title: The role of β-adrenergic receptors in the cardioprotective effects of beta-preconditioning (βPC).
abstract: OBJECTIVE
  To determine the mechanism whereby transient stimulation of the β-adrenergic receptor subtypes (β-AR) elicit cardioprotection against subsequent ischaemia.
  
  
  METHODS
  Isolated rat hearts were subjected to 35 min regional ischaemia (RI) and reperfusion and infarct size (IS) determined. Hearts were preconditioned with 5 min isoproterenol (β1/β2-AR agonist), denopamine (β1-AR agonist), formoterol hemifumarate (β2-AR agonist) or BRL37344 (β3-AR agonist) and 5 min reperfusion. The roles of the β-ARs, NO, PKA, and PI3-K were explored by using selective antagonists/blockers. Pertussis toxin was administered i.p., 48 h prior to experimentation.
  
  
  RESULTS
  IS of hearts preconditioned with either isoproterenol, denopamine or formoterol (% of area at risk: 23.6 ± 1.26; 24.52 ± 0.89; 20.74 ± 0.85 respectively) were significantly smaller than that of non-preconditioned hearts (41.7 ± 1.65) and associated with improvement in postischaemic mechanical performance. The β3-AR agonist BRL37344 could not reduce IS. The β1- and β2-AR blockers CGP-20712A and ICI-118551 abolished the reduction in IS and improvement in mechanical recovery during reperfusion induced by isoproterenol preconditioning, while the β3-AR blocker SR59230A was without effect. Both Rp-8-CPT-cAMPs and wortmannin significantly increased IS when administered before and during β1/β2-AR preconditioning and reduced mechanical recovery. PTX pretreatment had no significant effect on the reduction in IS induced by β1/β2-AR or β2-AR preconditioning, but reduced mechanical recovery in β2-AR preconditioning. Similarly the NOS inhibitors L-NAME and LNNA had no effect on IS in β1/β2-AR preconditioning, but depressed mechanical recovery.
  
  
  CONCLUSIONS
  Protection afforded by β-ARs stimulation, depends on activation of both β1-AR and β2-ARs but not β3-AR. With functional recovery as endpoint, results suggest involvement of NO in β1/β2-AR preconditioning and the Gi protein in β2-AR preconditioning. Both PKA and PI3-K activation were essential for β1/β2-AR cardioprotection.
authors.affiliation: Division Medical Physiology, Department of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, Republic of South Africa.
authors.forename: Ruduwaan
authors.initials: R
authors.lastname: Salie
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Moolman
authors.forename: Amanda
authors.initials: A
authors.lastname: Lochner
mesh_terms: D054758:A Kinase Anchor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D000068759:Formoterol Fumarate; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; C037293:denopamine