Cardioprotection with ischemic preconditioning and MLA: role of adenosine-regulating enzymes?
Both ischemic preconditioning and pretreatment with the endotoxin derivative monophosphoryl lipid A (MLA) protect the heart against infarction, yet the cellular mechanisms responsible for the cardioprotection achieved with either intervention are unknown. Using pentobarbital-anesthetized dogs, we tested the hypothesis that increased activity of 5'-nucleotidase (5'-NT), the enzyme that catalyzes the formation of adenosine from AMP, may play a role. Twenty-two dogs underwent 1 h of coronary occlusion and 4 h of reperfusion: eight controls received no intervention, seven animals were preconditioned with four 5-min episodes of brief ischemia, and seven received MLA (35 micrograms/kg iv) 24 h previously. Collateral blood flow was measured by injection of radiolabeled microspheres, infarct size was delineated by tetrazolium staining, and myocardial 5'-NT activities were measured by quantifying the release of adenosine from AMP. Despite comparable values of collateral blood flow in all groups, infarct size was reduced in preconditioned and MLA-treated dogs vs. controls. In addition, 5'-NT activities were increased throughout the heart with preconditioning and MLA treatment. However, single and multivariate regression analyses revealed no correlation between infarct size and 5'-NT activities for either treatment group. In fact, in the preconditioned cohort, animals with the highest enzyme activities developed the largest infarcts. This dissociation between infarct size and 5'-NT suggests that increased activity of 5'-NT is not the mechanism by which preconditioning or MLA treatment protects the canine heart against infarction.
Przyklenk
K
K
Heart Institute, Good Samaritan Hospital, Los Angeles 90017-2395, USA.
Zhao
L
L
Kloner
R A
RA
Elliott
G T
GT
D015720:5'-Nucleotidase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism*; D000248:Adenosine Kinase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D003326:Coronary Circulation; D004285:Dogs; D004734:Energy Metabolism; D004798:Enzymes / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010710:Phosphates / Q000378:metabolism; D012039:Regional Blood Flow
D000276:Adjuvants, Immunologic; D004798:Enzymes; D008050:Lipid A; D010710:Phosphates; D000255:Adenosine Triphosphate; D000248:Adenosine Kinase; D015720:5'-Nucleotidase; D000241:Adenosine; C048436:monophosphoryl lipid A