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

• Published in: European journal of pharmacology 2016-10, Vol.789, p.1-7
• Main Authors: See Hoe, Louise E., Schilling, Jan M., Busija, Anna R., Haushalter, Kristofer J., Ozberk, Victoria, Keshwani, Malik M., Roth, David M., Toit, Eugene Du, Headrick, John P., Patel, Hemal H., Peart, Jason N.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-1 Receptor Antagonists - pharmacology; Animals; Cardiac ischaemia; Cardiovascular drugs; Dose-Response Relationship, Drug; Heart Rate - drug effects; Ischaemia-reperfusion injury; Ischemic Preconditioning, Myocardial; Isoproterenol - pharmacology; L-Lactate Dehydrogenase - metabolism; Male; Mice; Mice, Inbred C57BL; Morphine; Myocardial Reperfusion Injury - enzymology; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - therapy; Myocardium - metabolism; Receptors, Adrenergic, beta-1 - metabolism; β-Adrenoceptors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.06.054

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.