title: The p38 MAPK inhibitor SB203580 blocks adenosine A(1) receptor-induced attenuation of in vivo myocardial stunning.
abstract: There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this study was to determine whether p38 MAPK plays a role in the adenosine A(1) receptor anti-stunning effect in in vivo porcine myocardium. Regional myocardial stunning in anesthetized, open-chest pigs was induced by 15 min of left anterior descending coronary artery (LAD) occlusion and 3 h of reperfusion (RP). Animals were treated with either vehicle (n = 5), AMP579 (70 microg/kg i.v.; 25 microg/kg bolus + 1.5 microg/kg/min for 30 min prior to ischemia, n = 5), the p38 MAPK inhibitor SB203580 (0.25 mg/kg i.v. bolus, n = 4) or a combination of SB203580 plus AMP579 (n = 5). Regional ventricular function was monitored by measurements of segment shortening and load insensitive parameters including preload recruitable stroke work (PRSW) and PRSW area (PRSWA). The ischemic area at risk was similar in all groups and there was no necrosis in any heart. Treatment with AMP579 significantly improved reperfusion regional PRSW and PRSWA compared to vehicle controls. The p38 inhibitor SB203580 alone did not alter the extent of myocardial stunning, but it abolished the beneficial effect of AMP579 pretreatment. These results provide the first evidence that p38 MAPK activation may play an important role in the mechanism by which adenosine agonists attenuate myocardial stunning.
authors.affiliation: Department of Surgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Gentian
authors.initials: G
authors.lastname: Kristo
authors.forename: Byron J
authors.initials: BJ
authors.lastname: Keith
authors.forename: Salik A
authors.initials: SA
authors.lastname: Jahania
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mentzer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Lasley
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000293:injuries / Q000503:physiopathology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000502:physiology; D013552:Swine; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D058916:Adenosine A1 Receptor Antagonists; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D043682:Receptor, Adenosine A1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580