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Age-related loss of cardiac preconditioning: impact of protein kinase A
Authors:Huhn Ragnar  Weber Nina C  Preckel Benedikt  Schlack Wolfgang  Bauer Inge  Hollmann Markus W  Heinen André
Affiliation:
  • a Department of Anaesthesiology, University Hospital Duesseldorf, Moorenstrasse 5, 40225 Duesseldorf, Germany
  • b Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Academic Medical Centre (AMC), University of Amsterdam, Meibergdreef 9, 1100 DD Amsterdam, The Netherlands
  • Abstract:
    Helium induces preconditioning (He-PC) by mitochondrial calcium-sensitive potassium (mKCa) 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 mKCa 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 × 5min (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 mKCa 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.
    Keywords:He-PC, helium preconditioning   H-89, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride   Forskolin, 7β-Acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one   NS1619, 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one   mKCa, mitochondrial calcium-sensitive potassium channel   AC, adenylyl cyclase   PKA, protein kinase A
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