Florida, USA

    Anastasios Lymperopoulos

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Femminella, G. et al. (2015). The Adrenergic System of the Myocardium. In: Lymperopoulos, A. (eds) The Cardiovascular Adrenergic System. Springer, Cham. https://doi.org/10.1007/978-3-319-13680-6_2

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