Limitation of myocardial reperfusion injury by AMP579, an adenosine A1/A2A receptor agonist: role of A2A receptor and Erk1/2.
AMP579, an adenosine A(1)/A(2A) receptor agonist, protects against myocardial infarction when given at the onset of reperfusion. However, it is unclear which receptor subtype mediates its protective actions. Anaesthetised rabbits were subjected to 30 min regional ischaemia/180 min reperfusion in vivo. AMP579 (30 microg kg(-1) bolus + 3 microg kg(-1) min(-1) for 70 min) reduced heart rate and mean arterial blood pressure with the latter being abolished with ZM241385 (a selective A(2A) receptor antagonist). AMP579 reduced infarct size from 46.0 +/- 3.4% in vehicle control hearts to 29.6 +/- 3.5% (P < 0.05), an effect that was attenuated in the presence of ZM241385, in a dose-dependent manner (38.2 +/- 4.9% at 1 mg kg(-1); 45.1 +/- 4.2% at 2.5 mg kg(-1)). CGS21680 (a selective A(2A) agonist, 30 microg kg(-1) bolus + 3 microg kg(-1) min(-1) for 70 min), or CCPA (a selective A(1) agonist, 50 microg kg(-1)), alone or in combination showed no protection (44.7 +/- 5.8%; 39.8 +/- 2.8%; 39.1 +/- 5.1%, respectively) when given at the commencement of reperfusion. Furthermore, we hypothesized that the prosurvival MEK1/2-Erk1/2 pathway was involved in the downstream mechanism of cardioprotection afforded by AMP579. PD098059, an inhibitor of MEK1/2 showed a dose dependent attenuation on infarct size (39.9 +/- 5.3% at 2 mg kg(-1); 48.3 +/- 5.7% at 4 mg kg(-1), i.v., respectively). PD098059 alone had no effect on infarct size (44.7 +/- 5.8%, 2 mg kg(-1), i.v.). We conclude that AMP579 limits myocardial infarction by activating A(2A) adenosine receptors that might be linked to further downstream kinases such as Erk1/2.
Kis
Adrienn
A
The Hatter Institute, UCL Hospitals and Medical School, London, UK.
Baxter
Gary F
GF
Yellon
Derek M
DM
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits
C113971:4-(7-((2-3-chloro-2-thienyl)-1-methyl-propylamino)-3H-imidazo(4,5-b)pyridyl-3-yl)cyclopentane carboxamide; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one