title: Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation.
abstract: A high rate of cardiac work increases citric acid cycle (CAC) turnover and flux through pyruvate dehydrogenase (PDH); however, the mechanisms for these effects are poorly understood. We tested the hypotheses that an increase in cardiac energy expenditure: (1) activates PDH and reduces the product/substrate ratios ([NADH]/[NAD(+)] and [acetyl-CoA]/[CoA-SH]); and (2) increases the content of CAC intermediates. Measurements were made in anaesthetized pigs under control conditions and during 15 min of a high cardiac workload induced by dobutamine (Dob). A third group was made hyperglycaemic (14 mm) to stimulate flux through PDH during the high work state (Dob + Glu). Glucose and fatty acid oxidation were measured with (14)C-glucose and (3)H-oleate. Compared with control, the high workload groups had a similar increase in myocardial oxygen consumption ( and cardiac power. Dob increased PDH activity and glucose oxidation above control, but did not reduce the [NADH]/[NAD(+)] and [acetyl-CoA]/[CoA-SH] ratios, and there were no differences between the Dob and Dob + Glu groups. An additional group was treated with Dob + Glu and oxfenicine (Oxf) to inhibit fatty acid oxidation: this increased [CoA-SH] and glucose oxidation compared with Dob; however, there was no further activation of PDH or decrease in the [NADH]/[NAD(+)] ratio. Content of the 4-carbon CAC intermediates succinate, fumarate and malate increased 3-fold with Dob, but there was no change in citrate content, and the Dob + Glu and Dob + Glu + Oxf groups were not different from Dob. In conclusion, compared with normal conditions, at high myocardial energy expenditure (1) the increase in flux through PDH is regulated by activation of the enzyme complex and continues to be partially controlled through inhibition by fatty acid oxidation, and (2) there is expansion of the CAC pool size at the level of 4-carbon intermediates that is largely independent of myocardial fatty acid oxidation.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Isidore C
authors.initials: IC
authors.lastname: Okere
authors.forename: Daniel Z
authors.initials: DZ
authors.lastname: Brunengraber
authors.forename: Tracy A
authors.initials: TA
authors.lastname: McElfresh
authors.forename: Kristen L
authors.initials: KL
authors.lastname: King
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: William C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002952:Citric Acid Cycle / Q000502:physiology*; D004280:Dobutamine / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D006943:Hyperglycemia / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D013552:Swine
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D011768:Pyruvate Dehydrogenase Complex; D019301:Oleic Acid; D019344:Lactic Acid; D004280:Dobutamine; D000244:Adenosine Diphosphate; C023010:4-hydroxyphenylglycine; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; D005998:Glycine