Limitation of Myocardial Reperfusion Injury by AMP579, an Adenosine A1/A2AReceptor Agonist: Role of A2AReceptor and Erk1/2
Autor: | A. Kis, Derek M. Yellon, Gary F. Baxter |
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Rok vydání: | 2003 |
Předmět: |
Male
Agonist medicine.medical_specialty Adenosine A2 Receptor Agonists Pyridines medicine.drug_class MAP Kinase Kinase 2 MAP Kinase Kinase 1 Myocardial Infarction Myocardial Reperfusion Injury chemistry.chemical_compound Internal medicine Animals Medicine Pharmacology (medical) Receptor Flavonoids Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Pharmacology Cardioprotection Mitogen-Activated Protein Kinase 3 Dose-Response Relationship Drug business.industry Imidazoles General Medicine Protein-Tyrosine Kinases Receptor antagonist medicine.disease Adenosine Adenosine receptor Adenosine A1 Receptor Agonists Endocrinology chemistry CCPA Rabbits Mitogen-Activated Protein Kinases Cardiology and Cardiovascular Medicine business Reperfusion injury medicine.drug |
Zdroj: | Cardiovascular Drugs and Therapy. 17:415-425 |
ISSN: | 0920-3206 |
Popis: | 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% (P0.05), 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. |
Databáze: | OpenAIRE |
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