Chronic β1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium

Eur J Pharmacol. 2016 Oct 15;789:1-7. doi: 10.1016/j.ejphar.2016.06.054. Epub 2016 Jun 30.


β-adrenoceptor antagonists are commonly used in ischaemic heart disease (IHD) patients, yet may impair signalling and efficacy of 'cardioprotective' interventions. We assessed effects of chronic β1-adrenoceptor antagonism on myocardial resistance to ischaemia-reperfusion (IR) injury and the ability of cardioprotective interventions [classic ischaemic preconditioning (IPC); novel sustained ligand-activated preconditioning (SLP)] to reduce IR injury in murine hearts. Young male C57Bl/6 mice were untreated or received atenolol (0.5g/l in drinking water) for 4 weeks. Subsequently, two cardioprotective stimuli were evaluated: morphine pellets implanted (to induce SLP, controls received placebo) 5 days prior to Langendorff heart perfusion, and IPC in perfused hearts (3×1.5min ischaemia/2min reperfusion). Atenolol significantly reduced in vivo heart rate. Untreated control hearts exhibited substantial left ventricular dysfunction (~50% pressure development recovery, ~20mmHg diastolic pressure rise) with significant release of lactate dehydrogenase (LDH, tissue injury indicator) after 25min ischaemia/45min reperfusion. Contractile dysfunction and elevated LDH were reduced >50% with IPC and SLP. While atenolol treatment did not modify baseline contractile function, post-ischaemic function was significantly depressed compared to untreated hearts. Atenolol pre-treatment abolished beneficial effects of IPC, whereas SLP protection was preserved. These data indicate that chronic β1-adrenoceptor blockade can exert negative effects on functional IR tolerance and negate conventional IPC (implicating β1-adrenoceptors in IR injury and IPC signalling). However, novel morphine-induced SLP is resistant to inhibition by β1-adrenoceptor antagonism.

Keywords: Cardiac ischaemia; Cardiovascular drugs; Ischaemia-reperfusion injury; Morphine; β-Adrenoceptors.

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects
  • Ischemic Preconditioning, Myocardial*
  • Isoproterenol / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / physiopathology*
  • Myocardial Reperfusion Injury / therapy*
  • Myocardium / metabolism*
  • Receptors, Adrenergic, beta-1 / metabolism*


  • Adrenergic beta-1 Receptor Antagonists
  • Receptors, Adrenergic, beta-1
  • L-Lactate Dehydrogenase
  • Isoproterenol