Skip to main content
SpringerLink
Log in
Book cover

Cardiovascular Biology of Purines pp 108–125Cite as

Regulation of Adenosine Receptor Subtypes and Cardiac Dysfunction in Human Heart Failure

  • Chapter

Part of the book series: Developments in Cardiovascular Medicine ((DICM,volume 209))

Summary

A defective adenosine receptor-mediated autoregulation of the heart has been hypothesized to cause cardiomyopathy. Regulation of gene expression of the four adenosine receptor subtypes A1, A2A, A2B, A3 and the A1-mediated antiadrenergic signal transduction pathway has been studied in nonfailing and failing human hearts. Gene expression of myocardial A1-adenosine receptors and A1-mediated inhibitory effects on cAMP levels or negative inotropic effects were not altered in failing compared to nonfailing human hearts, indicating that an impairment in the A1-mediated pathway may not be involved in the pathogenesis of heart failure. Furthermore, A3-adenosine receptor gene expression was unchanged in failing compared to nonfailing hearts, while A2B mRNA was not detectable. However, A2A-adenosine receptor gene expression was increased by about 60% in patients with dilated cardiomyopathy. Thus, the A2A-upregulation may indicate a pathophysiological role for adenosine and adds therefore to the increasingly complex picture of molecular alterations in heart failure.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Bardenheuer H, Whelton, B, Sparks HV Jr. Adenosine release by the isolated guinea pig heart in response to isoproterenol, acetytcholine, and acidosis: The minimal role of vascular endothelium. Circ Res 1987;61:594–600

    Article  PubMed  CAS  Google Scholar 

  • Bartel S, Stein B, Eschenhagen T, Mende U, Neumann J, Schmitz W, Krause EG, Karczewski P, Scholz H. Impaired phosphorylation of phospholamban, troponin I and C-protein in the failing human heart. Mol Cell Biochem 1996; 157:171–179

    Article  PubMed  CAS  Google Scholar 

  • Behnke N, Müller W, Neumann J, Schmitz W, Scholz H, Stein B. Differential antagonsim by 1,3-dipropylxanthine-8-cyclopentylxanthine and 9-chIoro-2-2-furanyI)-5,6-dihydro-l,2,4-tria2olo(l,5-c)quinazolin-5-imine of the effects of adenosine derivatives in the presence of isoprenaline on contractile response and cyclic AMP content in cardiomyocytes. Evidence for the coexistence of A1-and A2-adenosine receptors on cardiomyocytes. J Pharmacol Exp Ther 1990, 254:1017–1023

    PubMed  CAS  Google Scholar 

  • Belardinelli L, Isenberg G. Isolated atrial myocytes: Adenosine and acetylcholine increase in potassium conductance. Am J Physiol 1983;244:H291–H294

    Google Scholar 

  • Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Res 1989;32:73–97

    Article  CAS  Google Scholar 

  • Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995;9:359–365

    PubMed  CAS  Google Scholar 

  • Berne RM. Cardiac nucleotides in hypoxia: Possible role in regulation of coronary blood flow. Am J Physiol 1983;204:317–322

    Google Scholar 

  • Berne RM, Rubio R, Dobson JG Jr, Curnish RR. Adenosine and adenine nucleotides as possible mediators of cardiac and skeletal muscle blood flow regulation. Circ Res 1971, 71:115–119

    Google Scholar 

  • Bethke T, Klimkiewicz A, Kohl C, v d Leyen H, Mehl H, Mende U, Meyer W, Neumann J, Schmitz W, Scholz H, Starbatty J, Stein B, Wenzlaff H, Döring V, Kalmár P, Haverich A. Effects of isomazole on force of contraction and phosphodiesterase isoenzymes I-IV in nonfailing and failing human hearts. J Cardiovasc Pharmacol 1991;18:386–397

    Article  PubMed  CAS  Google Scholar 

  • Böhm M, Brückner R, Neumann J, Schmitz W, Scholz H, Starbatty J. Role of guanine nucleotide binding protein in the regulation by adenosine of cardiac potassium conductance and force of contraction. Naunyn-Schmiedebergs Arch Pharmacol 1986;332:403–405

    Article  PubMed  Google Scholar 

  • Böhm M, Beuckelmann D, Brown L, Feiler G, Lorenz B, Näbauer M, Kemkes B, Erdmann E. Reduction of B-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium. Eur Heart J 1988;9:844–852

    PubMed  Google Scholar 

  • Böhm M, Girschik P, Ungerer M, Erdmann E. Coupling of adenosine receptors to pertussis toxinsensitive G protein in the human heart Eur J Pharmacol 1989a; 172:407–411

    Article  PubMed  Google Scholar 

  • Böhm M, Meyer W, Mügge A, Schmitz W, Scholz H. Functional evidence for the existence of adenosine receptors in the human heart Eur J Pharmacol 1985; 116:323–326

    Article  PubMed  Google Scholar 

  • Böhm M, Pieske M, Ungerer M, Erdmann E. Characterization of A1-adenosine receptors in human atrial and ventricular myocardium from diseased human hearts. Circ Res 1989b;65:1201–1211

    Article  PubMed  Google Scholar 

  • Böhm M, Gierschik P, Jakobs KH, Schnabel P, Ungerer M, Erdmann E. Increase in Gi-proteins in human hearts with dilated but not ischemic cardiomyopathy. Circulation 1990;82:1249–1265

    Article  PubMed  Google Scholar 

  • Böhm M, Ungerer M, Erdmann E. Adenosine receptors in the human heart: Pharmacological characterization in nondiseased and cardiomyopathic tissue. Drug Dev Res 1993;28:268–276

    Article  Google Scholar 

  • Boknik P, Neumann J, Schmitz W, Scholz H, Wenzlaff H. Characterization of biochemical effects of CGS 21680C, an A2-adenosine receptor agonist, in the mammalian ventricle. J Cardiovasc Pharmacol 1998 (in press)

    Google Scholar 

  • Bristow MR Gainsburg R, Minobe W, Cubicciotti RS, Sageman WS, Luri K, Billingham ME, Harrrson DC Stinson EB. Decreased catecholamine activity and beta-adrenergic receptor density in failing human hearts. N Engl J Med 1982;307:205–211

    Article  PubMed  CAS  Google Scholar 

  • Brown LA, Humphrey SM, Harding SE. The anti-adrenergic effect of adenosine and its blockade by pertussis toxin: a comparative study in myocytes isolated from guinea-pig, rat, and failing human hearts. Br J Pharmacol 1990; 101:484–488

    Article  PubMed  CAS  Google Scholar 

  • deGubareff T, Sleator WJ. Effects of caffeine on mammalian atrial muscle and its interaction with adenosine and calcium. J Pharmacol Exp Ther 1965;148:202–214

    PubMed  CAS  Google Scholar 

  • Dobson JG Jr. Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3′,5′-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Circ Res 1978, 43:785–792

    Article  PubMed  CAS  Google Scholar 

  • Dobson JG Jr. Adenosine reduces catecholamine contractile responses in oxygenated and hypoxic atria. Am JPhysiol 1983;245:H468–H474

    CAS  Google Scholar 

  • Dobson JG Jr, Fenton RA. “Antiadrenergic effects of adenosine in the heart”;. In: Regulatory function of adenosine, RM Berne, TW Rall, R Rubio, eds. Oak Park, L.1993, pp363–376

    Google Scholar 

  • Dobson JG Jr, Fenton RA Adenosine A2-receptor agonists elicit positive inotropic response and increase in adenylyl cyclase activity in rat ventricular myocytes. Drug Dev Res 1994;31:1232

    Google Scholar 

  • Dobson JG Jr, Ordway RW, Fenton RA. Endogenous adenosine inhibits catecholmanine contractile responses in normoxic hearts. Am J Physiol 1986;251:H455–H462

    PubMed  CAS  Google Scholar 

  • Drury AN, Szént-György. The physiological activity of adenine compounds with especial reference in their action upon the mammalian heart. J Physiol 1929;68:213–237

    PubMed  CAS  Google Scholar 

  • Feldman AM, Cates AE, Veazey WB, Hershberger RE, Bristow MR, Baughman KL, Baumgartner WA, Van Dop C. Increase of a 40,000 mol-wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest 1988;82:189–197

    Article  PubMed  CAS  Google Scholar 

  • Fenton RA, Dobson JG Jr. Measurement by fluorescence of intestinal adenosine levels in normoxic, hypoxic, and ischemic perfused rat hearts. Circ Res 1987;60:177–184

    Article  PubMed  CAS  Google Scholar 

  • Fenton RA, Dobson JG Jr. Hypoxia enhances isopreterenol-induced increase in heart intestinal adenosine, depressing ß-adrenergic contractile responses. Circ Res 1993;72:571–578

    Article  PubMed  CAS  Google Scholar 

  • Fenton RA, Tsimikas S, Dobson JG Jr. Influence of ß-adrenergic stimulation and contraction frequency on rat heart interstitial adenosine. Circ Res 1990;66:457–468

    Article  PubMed  CAS  Google Scholar 

  • Fox AC, Reed GE, Glassma E, Kaltman AJ, Silk BB. Release of adenosine formation from human hearts during angina induced by rapid atrial pacing. J Clin Invest 1974;53:1447–1457.

    Article  PubMed  CAS  Google Scholar 

  • Fozard JR, Pfannekuche H-J, Schurman H-J. Mast cell degranulation following adenosine A3 receptor activation in rats. EUT J Pharmacol 1996;298:293–297

    Article  CAS  Google Scholar 

  • Fredholm BB, Abbracho MP, Burnstock G, Daly JW, Harden TK, Jacobson KA, Leff P, Williams M. Nomenclature and classification of purinoceptors. Pharmacol Rev 1994, 46:143–156

    PubMed  CAS  Google Scholar 

  • Fredholm BB, Sollevi A. Cardiovascular effects of adenosine. Clin Physiol 1986, 6:1–21

    Article  PubMed  CAS  Google Scholar 

  • Gupta RC, Neumann J, Durant P, Watanabe AM. A1,-adenosine receptor-mediated inhibition of isoproterenol-stimulated protein phosphorylation in ventricular myocytes. Evidence against a cyclic AMP-dependent effect Circ Res 1993;72:65–74

    CAS  Google Scholar 

  • Gupta RC, Neumann J, Watanabe AM, Lesch M, Sabbah HN. Evidence for the existence and hormonal regulation of protein phosphatase inhibitor-l in ventricular cardiomyocytes. Am J Physiol 1996;270:H1159–H1164

    PubMed  CAS  Google Scholar 

  • Headrick JP, Willis RJ. 5′Nucleotidase activity and adenosine formation in stimulated, hypoxic and underperfused rat heart. Biochem J 1989;261:541–550

    PubMed  CAS  Google Scholar 

  • Hernández J, Ribeiro JA. Excitatory actions of adenosine on ventricular automaticity. TIBS 1996;17:141–144

    Google Scholar 

  • Hershberger RE, Feldman AM, Bristow M. A1-adenosine receptor inhibition of adenylate cyclase in failing and nonfailing human ventricular myocardium. Circulation 1991; 83:1343–1351

    Article  PubMed  CAS  Google Scholar 

  • Ihl-Vahl R, Eschenhagen T, Kübier W, Marquetant R, Nose M, Schmitz W, Scholz H, Strasser RH. Differential regulation of mRNA specific for ßl-and ß2-adrenergic receptors in human failing hearts. Evaluation of the absolute cardiac mRNA levels by two independent methods. J Mol Cell Cardiol 1996;28:1–10

    Article  PubMed  CAS  Google Scholar 

  • Jakob H, Oelert H, Rupp J, Nawrath H. Functional role of cholinoceptors and purinoceptors in human isolated atrial and ventricular heart muscle. Br J Pharmacol 1989; 97:1199–1208

    Article  PubMed  CAS  Google Scholar 

  • Jochen G, Nawrath H. Adenosine activates a potassium conductance in atrial heart muscle. Experienta Basel 1983;39:1347–1349

    Article  Google Scholar 

  • Keddi JR, Poucher SM, Shaw GR, Brooks R, Collis MG. In vivo characterization of ZM 241385, a selective adenosine A2a receptor antagonist Eur J Pharmacol 1996; 301:107

    Article  Google Scholar 

  • Law WR, Carney PJ, McLane MP. Influence of adenosine on the stimulatory effects of isoprenaline and insulin on myocardial contractility in vivo. Cardiovasc Res 1991;25:151–157

    Article  PubMed  CAS  Google Scholar 

  • Ledent C, Dumont JE, Vassart G, Parmentier M. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J 1992; 11:537–542

    PubMed  CAS  Google Scholar 

  • Liang BT. Adenosine receptors and cardiac function. Trends Cardiovasc Med 1992; 2:100–108

    Article  PubMed  CAS  Google Scholar 

  • Liang BT, Haltiwanger B. Adenosine A2A and A2B receptors in cultured fetal chick heart cells. High and low-affinity coupling to stimulation of myocyte contractility and cAMP accumulation. Circ Res 1995;76:242–251

    Article  PubMed  CAS  Google Scholar 

  • Liang BT, Morley JF. A new cyclic AMP-independent, Gs-mediated stimulatory mechanism via the adenosine A2A receptor in the intact cardiac cell. J Biol Chem 1996;2: 18678–19658

    Google Scholar 

  • Mittmann C, Eschenhagen T, Scholz H. Cellular and molecular aspects of contractile dysfunction in heart failure. Cardiovasc Res 1998 (submitted)

    Google Scholar 

  • Müller E, Stein E Adenosine receptor antagonists: Structures and therapeutical applications. Curr Pharm Design 1996; 2:501–530

    Google Scholar 

  • Neumann J, Boknik P, Kaspareit G, Bartel S, Krause E-G, Pask HT, Schmitz W, Scholz H. Effects of the phosphatase inhibitor calyculin-A on the phosphorylation of C-protein in mammalian ventricular cardiomyocytes. Biochem Pharmacol 1995a; 49:1583–1588

    Article  PubMed  CAS  Google Scholar 

  • Neumann J, Boknik P, Bodor GS, Jones LR, Schmitz W, Scholz H. Effects of adenosine receptor and muscarinic cholinergic receptor on cardiac protein phosphorylation. Influence of pertussis toxin. J Pharmacol Exp Ther 1994; 269:1310–1318

    PubMed  CAS  Google Scholar 

  • Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N. Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol 1997; 29:265–272

    Article  PubMed  CAS  Google Scholar 

  • Neumann J, Gupta RC, Jones LR, Bodor GS, Bartel S, Krause EG, Pask HT, Schmitz W, Scholz H, Watanabe AM. Interaction of ß-adrenoceptor and adenosine receptor agonists on phosphorylation. J Mol Cell Cardiol 1995b; 27:1655–1667

    Article  PubMed  CAS  Google Scholar 

  • Neumann J, Gupta RC, Schmitz W, Scholz H, Narin AC, Watanabe AM. Evidence for isoproterenol-induced phosphorylation of phosphatase inhibitor-1 in the intact heart. Circ Res 1991; 61:1450–1457

    Article  Google Scholar 

  • Neumann J, Schmitz W, Scholz H, Stein B. Effects of adenosine analogues on contractile response and cAMP content in guinea-pig isolated ventricular myocytes. Naunyn-Schmiedebergs Arch Pharmacol 1989; 340:689–695

    Article  PubMed  CAS  Google Scholar 

  • Neumann J, Schmitz W, Scholz H, v Meyerinck L, Döring V, Kalmár P. Increase in myocardial Gi proteins in heart failure. Lancet 1988; 19:936–937

    Article  Google Scholar 

  • Newman WH, Grossman SJ, Francis MB, Webb JG. Increased myocardial adenosine release in heart failure. J Mol Cell Cardiol 1984;16:577–580

    Article  PubMed  CAS  Google Scholar 

  • Olsson RA.. Adenosine receptors in the cardiovascular system. Drug Dev Res 1996;3:133

    Google Scholar 

  • Pelleg A, Kutalek SP. Adenosine in the mammalian heart: Nothing to get excited about. TIPS 1997, 18:236–238

    PubMed  CAS  Google Scholar 

  • Romano FD, Naimi TS, Dobson JG Jr. Adenosine attenuation of catecholamine-enhanced contractility of rat heart in vivo. Am J Physiol 1991; 260: H1635–H1639

    PubMed  CAS  Google Scholar 

  • Rozengurt E. Early signals in the mitogenic response. Science 1986; 234:161–166

    Article  PubMed  CAS  Google Scholar 

  • Rubio R, Berne RM, Dobson JG Jr. Sites of adenosine production in cardiac and skeletal muscle. Am J Physiol 1973; 225:938–953

    PubMed  CAS  Google Scholar 

  • Schrader J, Baumann G, Gerlach E. Adenosine as inhibitor of myocardial effects of catecholamines. Pflügers Arch 1977; 372:29–35

    Article  PubMed  CAS  Google Scholar 

  • Schrader J, Deussen A, Decking UKM. “Adenosine metabolism and transport in the mammalian heart.“ In Effects of extracellular adenosine and ATP on cardiac myocytes. Amir Pelleg ed. Landes Bioscience Publisher, Austin, Texas, 1998 in press

    Google Scholar 

  • Sexl V, Mancusi G, Höller C, Gloria-Maercker E, Schütz W, Freissmuth M. Stimulation of the mitogenactivated protein kinase via the A2A-adenosine receptor in primary human endothelial cells. J Biol Chem 1997; 272:5792–5799

    Article  PubMed  CAS  Google Scholar 

  • Shryock J, Song Y, Wang D, Baker SP, Olsson R, Belardinelli L. Selective A2-adenosine receptor agonists do not alter action potential duration, twitch shortening, or cAMP accumulation in guinea pi, rat, or rabit isolated ventricular myocytes. Circ Res 1993; 72:194–205

    Article  PubMed  CAS  Google Scholar 

  • Stein B, Mende U, Neumann J, Schmitz W, Scholz H. Petussis toxin unmasks stimulatory myocardial A2-adenosine receptors on ventricular cardiomyocytes. J Mol Cell Cardiol 1993; 25:655–659

    Article  PubMed  CAS  Google Scholar 

  • Stein B, Schmitz W, Scholz H Seeland C. Pharmacological characterization of A2-adenosine receptors in guinea-pig ventricular cardiomyocytes. J Mol Cell Cardiol 1994, 26:403–414

    Article  PubMed  CAS  Google Scholar 

  • Steinfath M, Geertz B, Schmitz, W, Scholz H, Haverich A, Brel I, Hanrath P, Reupke C, Sigmund M, Loh B. Distinct downregulation of cardiac ßl and ß2-adrenoceptors in different human heart diseases. Naunyn-Schmiedebergs Arch 1991; 343:217–220

    Article  CAS  Google Scholar 

  • Steinfath M, Danielsen W, v d Leycn H, Mende U, Meyer W, Neumann J, Nose M, Reich T, Schmitz W, Scholz H, Starbatty J, Stein B, Döring V, Kalmár P, Haverich A. Reduced ßl-and ß2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure. Br J Pharmacol 1992; 105, 463–469

    Article  PubMed  CAS  Google Scholar 

  • Thomas RA, Rubo R, Berne RM. Comparison of the adenine nucleotide metabolism of dog atrial and ventricular myocardium. J Mol Cell Cardiol 1975; 7:115–123

    Article  PubMed  CAS  Google Scholar 

  • Tucker A, Linden J. Cloned receptors and cardiovascular responses to adenosine. Cardiovasc Res 1993; 27:62–67

    Article  PubMed  CAS  Google Scholar 

  • Ungerer M, Böhm M, Schwinger RHG, Erdmann E. Antagonism of novel inotropic agents at A1-adenosine receptors and cholinoceptors in human myocardium. Naunyn-Schmiedebergs Arch Pharmacol 1990; 341:577–585

    PubMed  CAS  Google Scholar 

  • v der Leyen H, Mende U, Meyer W, Neumann J, Nose M, Schmitz W, Scholz H, Starbatty J, Stein J, Wenzlaff H, Döring V, Kalmár P, Haverich A. Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase HI inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations. Naunyn-Schmiedebergs Arch Pharmacol 1991; 344:90–100

    PubMed  Google Scholar 

  • Watt AH. Hypertrophic cardiomyopathy: A disease of impaired adenosine-mediated autoregulation of the heart. Lancet 1984; 9:1271–1273

    Article  Google Scholar 

  • Xu D, Kong H, Liang BT. Expression and pharmacological characterization of a stimulatory subtype of adenosine receptor in fetal chick ventricular myocytes. Circ Res 1992; 70:56–65

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Stein B, Liang BT. Characterization of a stimulatory adenosine A2A receptor in adult rat ventricular myocyte. Am J Physiol 1996; 39: H1655–H1661

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmakologisches Institut, Universitäts-Krankenhaus Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany

    Birgitt Stein PhD & Jasper Kiehn

  2. Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität Münster, Domagkstraße 12, D-48129, Münster, Germany

    Joachim Neumann MD

Authors
  1. Birgitt Stein PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jasper Kiehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joachim Neumann MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, UK

    Geoffrey Burnstock D. Sc.

  2. University of Massachusetts, USA

    James G. Dobson Jr. Ph. D.

  3. University of Pennsylvania, USA

    Bruce T. Liang M.D.

  4. University of Virginia, USA

    Joel Linden Ph. D.

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Science+Business Media New York

About this chapter

Cite this chapter

Stein, B., Kiehn, J., Neumann, J. (1998). Regulation of Adenosine Receptor Subtypes and Cardiac Dysfunction in Human Heart Failure. In: Burnstock, G., Dobson, J.G., Liang, B.T., Linden, J. (eds) Cardiovascular Biology of Purines. Developments in Cardiovascular Medicine, vol 209. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5603-9_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-5603-9_7

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7563-0

  • Online ISBN: 978-1-4615-5603-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation