title: Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, Ohio 44106-4970, USA.
authors.forename: Isidore C
authors.initials: IC
authors.lastname: Okere
authors.forename: Tracy A
authors.initials: TA
authors.lastname: McElfresh
authors.forename: Daniel Z
authors.initials: DZ
authors.lastname: Brunengraber
authors.forename: Wenjun
authors.initials: W
authors.lastname: Martini
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sterk
authors.forename: Hazel
authors.initials: H
authors.lastname: Huang
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Henri
authors.initials: H
authors.lastname: Brunengraber
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: 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
chemical_list: D002208:Caproates; D006537:Heptanoates; C037652:hexanoic acid