title: Age-related loss of cardiac preconditioning: impact of protein kinase A.
abstract: 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 3×5 min (He-PC). The PKA-blocker H-89 (10 μg/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 μg/kg) and aged animals (300 and 1000 μg/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 μg/kg reduced infarct size in young (37±6%; p<0.05) but not in aged rats (48±13%; n.s.). In contrast, 1000 μg/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.
authors.affiliation: Department of Anaesthesiology, University Hospital Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany. Ragnar.Huhn@med.uni-duesseldorf.de
authors.forename: Ragnar
authors.initials: R
authors.lastname: Huhn
authors.forename: Nina C
authors.initials: NC
authors.lastname: Weber
authors.forename: Benedikt
authors.initials: B
authors.lastname: Preckel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlack
authors.forename: Inge
authors.initials: I
authors.lastname: Bauer
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: André
authors.initials: A
authors.lastname: Heinen
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006371:Helium / Q000494:pharmacology; D006439:Hemodynamics / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D000099211:Phospholamban
chemical_list: D050882:CREB-Binding Protein; D002135:Calcium-Binding Proteins; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006371:Helium; D000099211:Phospholamban