High levels of fatty acids increase contractile function of neonatal rabbit hearts during reperfusion following ischemia.
In the neonatal heart the transition from using carbohydrates to using fatty acids has not fully matured and oxidative metabolism/ATP generation may be limiting contractile function after ischemia. This study tested the hypothesis that increasing fatty acid availability increases recovery of left ventricular (LV) work by increasing palmitate oxidation, tricarboxylic acid (TCA) cycle activity, and ATP generation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution containing low (0.4 mM) or high (2.4 mM) palmitate and 5.5 mM glucose. Hearts were subjected to 35-min global ischemia before 40-min reperfusion, and rates of glycolysis, glucose oxidation, and palmitate oxidation were assessed. LV work was similar before ischemia but was greater during reperfusion in hearts perfused with 2.4 mM palmitate compared with hearts perfused with 0.4 mM palmitate [6.98 +/- 0.14 (n = 15) vs. 3.01 +/- 0.23 (n = 16) mJ.beat(-1).g dry wt(-1); P < 0.05]. This was accompanied by increased LV energy expenditure during reperfusion [35.98 +/- 0.16 (n = 8) vs. 19.92 +/- 0.18 (n = 6) mJ.beat(-1).g dry wt(-1); P < 0.05]. During reperfusion the rates of palmitate oxidation [237.5 +/- 28.10 (n = 7) vs. 86.0 +/- 9.7 (n = 6) nmol.g dry wt(-1).min(-1); P < 0.05], total TCA cycle activity [2.65 +/- 0.39 (n = 7) vs. 1.36 +/- 0.14 (n = 6) micromol acetyl-CoA.g dry wt(-1).min(-1); P < 0.05], and ATP generation attributable to palmitate oxidation [26.6 +/- 3.1 (n = 7) vs. 12.6 +/- 1.7 (n = 6) micromol.g dry wt(-1).min(-1); P < 0.05] were greater in hearts perfused with 2.4 mM palmitate. These data indicate that the neonatal heart has decreased energy reserve, and, in contrast to the mature heart, increasing availability of fatty acid substrate increases energy production and improves recovery of function after ischemia.
Departments of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 423 Heritage Medical Research Centre, Edmonton, AB, Canada.
Masayoshi
M
Ito
Jagdip S
JS
Jaswal
Victoria H
VH
Lam
Tatsujiro
T
Oka
Liyan
L
Zhang
Donna L
DL
Beker
Gary D
GD
Lopaschuk
Ivan M
IM
Rebeyka
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D015153:Blotting, Western; D002262:Carboxy-Lyases / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D010477:Perfusion; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011817:Rabbits; D016277:Ventricular Function, Left / Q000187:drug effects
D005227:Fatty Acids; D019308:Palmitic Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D002950:Citrate (si)-Synthase; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose