title: Exogenous nitric oxide reduces glucose transporters translocation and lactate production in ischemic myocardium in vivo.
abstract: Nitric oxide (NO) inhibits myocardial glucose transport and metabolism, although the underlying mechanism(s) and functional consequences of this effect are not clearly understood. We tested the hypothesis that NO inhibits the activation of AMP-activated protein kinase (AMPK) and translocation of cardiac glucose transporters (GLUTs; GLUT-4) and reduces lactate production. Ischemia was induced in open-chest dogs by a 66% flow reduction in the left anterior descending coronary artery (LAD). During ischemia, dogs were untreated (control) or treated by direct LAD infusion of (i) nitroglycerin (NTG) (0.5 microg.kg(-1).min(-1)); (ii) 8-Br-cGMP (50 microg.kg(-1).min(-1)); or (iii) NO synthase inhibitor L-nitro-argininemethylester (40 microg.kg(-1).min(-1); n = 9 per group). Cardiac substrate oxidation was measured with isotopic tracers. There were no differences in myocardial blood flow or oxygen delivery among groups; however, at 45 min of ischemia, the activation of AMPK was significantly less in NTG (77 +/- 12% vs. nonischemic myocardium) and 8-Br-cGMP (104 +/- 13%), compared with control (167 +/- 17%). Similarly, GLUT-4 translocation was significantly reduced in NTG (74 +/- 7%) and 8-Br-cGMP (120 +/- 11%), compared with control (165 +/- 17%). Glucose uptake and lactate output were 30% and 60% lower in NTG compared with control. Inhibition of NO synthesis stimulated glucose oxidation (67% increase compared with control) but did not affect AMPK phosphorylation, GLUT-4 translocation and glucose uptake. Contractile function in the ischemic region was significantly improved by NTG and L-nitro-argininemethylester. In conclusion, in ischemic myocardium an NO donor inhibits glucose uptake and lactate production via a reduction in AMPK stimulation of GLUT-4 translocation, revealing a mechanism of metabolic modulation and myocardial protection activated by NO donors.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Biao
authors.initials: B
authors.lastname: Lei
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuo
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Labinskyy
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Anna
authors.initials: A
authors.lastname: Ahn
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: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001692:Biological Transport; D001706:Biopsy; D002462:Cell Membrane / Q000378:metabolism; D003331:Coronary Vessels / Q000473:pathology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004285:Dogs; D005947:Glucose / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D007773:Lactates / Q000378:metabolism*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D017202:Myocardial Ischemia / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011522:Protons; D013347:Subcellular Fractions; D013997:Time Factors
chemical_list: D007773:Lactates; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D011522:Protons; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D006152:Cyclic GMP; D005947:Glucose; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester