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Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Because adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic and pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia-reperfusion was also determined. The following groups were used in an in vivo rat ischemia-reperfusion model: 1) control (10% DMSO iv), 2) the A1/A2a adenosine receptor AMP-579 (50 μg/kg iv), 3) AMP-579 + the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg iv), 4) AMP-579 + the p38 MAPK inhibitor SB-203580 (1 mg/kg iv), and 5) SB-203580 alone. p38 MAPK activation was measured by Western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at preischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP-579 PC, an effect blocked by DPCPX or SB-203580 pretreatment. AMP-579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction before ischemia, whereas no activation of this kinase occurred during ischemia or reperfusion. In contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and in the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control group. SB-203580 blocked the AMP-579-induced increase in phosphorylation of the downstream p38 substrate activating transcription factor-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC. [ABSTRACT FROM AUTHOR]

Laminar, or sheet, architecture of the left ventricle (LV) is a structural basis for normal systolic and diastolic LV dynamics, but transmural sheet orientations remain incompletely characterized. We directly measured the transmural distribution of sheet angles in the ovine anterolateral LV wall. Ten Dorsett-hybrid sheep hearts were perfusion fixed in situ with 5% buffered glutaraldehyde at end diastole and stored in 10% formalin. Transmural blocks of myocardial tissue were excised, with the edges cut parallel to local circumferential, longitudinal, and radial-axes, and sliced into 1-mm-thick sections parallel to the epicardial tangent plane from epicardium to endocardium. Mean fiber directions were determined in each section from five measurements of fiber angles. Each section was then cut transverse to the fiber direction, and five sheet angles (β) were measured and averaged. Mean fiber angles progressed nearly linearly from -41° (SD 11) at the epicardium to +42° (SD 16) at the endocardium. Two families of sheets were identified at approximately +45° (β+) and -45° (β-). In the lateral region (n = 5), near the epicardium, sheets belonged to the β+ family: in the midwall, to the β- family; and near the endocardium, to the β+ family. This pattern was reversed in the basal anterior region (n = 4). Sheets were uniformly β- over the anterior papillary muscle (n = 2). These direct measurements of sheet angles reveal, for the first time, alternating transmural families of predominant sheet angles. This may have important implications in understanding wall mechanics in the normal and the failing heart. [ABSTRACT FROM AUTHOR]