Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial K-ATP channels

We investigated the role of p38 mitogen-activated protein kinase (MAPK) pho sphorylation and opening of the mitochondrial ATP-sensitive K+ [(K-ATP)(mit o)] channel in the adenosine A(1) receptor (A(1)AR)-induced delayed cardiop rotective effect in the mouse heart. Adult male mice were treated with vehi cle (5% DMSO) or the A1 AR agonist 2-chloro-N-6-cyclopentyladenosine (CCPA; 0.1 mg/kg ip). Twenty-four hours later, hearts were subjected to 30 min of global ischemia and 30 min of reperfusion in the Langendorff mode. Geniste in or SB-203580 (1 mg/kg ip) given 30 min before CCPA treatment was used to block receptor tyrosine kinase or p38 MAPK phosphorylation, respectively. 5-Hydroxydecanoate (5-HD; 200 muM) was used to block (K-ATP)(mito) channels . CCPA produced marked improvement in left ventricular function, which was partially blocked by SB-203580 and 5-HD and completely abolished with genis tein. CCPA caused a reduction in infarct size (12.0 +/- 2.0 vs. 30.3 +/- 3. 0% in vehicle), which was blocked by genistein (29.4 +/- 2.3%), SB-203580 ( 28.3 +/- 2.6%), and 5-HD (33.9 +/- 2.4%). CCPA treatment also caused increa sed phosphorylation of p38 MAPK during ischemia, which was blocked by genis tein, SB-203580, and 5-HD. The results suggest that A(1)AR-triggered delaye d cardioprotection is mediated by p38 MAPK phosphorylation. Blockade of car dioprotection with 5-HD concomitant with decrease in p38 MAPK phosphorylati on suggests a potential role of (K-ATP)(mito) channel opening in phosphoryl ation and ensuing the late preconditioning effect of A(1)AR.