Skip to main content

Advertisement

SpringerLink
Log in

Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from –logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P (2005) Phosphodiesterase III inhibitors for heart failure. Cochrane Database Syst Rev Jan 25; (1): CD002230

    Google Scholar 

  • Anderson JL (1991) Hemodynamic and clinical benefits with intravenous milrinone in severe chronic heart failure: results of a multicenter study in the United States. Am Heart J 121:1956–1964

    Article  CAS  PubMed  Google Scholar 

  • Baker JG (2005) The selectivity of β-adrenoceptor antagonists at the human β1-, β2 and β3-adrenoceptors. Br J Pharmacol 144:317–322

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58:488–520

    Article  CAS  PubMed  Google Scholar 

  • Bristow MR (2000) β-Adrenergic receptor blockade in chronic heart failure. Circulation 101:558–569

    Article  CAS  PubMed  Google Scholar 

  • Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R (1989) β1- and β2-adrenergic receptor-mediated adenylate cyclase stimulation in non-failing and failing human myocardium. Mol Pharmacol 35:295–303

    CAS  PubMed  Google Scholar 

  • Chiale PA, Rosenbaum MB, Elizari MV, Hjalmarson A, Magnusson Y, Wallukat G, Hoebeke J (1995) High prevalence of antibodies against beta1- and beta2-adrenoceptors in patients with primary electrical cardiac abnormalities. J Am Coll Cardiol 26:864–869

    Article  CAS  PubMed  Google Scholar 

  • Christ T, Engel A, Ravens U, Kaumann AJ (2006) Cilostamide potentiates more the positive inotropic effects of (-)-adrenaline through β2-adrenoceptors than the effects of (-)-noradrenaline through β1-adrenoceptors in human atrial myocardium. Naunyn-Schmiedeberg’s Arch Pharmacol 374:249–253

    Article  CAS  Google Scholar 

  • De Santiago J, Ai X, Islam M, Acuna G, Ziolo MT, Bers D, Pogwizd SM (2008) Arrhythmogenic effects of β2-adrenergic stimulation in the failing heart are attributable to enhanced sarcoplasmic reticulum Ca load. Circ Res 102:1389–1397

    Article  Google Scholar 

  • Di Lenarda A, Sabbadini G, Salvatore L, Sinagra G, Mestroni L, Pinamonti B, Gregori D, Ciani F, Muzzi A, Klugmann S, Camerini F (1999) Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group. J Am Coll Cardiol 33:1926–1934

    Article  PubMed  Google Scholar 

  • Eschenhagen (2013) PDE4 in the human heart—major player or little helper? Br J Pharmacol 169:524–527

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Galindo-Tovar A, Kaumann AJ (2008) Phosphodiesterase-4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (-)-adrenaline mediated through mouse cardiac β1-adrenoceptors. Br J Pharmacol 153:710–720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gettys TW, Blackmore PF, Redmon JB, Beebe SJ, Corbin JD (1987) Short-term feedback regulation of cAMP by accelerated degradation in rat tissues. J Biol Chem 262:333–339

    CAS  PubMed  Google Scholar 

  • Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, Larrabee P, Bristow MR (1996) Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 94:2817–2825

    Article  CAS  PubMed  Google Scholar 

  • Gille E, Lemoine H, Ehle B, Kaumann AJ (1985) The affinity of (-)-propranolol for β1- and β2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline. Naunyn Schmiedebergs Arch Pharmacol 331:60–67

    Article  CAS  PubMed  Google Scholar 

  • Green SA, Holt BD, Liggett SB (1992) β1- and β2-adrenergic receptors display subtype-selective coupling to Gs. Mol Pharmacol 41:889–893

    CAS  PubMed  Google Scholar 

  • Heilbrunn SM, Shah P, Bristow MR, Valantine HA, Ginsburg R, Fowler MB (1989) Increased β-receptor density and improved hemodynamic responses to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation 70:483–490

    Article  Google Scholar 

  • Kaumann AJ (2011) Phosphodiesterases reduce spontaneous sinoatrial beating but not the ‘fight or flight’ tachycardia elicited by agonists through Gs-protein coupled receptors. Trends Pharmacol Sci 32:377–383

    Article  CAS  PubMed  Google Scholar 

  • Kaumann AJ, Bartel S, Molenaar P, Sanders L, Burrell K, Vetter D, Hempel P, Karczewski P, Krause E-G (1999) Activation of β2-adrenergic receptors hastens relaxation and mediates phosphorylation of phospholamban, troponin I, and C-protein in ventricular myocardium from patients with terminal heart failure. Circulation 99:65–72

    Article  CAS  PubMed  Google Scholar 

  • Kaumann AJ, Lemoine H (1987) β2-adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium. Quantitative discrepancies with binding and adenylate cyclase stimulation. Naunyn Schmiedebergs Arch Pharmacol 335:403–411

    Article  CAS  PubMed  Google Scholar 

  • Kaumann AJ, Lynham J, Sanders L, Brown AM, Molenaar P (1995) Contribution of differential efficacy to the pharmacology of human β1- and β2-adrenoceptors. Pharmacol Commun 6:215–222

    CAS  Google Scholar 

  • Kaumann AJ, Sanders L (1993) Both β1- and β2-adrenoceptors mediate catecholamine-evoked arrhythmias in isolated human right atrium. Naunyn Schmiedebergs Arch Pharmacol 348:536–540

    Google Scholar 

  • Kaumann AJ, Sanders L, Lynham JA, Bartel S, Kuschel M, Karczewski P, Krause EG (1996) β2-Adrenoceptor activation by zinterol causes protein contractile effects and relaxant effects through a cAMP pathway in human atrium. Mol Cell Biochem 163–164:113–123

    Article  PubMed  Google Scholar 

  • Kaumann AJ, Semmler AB, Molenaar P (2007) The effects of both noradrenaline and CGP12177, mediated through human β1-adrenoceptors, are reduced by PDE3 in human atrium but PDE4 in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 375:123–131

    Article  CAS  PubMed  Google Scholar 

  • Kilts JD, Gerhardt MA, Richardson MD, Sreeram G, Mackensen GB, White WD, Davis RD, Newman MF, Reves JG, Schwinn DA, Kwatra MM (2000) β2-Adrenergic and several other G protein-coupled receptors in human atrial membranes activate both Gs and Gi. Circ Res 87:635–639

    Article  Google Scholar 

  • Kindermann M, Maack C, Schaller S, Finkler N, Schmidt KI, Läer S, Wuttke H, Schäfers H-J, Böhm M (2004) Carvedilol but not metoprolol reduces β-adrenergic responsiveness after complete elimination from plasma in vivo. Circulation 109:3182–3190

    Article  CAS  PubMed  Google Scholar 

  • Lehnhart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin S-LC, Conti M, Marks AR (2005) Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 123:25–35

    Article  Google Scholar 

  • Levy FO, Zhu X, Kaumann AJ, Birnbaumer L (1993) Efficacy of β1-adrenergic receptors is lower than that of β2-adrenergic receptors. Proc Natl Acad Sci U S A 90:10798–10802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li XD, Wang JC, Zhao Y, Zhou NN, Zhu X (2010) Effects of carvedilol and metoprolol on expression of autoantibodies against cardiac adrenergic receptors in aged patients with chronic heart failure and ventricular arrhythmias. Chin J Cardiol 38:584–587

    CAS  Google Scholar 

  • Lugnier C, Muller B, Le Bec A, Beaudry C, Rousseau E (1993) Characterization of indolidan- and rolipram-sensitive cyclic nucleotide phosphodiesterases in canine and human cardiac microsomal fractions. J Pharmacol Exp Ther 265:1142–1151

    CAS  PubMed  Google Scholar 

  • Mehel H, Emons J, Vettel C, Wittköpper K, Seppelt D, Dewenter M, Lutz S, Sossalla S, Maier LS, Lechêne P, Leroy J, Lefebvre F, Varin A, Eschenhagen T, Nattel S, Dobrev D, Zimmermann WH, Nikolaev VO, Vandecasteele G, Fischmeister R, El-Armouche A (2013) Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes. J Am Coll Cardiol 62:1596–1606

    Article  CAS  PubMed  Google Scholar 

  • Molenaar P, Bartel S, Cochrane A, Vetter D, Jalali H, Pohlner P, Burrell K, Karczewski P, Krause E-G, Kaumann A (2000) Both β2-and β1-adrenergic receptors mediate hastened relaxation and phosphorylation of phospholamban and troponin I in ventricular myocardium of Fallot infants, consistent with selective coupling of β2-adrenergic receptors to Gs-protein. Circulation 102:1814–1821

    Article  CAS  PubMed  Google Scholar 

  • Molenaar P, Christ T, Hussain RI, Engel A, Berk E, Gillette KT, Chen L, Galindo-Tovar A, Krobert KA, Ravens U, Levy FO, Kaumann AJ (2013) PDE3, but not PDE4, reduce β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. Br J Pharmacol 169:528–538

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Molenaar P, Christ T, Ravens U, Kaumann AJ (2006) Carvedilol blocks β2- more than β1-adrenoceptors in human heart. Cardiovasc Res 69:128–139

    Article  CAS  PubMed  Google Scholar 

  • Molenaar P, Savarimuthu SM, Sarsero D, Chen L, Semmler AB, Carle A, Yang I, Bartel S, Vetter D, Beyerdörfer I, Krause E-G, Kaumann AJ (2007) (-)-Adrenaline elicits positive inotropic, lusitropic, and biochemical effects through β2-adrenoceptors in human atrial myocardium from non-failing and failing hearts, consistent with Gs coupling but not with Gi coupling. Naunyn Schmiedebergs Arch Pharmacol 375:11–28

    Article  CAS  PubMed  Google Scholar 

  • Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee IO, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R (2012) Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 59:2182–2190

    Article  CAS  PubMed  Google Scholar 

  • Movsesian MA, Smith CJ, Krall J, Bristow MR, Manganiello VC (1991) Sarcoplasmic reticulum-associated cyclic adenosine 5′-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest 88:15–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Neumann J, Schmitz W, Scholz H, von Meyerinck L, Doring V, Kalmar P (1988) Increase in myocardial Gi-proteins in heart failure. Lancet 2:936–937

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev VO, Bünemann M, Schmitteckert E, Lohse MJ, Engelhardt S (2006) Cyclic AMP imagining in adult cardiac myocytes reveals far-reaching β1-adrenergic but locally confined β2-adrenergic receptor-mediated signaling. Circ Res 99:1084–1091

    Article  CAS  PubMed  Google Scholar 

  • Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010) β2-Adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327:1653–1657

    Article  CAS  PubMed  Google Scholar 

  • Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, Sollano JA, Shannon J, Tandon PK, DeMets DL (1991) Effect of oral milrinone on mortality in severe chronic heart failure. The Promise Study Research Group. N Engl J Med 325:1468–1475

    Article  CAS  PubMed  Google Scholar 

  • Perera RK, Nikolaev VO (2013) Compartmentation of cAMP signalling in cardiomyocytes in health and disease. Acta Physiol 207:650–662

    Article  CAS  Google Scholar 

  • Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajada M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A, Carvedilol or Metoprolol European Trial Investigators (2003) Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomized control trial. Lancet 362:7–13, For the COMET investigators

    Google Scholar 

  • Remme WJ, Cleland JG, Erhardt, Spark P, Torp-Pedersen C, Metra M, Komajda M, Moullet C, Lukas MA, Poole-Wilson P, Di Lenarda A, Swedberg K (2007) Effect of carvedilol and metoprolol on the mode of death in patients with heart failure. Eur J Heart Failure 9:1128–1135

    Article  CAS  Google Scholar 

  • Reves JG, Karp RB, Buttner EE, Tosone S, Smith LR, Samuelson PN, Kreusch GR, Oparil S (1982) Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man. Circulation 66:49–55

    Article  CAS  PubMed  Google Scholar 

  • Richter W, Xie M, Scheitrum C, Krall J, Movsesian MA, Conti M (2011) Conserved expression and functions of PDE4 in rodent and human heart. Basic Res Cardiol 106:249–262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rickham PP (1964) Human experimentation. Code of ethics of the World Medical Association. Declaration of Helsinki. Br Med J 2:177

    Article  CAS  PubMed  Google Scholar 

  • Sigmund M, Jacob H, Becker H, Hanrath P, Schumacher C, Eschenhagen T, Schmitz W, Scholz H, Steinfath M (1996) Effects of metoprolol on myocardial β-adrenoceptors and Giά-proteins in patients with congestive heart failure. Eur J Clin Pharmacol 51:127–132

    Article  CAS  PubMed  Google Scholar 

  • Van Tassel BW, Radwanski P, Movsesian M, Munger MA (2008) Combination therapy with β-adrenergic receptor antagonists and phosphodiesterase inhibitors for chronic heart failure. Pharmacotherapy 28:1523–1530

    Article  Google Scholar 

  • Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC (2005) Neurohumoral features of myocardial stunning due to sudden emotional stress. N Eng J Med 352:539–548

    Article  CAS  Google Scholar 

  • Wortsman J (2002) Role of epinephrine in acute stress. Endocrinol Metab Clin North Am 31:79–106

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the transplant heart surgeons and coordinators of The Prince Charles Hospital, Chermside and Carl Gustav Carus Hospital Dresden. This work was supported in part through the Prince Charles Hospital Foundation.

Conflict of interest

None declared.

Author information

Author notes

  1. Torsten Christ

    Present address: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Authors and Affiliations

  1. Faculty of Health, QUT, Brisbane; School of Medicine, University of Queensland and Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, 4032, Australia

    Peter Molenaar & Katherine T. Gillette

  2. Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany

    Torsten Christ, Emanuel Berk, Andreas Engel & Ursula Ravens

  3. Research Unit of the University Hospital Virgen de la Arrixaca and Department of Pharmacology, University of Murcia, 30100, Murcia, Spain

    Alejandro Galindo-Tovar & Alberto J. Kaumann

Authors
  1. Peter Molenaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Torsten Christ
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emanuel Berk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katherine T. Gillette
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alejandro Galindo-Tovar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ursula Ravens
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alberto J. Kaumann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peter Molenaar or Alberto J. Kaumann.

Additional information

Peter Molenaar and Torsten Christ contributed equally to this work

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 47 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Molenaar, P., Christ, T., Berk, E. et al. Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium. Naunyn-Schmiedeberg's Arch Pharmacol 387, 629–640 (2014). https://doi.org/10.1007/s00210-014-0974-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-014-0974-4

Keywords

Search

Navigation