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.