title: Chronic β1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium.
abstract: 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.
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Southport, Australia.
authors.forename: Louise E
authors.initials: LE
authors.lastname: See Hoe
authors.affiliation: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.affiliation: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Busija
authors.affiliation: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA; Department of Chemistry and Biochemistry, University of California San Diego, USA.
authors.forename: Kristofer J
authors.initials: KJ
authors.lastname: Haushalter
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Southport, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ozberk
authors.affiliation: Department of Pharmacology, University of California San Diego, USA.
authors.forename: Malik M
authors.initials: MM
authors.lastname: Keshwani
authors.affiliation: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Southport, Australia.
authors.forename: Eugene Du
authors.initials: ED
authors.lastname: Toit
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Southport, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.affiliation: VA San Diego Healthcare System, San Diego, USA; Department of Anesthesiology, University of California San Diego, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Menzies Health Institute Queensland, Griffith University, Southport, Australia. Electronic address: j.peart@griffith.edu.au.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Peart
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D007545:Isoproterenol / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D007770:L-Lactate Dehydrogenase; D007545:Isoproterenol
keywords: Cardiac ischaemia; Cardiovascular drugs; Ischaemia-reperfusion injury; Morphine; β-Adrenoceptors