Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion.
In the normal heart, there is loss of citric acid cycle (CAC) intermediates that is matched by the entry of intermediates from outside the cycle, a process termed anaplerosis. Previous in vitro studies suggest that supplementation with anaplerotic substrates improves cardiac function during myocardial ischemia and/or reperfusion. The present investigation assessed whether treatment with the anaplerotic medium-chain fatty acid heptanoate improves contractile function during ischemia and reperfusion. The left anterior descending coronary artery of anesthetized pigs was subjected to 60 min of 60% flow reduction and 30 min of reperfusion. Three treatment groups were studied: saline control, heptanoate (0.4 mM), or hexanoate as a negative control (0.4 mM). Treatment was initiated after 30 min of ischemia and continued through reperfusion. Myocardial CAC intermediate content was not affected by ischemia-reperfusion; however, treatment with heptanoate resulted in a more than twofold increase in fumarate and malate, with no change in citrate and succinate, while treatment with hexanoate did not increase fumarate or malate but increased succinate by 1.8-fold. There were no differences among groups in lactate exchange, glucose oxidation, oxygen consumption, and contractile power. In conclusion, despite a significant increase in the content of carbon-4 CAC intermediates, treatment with heptanoate did not result in improved mechanical function of the heart in this model of reversible ischemia-reperfusion. This suggests that reduced anaplerosis and CAC dysfunction do not play a major role in contractile and metabolic derangements observed with a 60% decrease in coronary flow followed by reperfusion.
Okere
Isidore C
IC
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, Ohio 44106-4970, USA.
McElfresh
Tracy A
TA
Brunengraber
Daniel Z
DZ
Martini
Wenjun
W
Sterk
Joseph P
JP
Huang
Hazel
H
Chandler
Margaret P
MP
Brunengraber
Henri
H
Stanley
William C
WC
D000818:Animals; D002208:Caproates / Q000008:administration & dosage*; D002952:Citric Acid Cycle / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D006537:Heptanoates / Q000008:administration & dosage*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D013552:Swine; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control
D002208:Caproates; D006537:Heptanoates; C037652:hexanoic acid