title: PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning.
abstract: OBJECTIVE
  Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological preconditioning (PC) induced by transient beta1-adrenoreceptor (beta1-AR) stimulation with xamoterol (XA).
  
  
  METHODS
  After 6-hydroxydopamine (6-OHDA) pretreatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); exposed to 0.01 microM XA for 5 min with or without 10 microM atenolol (ATE), a specific antagonist of beta1-AR, followed by a 15-min XA-free perfusion before I/R (PC, ATE-PC, respectively); treated during 20 min with either phosphoinositide (PI) 3-kinase inhibitors, LY-294002 (LY, 15 microM), or wortmaninn (WO, 0.1 microM); protein kinase C (PKC) inhibitor, GF-109203X (GF, 4 nM); or protein kinase A (PKA) inhibitor, H89 (H89, 1 microM), with an infusion starting 3 min before XA (LY-PC, WO-PC, GF-PC, and H89-PC, respectively). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP), and creatine kinase (CK) release.
  
  
  RESULTS
  XA induced an increase in the MCF after I/R (t 105 min) and a protective effect on the LVEDP, which were blocked by ATE and abolished with the different inhibitors. The transient increase in RPP following XA infusion was blocked by ATE and was not modified by the inhibitors except for H89. Recovery of RPP, measured 25 min after reperfusion, was improved by XA, blocked by ATE, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. XA provided significant protection whereas ATE and the four inhibitors suppressed XA-induced protection.
  
  
  CONCLUSIONS
  The transient preischemic exposure to nanomolar concentrations of a beta1-AR agonist is protective against I/R. PI 3-kinase, PKC, and PKA are implicated in the trigger phase of PC. These observations were confirmed by Western blots.
authors.affiliation: Department of Pharmacology, Reims University Hospital, France. arnaud.robinet@univ-reims.fr
authors.forename: Arnaud
authors.initials: A
authors.lastname: Robinet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Hoizey
authors.forename: Hervé
authors.initials: H
authors.lastname: Millart
mesh_terms: D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002867:Chromones / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology*; D016627:Oxidopamine / Q000494:pharmacology; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D000077191:Wortmannin; D017307:Xamoterol / Q000627:therapeutic use
chemical_list: D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D002867:Chromones; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009025:Morpholines; D016627:Oxidopamine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D013449:Sulfonamides; D000077191:Wortmannin; D017307:Xamoterol; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide