title: Myocardial mechanical dysfunction following endotoxemia: role of changes in energy substrate metabolism.
abstract: Cardiovascular depression due to endotoxemia remains a major cause of mortality in intensive care patients. To determine whether drug-induced alterations in cardiac metabolism may be a viable strategy to reduce endotoxemia-mediated cardiac dysfunction, we assessed endotoxemia-induced changes in glucose and fatty acid metabolism under aerobic and post-ischemic conditions. Endotoxemia was induced in male Sprague-Dawley rats by lipopolysaccharide (Escherichia coli 0111:B4c, 4 mg/kg, i.p.) 6 h prior to heart removal for ex vivo assessment of left ventricular (LV) work and rates of glucose metabolism (glucose uptake, glycogen synthesis, glycolysis and glucose oxidation) and palmitate oxidation. Under aerobic conditions, endotoxemic hearts had impaired LV function as judged by echocardiography in vivo (% ejection fraction, 66.0 ± 3.2 vs 78.0 ± 2.1, p < 0.05) or by LV work ex vivo (2.14 ± 0.16 vs 3.28 ± 0.16, Joules min(-1) g dry wt(-1), p < 0.05). However, rates of glucose uptake, glycogen synthesis, glycolysis, and glucose oxidation were not altered. Palmitate oxidation was lower in endotoxemic hearts in proportion to the decreased workload, thus metabolic efficiency was unaffected. In hearts reperfused following global ischemia, untreated hearts had impaired recovery of LV work (52.3 ± 9.4 %) whereas endotoxemic hearts had significantly higher recovery (105.6 ± 11.3 %, p < 0.05). During reperfusion, fatty acid oxidation, acetyl CoA production and metabolic efficiency were similar in both groups. As impaired cardiac function appeared unrelated to depression of energy substrate oxidation, it is unlikely that drug-induced acceleration of fatty acid oxidation will improve mechanical function. The beneficial repartitioning of glucose metabolism in reperfused endotoxemic hearts may contribute to the cardioprotected phenotype.
authors.affiliation: Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran.|Department of Pharmacology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Soraya
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-70 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada.
authors.forename: Waleed G T
authors.initials: WG
authors.lastname: Masoud
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-70 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada.
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Garjani
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-70 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada. sandy.clanachan@ualberta.ca.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D004452:Echocardiography; D019446:Endotoxemia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008168:Lung / Q000201:enzymology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism*; D010477:Perfusion; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left
chemical_list: D010168:Palmitates; D019001:Nitric Oxide Synthase; D005947:Glucose
keywords: Cardiac fatty acid metabolism; Cardiac function; Cardiac glucose metabolism; Endotoxemia; Reperfusion injury