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

• Published in: Basic research in cardiology 2012-09, Vol.107 (5), p.281-281, Article 281
• Main Authors: Salie, Ruduwaan, Moolman, Johannes A, Lochner, Amanda
• Format: Article
• Language: English
• Subjects: Adenosine - physiology; Animals; Cardiology; Ethanolamines - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Formoterol Fumarate; Ischemic Preconditioning, Myocardial; Isoproterenol - pharmacology; Medicine; Medicine & Public Health; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Original Contribution; Phosphatidylinositol 3-Kinases - physiology; Potassium Channels - physiology; Protein Kinase C - physiology; Proto-Oncogene Proteins c-akt - metabolism; Rats; Reactive Oxygen Species - metabolism; Receptors, Adrenergic, beta - physiology; Receptors, Purinergic P1 - physiology; Triazines - pharmacology; Triazoles - pharmacology
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-012-0281-5

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 K ATP channels as well as the phosphoinositide-3-kinase (PI 3 K)/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 PI 3 K and ERK inhibitors, wortmannin and PD98,059, bracketing the triggering and mediating phases. Involvement of ROS, PKC, the mitochondrial K ATP channels, release of endogenous opioids and bradykinin was studied by administration of N-acetyl cysteine (NAC), bisindolylmaleimide, the K ATP 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 A 2B receptor antagonist, during the triggering phase and abolished during reperfusion. The mediation phase of beta1/beta2 PC was also abolished by ZM241385, an adenosine A 2A 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 K ATP 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 A 3 adenosine receptors