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The mechanism of beta-adrenergic preconditioning: roles for adenosine and ROS during triggering and mediation

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Abstract

The aim of this study was to investigate the mechanism of beta-adrenergic preconditioning (BPC). The roles of adenosine and its receptor subtypes, the generation of oxygen free radicals (ROS) and activation of the KATP channels as well as the phosphoinositide-3-kinase (PI3K)/PKB/Akt and extracellular signal-regulated kinase (ERK) signal transduction pathways during the triggering and mediation phases were evaluated. Using the isolated working rat heart, BPC was elicited by administration of denopamine (beta1 adrenergic receptor agonist, 10−7 M), isoproterenol (beta1/beta2 adrenergic receptor agonist, 10−7 M) or formoterol (beta2 adrenergic receptor agonist, 10−9 M) for 5 min followed by 5 min washout. Index ischaemia was 35 min regional ischaemia and infarct size determined using the tetrazolium method. The role of adenosine was studied using adenosine deaminase and selective antagonists as well as the PI3K and ERK inhibitors, wortmannin and PD98,059, bracketing the triggering and mediating phases. Involvement of ROS, PKC, the mitochondrial KATP channels, release of endogenous opioids and bradykinin was studied by administration of N-acetyl cysteine (NAC), bisindolylmaleimide, the KATP channel blocker 5-hydroxydecanoate (5-HD), naloxone or HOE140, respectively. Activation of PKB/Akt and ERKp44/p42 during triggering and reperfusion was determined by Western blot. Preconditioning with all three beta-adrenergic receptor agonists caused a reduction in infarct size and an improvement in postischaemic function. BPC preconditioning with isoproterenol, denopamine or formoterol was abolished by the adenosine A3 receptor antagonist MRS1191 during both the triggering and

mediation phases. Isoproterenol-induced preconditioning (beta1/beta2 PC) was attenuated by MRS1754, an adenosine A2B receptor antagonist, during the triggering phase and abolished during reperfusion. The mediation phase of beta1/beta2 PC was also abolished by ZM241385, an adenosine A2A antagonist. The free radical scavenger NAC caused a significant attenuation of cardioprotection induced by isoproterenol when administered during both trigger and mediation phases, while being effective during the trigger phase with denopamine and during reperfusion in formoterol preconditioned hearts. The mitochondrial KATP channel blocker, 5-HD, was without effect on beta1/beta2 PC during both triggering and mediation phases. BPC in rat hearts is dependent on activation of the A3 adenosine receptors by endogenously produced adenosine and production of free radicals during the triggering and mediation phases while the A2A and A2B adenosine receptors participate mainly during reperfusion. The mitochondrial KATP channels do not contribute to cardioprotection at any stage. Activation of ERK and PI3K/PKB/Akt during the triggering and reperfusion phases is associated with cardioprotection.

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Abbreviations

AR:

Adrenergic receptor

AC:

Adenylyl cyclase

AdoR:

Adenosine receptor

ROS:

Reactive oxygen species

MPTP:

Mitochondrial permeability transition pore

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  1. Division Medical Physiology, Department Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, P.O Box 19063, Tygerberg, 7505, Republic of South Africa

    Ruduwaan Salie, Johannes A Moolman & Amanda Lochner

  2. Cape Heart Centre of the Medical Research Council of South Africa, Tygerberg, Republic of South Africa

    Ruduwaan Salie, Johannes A Moolman & Amanda Lochner

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  1. Ruduwaan Salie
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Salie, R., Moolman, J.A. & Lochner, A. The mechanism of beta-adrenergic preconditioning: roles for adenosine and ROS during triggering and mediation. Basic Res Cardiol 107, 281 (2012). https://doi.org/10.1007/s00395-012-0281-5

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