Skip to main content

Advertisement

SpringerLink
Log in

β2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart

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

Abstract

Endogenous catecholamines released during myocardial ischemia have been considered both to aggravate cell injury and exacerbate arrhythmias and to exert a protective action on the post-ischemic contractile function. The present work was addressed to look for evidence to explain this controversy. The effects of cardiac catecholamine depletion and of α- and β-adrenoceptor (AR) blockade on the post-ischemic contractile dysfunction, as well as its possible relationship with cardiac oxidative stress, were studied in isolated and perfused rat hearts submitted to 20 min of ischemia and 30 min of reperfusion (stunning). Catecholamine depletion improves the contractile recovery in the stunned heart. This mechanical effect was associated with decreased levels of lipid peroxidation. A similar enhancement of the contractile function during reperfusion was detected after the simultaneous blockade of α1- and β-ARs with prazosin plus propranolol. To ascertain which specific AR pathway was involved in the effects of catecholamines on the stunned heart, selective AR blockers, prazosin (α1-blocker), atenolol (β1-blocker), ICI 118,551 (β2-blocker) and selective inhibitors of Gi-PI3K pathway (pertussis toxin and wortmannin) were alternatively combined. The results indicate that catecholamines released during ischemia exert a dual action on the contractile behavior of the stunned heart: a deleterious effect, related to the activation of the β2-AR-Gi-PI3K-pathway, which was counteracted by a beneficial effect, triggered by the stimulation of α1-AR. Neither the depression nor the enhancement of the post-ischemic contractile recovery were related with the increase in ROS formation induced by endogenous catecholamines.

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

Similar content being viewed by others

References

  • Amin JK, Xiao L, Pimentel DR, Pagano PJ, Singh K, Sawyer DB, Colucci WS (2001) Reactive oxygen species mediate α-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol 33:131–139. DOI 10.1006/jmcc.2000.1285

    Article  PubMed  CAS  Google Scholar 

  • Angelos MG, Murray HN, Waite MD, Gorsline RT (2002) Postischemic inotropic support of the dysfunctional heart. Crit Care Med 30:410–416

    Article  PubMed  Google Scholar 

  • Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB, Brew EC, Cairns CB, Bensard DD, Harken AH (1993) Preconditioning against myocardial dysfunction after ischemia and reperfusion by an α1-adrenergic mechanism. Circ Res 73:656–670

    PubMed  CAS  Google Scholar 

  • Bartels LA, Clifton GD, Szabo TS (1998) Influence of myocardial ischemia and reperfusion on β-adrenoceptor subtype expression. J Cardiovasc Pharmacol 31:484–487

    Article  PubMed  CAS  Google Scholar 

  • Bers DM (2001) Excitation-contraction coupling and cardiac contractile force, 2nd edn. Kluwer Academic Publishers, The Netherlands, pp 275–282

    Google Scholar 

  • Bolli R (1990) Mechanism of myocardial “stunning”. Ciculation 82:723–738

    CAS  Google Scholar 

  • Bolli R, Marbán E (1999) Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79:609–634

    PubMed  CAS  Google Scholar 

  • Bolli R, Zhu WX, Myers ML, Hartley CJ, Roberts R (1985) Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol 56:964–968

    Article  PubMed  CAS  Google Scholar 

  • Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Meth Enzymol 52:302–309

    Article  PubMed  CAS  Google Scholar 

  • Carrozza JP Jr, Bentivegna LA, Williams CP, Kuntz RE, Grossman W, Morgan JP (1992) Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. Circ Res 71:1334–1340

    PubMed  CAS  Google Scholar 

  • Chiappe de Mon LE, Chiappe de Cingolani GE, Cingolani HE (1978) Effect of acidosis on heart cAMP-dependent protein kinase. Arch Int Physiol Biochim 86:277–287

    Article  PubMed  CAS  Google Scholar 

  • Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A. Nature 390:88–91

    Article  PubMed  CAS  Google Scholar 

  • Dart AM, Du XJ (1993) Unexpected drug effects on autonomic function during myocardial ischaemia. Cardiovasc Res 27:906–914

    PubMed  CAS  Google Scholar 

  • Du XJ, Vincan E, Woodcock DM, Milano CA, Dart AM, Woodcock EA (1996) Response to cardiac sympathetic activation in transgenic mice overexpressing β2-adrenergic receptor. Am J Physiol 271:H630–H636

    PubMed  CAS  Google Scholar 

  • Egert S, Nguyen N, Schwaiger M (1999) Contribution of α-adrenergic and β-adrenergic stimulation to ischemia-induced glucose transporter (GLUT) 4 and GLUT1 translocation in the isolated perfused rat heart. Circ Res 84:1407–1415

    PubMed  CAS  Google Scholar 

  • Endoh M (1999) Muscarinic regulation of Ca2+ signaling in mammalian atrial and ventricular myocardium. Eur J Pharmacol 375:177–196

    Article  PubMed  CAS  Google Scholar 

  • Frances C, Nazeyrollas P, Prevost A, Moreau F, Pisani J, Davani S, Kantelip JP, Millart H (2003) Role of β1- and β2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion. J Cardiovasc Pharmacol 41:396–405

    Article  PubMed  CAS  Google Scholar 

  • Grimm M, Kurz T, Schwarz M, Richardt D, Schäfer U, Katus HA, Richardt G (2001) Presynaptic regulation of cardiac norepinephrine release in ischemia. J Cardiovasc Pharmacol 38:58–68

    Article  PubMed  CAS  Google Scholar 

  • He JQ, Balijepalli RC, Haworth RA, Kamp TJ (2005) Crosstalk of beta-adrenergic receptor subtypes through Gi blunts beta-adrenergic stimulation of L-type Ca2+ channels in canine heart failure. Circ Res 97:566–573. DOI 10.1161/01.RES.0000181160.31851.05

    Article  PubMed  CAS  Google Scholar 

  • Hearse DJ, Sutherland FJ (1999) Catecholamines and preconditioning: studies of contraction and function in isolated rat hearts. Am J Physiol 277:H136–H143

    PubMed  CAS  Google Scholar 

  • Huang CH, Vatner SF, Peppas AP, Yang G, Kudej RK (2003) Cardiac nerves affect myocardial stunning through reactive oxygen and nitric oxide mechanisms. Circ Res 93:866–873. DOI 10.1161/01.RES.0000097762.64561.D2

    Article  PubMed  CAS  Google Scholar 

  • Ishiguro Y, Morgan JP (2001) Effect of endogenous catecholamines on myocardial stunning in a simulated ischemia model. Fund Clin Pharmacol 15:111–116

    Article  CAS  Google Scholar 

  • Kim SJ, Depre C, Vatner SF (2003) Novel mechanisms mediating stunned myocardium. Heart Fail Rev 8:143–153

    Article  PubMed  CAS  Google Scholar 

  • Lameris TW, de Zeeuw S, Alberts G, Boomsma F, Duncker DJ, Verdouw PD, Man in’t Veld AJ, van den Meiracker AH (2000) Time course and mechanism of myocardial catecholamine release during transient ischemia in vivo. Circulation 101:2645–2650

    PubMed  CAS  Google Scholar 

  • Lavallee M, Amano J, Vatner SF, Manders WT, Randall WC, Thomas JX Jr (1985) Adverse effects of chronic cardiac denervation in conscious dogs with myocardial ischemia. Circ Res 57:383–392

    PubMed  CAS  Google Scholar 

  • Lubbe WF, Podzuweit T, Opie LH (1992) Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: Implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am Coll Cardiol 19:1622–1633

    Article  PubMed  CAS  Google Scholar 

  • Miki T, Cohen MV, Downey JM (1999) Failure of N-2-mercaptopropionyl glycine to reduce myocardial infarction after 3 days of reperfusion in rabbits. Basic Res Cardiol 94:180–187

    Article  PubMed  CAS  Google Scholar 

  • Mosca SM, Gelpi RJ, Milei J, Fernández Alonso G, Cingolani HE (1998) Is stunning prevented by ischemic preconditioning? Mol Cell Biochem 186:123–129

    Article  PubMed  CAS  Google Scholar 

  • Nagata K, Ye C, Jain M, Milstone DS, Liao R, Mortensen RM (2000) Gαi2 but not Gαi3 is required for muscarinic inhibition of contractility and calcium currents in adult cardiomyocytes. Circ Res 87:903–909

    PubMed  CAS  Google Scholar 

  • Nonomura M, Nozawa T, Matsuki A, Nakadate T, Igarashi N, Kato B, Fujii N, Igawa A, Asanoi H, Kondo T, Inoue H (2005) Ischemia-induced norepinephrine release, but not norepinephrine-derived free radicals, contributes to myocardial ischemia-reperfusion injury. Circ J 69:590–595

    Article  PubMed  CAS  Google Scholar 

  • Obata T (2002) Adenosine production and its interaction with protection of ischemic and reperfusion injury of the myocardium. Life Sci 71:2083–2103

    Article  PubMed  CAS  Google Scholar 

  • Obata T, Hosokawa H, Yamanaka Y (1994) In vivo monitoring of norepinephrine and OH generation on myocardial ischemic injury by dialysis technique. Am J Physiol 266:H903–H908

    PubMed  CAS  Google Scholar 

  • Oudit GY, Sun H, Kerfant BG, Crackower MA, Penninger JM, Backx PH (2004) The role of phosphoinositide 3-kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol 37:449–471. DOI 10.1016/j.yjmcc.2004.05.015

    Article  PubMed  CAS  Google Scholar 

  • Penny WJ, Culling W, Lewis MJ, Sheridan DJ (1985) Antiarrhythmic and electrophysiological effects of alpha adrenoceptor blockade during myocardial ischaemia and reperfusion in isolated guinea-pig hearts. J Mol Cell Cardiol 17:399–409

    Article  PubMed  CAS  Google Scholar 

  • Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, Colucci WS (2003) β-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH 2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92:136–138. DOI 10.1161/01.RES.0000054624.03539.B4

    Article  PubMed  CAS  Google Scholar 

  • Richard VJ, Murry CE, Jennings RB, Reimer KA (1988) Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs. Circulation 78:473–480

    PubMed  CAS  Google Scholar 

  • Rona G (1985) Catecholamine cardiotoxicity. J Mol Cell Cardiol 17:291–306

    Article  PubMed  CAS  Google Scholar 

  • Rump AF, Rosen R, Klaus W (1993) Cardioprotection by superoxide dismutase: a catecholamine-dependent process? Anesth Analg 76:239–246

    Article  PubMed  CAS  Google Scholar 

  • Salvi S (2001) Protecting the myocardium from ischemic injury. A critical role for α1-adrenoceptors? Chest 119:12142–12149

    Google Scholar 

  • Schömig A, Dart AM, Dietz R, Mayer E, Kübler W (1984) Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release. Circ Res 55:689–701

    PubMed  Google Scholar 

  • Tatarkova Z, Aplan P, Matejovicova M, Lehotsky J, Dobrota D, Flameng W (2005) Effect of ischemia and reperfusión on protein oxidation in isolated rabbit hearts. Physiol Res 54:185–191

    PubMed  CAS  Google Scholar 

  • Vatner DE, Vatner SF (1998) Physiological and biochemical adrenergic regulation of the stunned myocardium. Mol Cell Biochem 186:131–137

    Article  PubMed  CAS  Google Scholar 

  • Vittone L, Mundiña-Weilenmann C, Said M, Ferrero P, Mattiazzi A (2002) Time course and mechanisms of phosphorylation of phospholamban residues in ischemia-reperfused rat hearts. Dissociation of phospholamban phosphorylation pathways. J Mol Cell Cardiol 34:39–50. DOI 10.1006/jmcc.2001.1488

    Article  PubMed  CAS  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 Engl J Med 352:539–548

    Article  PubMed  CAS  Google Scholar 

  • Xiao RP, Zhu W, Zheng M, Chakir K, Bond R, Lakatta EG, Cheng H (2004) Subtype-specific β-adrenoceptor signaling pathways in the heart and their potential clinical implications. Trends Pharmacol Sci 25:358–365. DOI 10.1016/j.tips.2004.05.007

    Article  PubMed  CAS  Google Scholar 

  • Zhang GX, Kimura S, Nishiyama A, Shokoji T, Rahman M, Yao L, Nagai Y, Fujisawa Y, Miyatake A, Abe Y (2005) Cardiac oxidative stress in acute and chronic isoproterenol-infused rats. Cardiovasc Res 65:230–238. DOI 10.1016/j.cardiores.2004.08.013

    Article  PubMed  CAS  Google Scholar 

  • Zou Y, Komuro I, Yamazaki T, Kudoh S, Uozumi H, Kadowaki T, Yazaki Y (1999) Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. J Biol Chem 274:9760–9770

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (CONICET): PIP 02257 CONICET to Dr. Leticia Vittone and PIP 02256 to Dr. Alicia Mattiazzi. L. Vittone, M. Said and A. Mattiazzi are established investigators of CONICET.

Author information

Authors and Affiliations

  1. Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900, La Plata, Argentina

    Leticia Vittone, Matilde Said & Alicia Mattiazzi

Authors
  1. Leticia Vittone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matilde Said
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alicia Mattiazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leticia Vittone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vittone, L., Said, M. & Mattiazzi, A. β2-Adrenergic stimulation is involved in the contractile dysfunction of the stunned heart. Naunyn Schmied Arch Pharmacol 373, 60–70 (2006). https://doi.org/10.1007/s00210-006-0045-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-006-0045-6

Keywords

Search

Navigation