Age-related loss of cardiac preconditioning: Impact of protein kinase A

Helium induces preconditioning (He-PC) by mitochondrial calcium-sensitive potassium (mK(Ca)) channel-activation, but this effect is lost in the aged myocardium. Both, the upstream signalling pathway of He-PC and the underlying mechanisms for an age-related loss of preconditioning are unknown. A possible candidate as upstream regulator of mK(Ca) channels is protein kinase A (PKA). We investigated whether 1) regulation of PKA is involved in He-PC and 2) regulation of PKA is age-dependent. Young (2-3 months) and aged (22-24 months) Wistar rats were randomised to eight groups (each n =8). All animals underwent 25 min regional myocardial ischemia and 120 min reperfusion. Control (Con, Age Con) animals were not further treated. Young rats inhaled 70% helium for 3 x 5min (He-PC). The PKA-blocker H-89 (10 mu g/kg) was administered with and without helium (He-PC + H-89, H-89). Furthermore, we tested the effect of direct activation of mK(Ca) channels with NS1619. The adenylyl cyclase activator forskolin (For) was administered in young (300 mu g/kg) and aged animals (300 and 1000 mu g/kg). He-PC reduced infarct size from 60 +/- 4% (Con) to 37 +/- 10% (p <0.05). Infarct size reduction was completely abolished by H-89 (58 +/- 5%; p <0.05), but H-89 alone had no effect (57 +/- 2%). NS1619 reduced infarct size in the same concentration in both, young and aged rats (35 +/- 6%; p <0.05 vs. Con and 34 +/- 8%; p <0.05 vs. Age Con). Forskolin in a concentration of 300 mu g/kg reduced infarct size in young (37 6%; p <0.05) but not in aged rats (48 +/- 13%; n.s.). In contrast, 1000 mu g/kg Forskolin reduced infarct size also in aged rats (28 +/- 3%; p <0.05). He-PC is mediated by activation of PKA. Alterations in PKA regulation might be an underlying mechanism for the age-dependent loss of preconditioning. (C) 2011 Elsevier Inc. All rights reserved