title: Altered cardiac metabolic phenotype after prolonged inhibition of NO synthesis in chronically instrumented dogs.
abstract: Acute inhibition of nitric oxide (NO) synthase causes a reversible alteration in myocardial substrate metabolism. We tested the hypothesis that prolonged NO synthase inhibition alters cardiac metabolic phenotype. Seven chronically instrumented dogs were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 35 mg.kg(-1).day(-1) po) for 10 days to inhibit NO synthesis, and seven were used as controls. Cardiac free fatty acid, glucose, and lactate oxidation were measured by infusion of [(3)H]oleate, [(14)C]glucose, and [(13)C]lactate, respectively. After 10 days of L-NAME administration, despite no differences in left ventricular afterload, cardiac O(2) consumption was significantly increased by 30%, consistent with a marked enhancement in baseline oxidation of glucose (6.9 +/- 2.0 vs. 1.7 +/- 0.5 micromol.min(-1).100 g(-1), P < 0.05 vs. control) and lactate (21.6 +/- 5.6 vs. 11.8 +/- 2.6 micromol.min(-1).100 g(-1), P < 0.05 vs. control). When left ventricular afterload was increased by ANG II infusion to stimulate myocardial metabolism, glucose oxidation was augmented further in the L-NAME than in the control group, whereas free fatty acid oxidation decreased. Exogenous NO (diethylamine nonoate, 0.01 micromol.kg(-1).min(-1) iv) could not reverse this metabolic alteration. Consistent with the accelerated rate of carbohydrate oxidation, total myocardial pyruvate dehydrogenase activity and protein expression were higher (38 and 34%, respectively) in the L-NAME than in the control group. Also, protein expression of the constitutively active glucose transporter GLUT-1 was significantly elevated (46%) vs. control. We conclude that prolonged NO deficiency causes a profound alteration in cardiac metabolic phenotype, characterized by selective potentiation of carbohydrate oxidation, that cannot be reversed by a short-term infusion of exogenous NO. This phenomenon may constitute an adaptive mechanism to counterbalance cardiac mechanical inefficiency.
authors.affiliation: Dept. of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: d'Agostino
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Labinskyy
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Biao
authors.initials: B
authors.lastname: Lei
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuo
authors.forename: Michelle
authors.initials: M
authors.lastname: Bellomo
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Xu
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D050260:Carbohydrate Metabolism / Q000502:physiology*; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D008297:Male; D008991:Monitoring, Physiologic; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010641:Phenotype; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester