title: High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury.
abstract: BACKGROUND
  The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury.
  
  
  RESULTS
  Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5x10(-6) mol/L i.c.) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (Delta dP/dtmax, -878+/-586 versus -1956+/-351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3+/-5.3% versus 5.1+/-0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (-78.4+/-9.3% versus -71.2+/-13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740+/-58 nmol/g; ischemia, 947+/-55 nmol/g; ischemia plus FA, 1332+/-101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124+/-280 cpm/mg FA versus 5898+/-474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8+/-1.2% versus 60.3+/-4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA.
  
  
  CONCLUSIONS
  FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.
authors: Johns Hopkins Medical Institutions, Division of Cardiology, Baltimore, MD 21205, USA.
authors: An L
authors: AL
authors: Moens
authors: Hunter C
authors: HC
authors: Champion
authors: Marc J
authors: MJ
authors: Claeys
authors: Barbara
authors: B
authors: Tavazzi
authors: Pawel M
authors: PM
authors: Kaminski
authors: Michael S
authors: MS
authors: Wolin
authors: Dirk J
authors: DJ
authors: Borgonjon
authors: Luc
authors: L
authors: Van Nassauw
authors: Azeb
authors: A
authors: Haile
authors: Muz
authors: M
authors: Zviman
authors: Djahida
authors: D
authors: Bedja
authors: Floris L
authors: FL
authors: Wuyts
authors: Rebecca S
authors: RS
authors: Elsaesser
authors: Paul
authors: P
authors: Cos
authors: Kathy L
authors: KL
authors: Gabrielson
authors: Giuseppe
authors: G
authors: Lazzarino
authors: Nazareno
authors: N
authors: Paolocci
authors: Jean-Pierre
authors: JP
authors: Timmermans
authors: Christiaan J
authors: CJ
authors: Vrints
authors: David A
authors: DA
authors: Kass
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054059:Coronary Occlusion / Q000188:drug therapy* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020138:Hyperhomocysteinemia / Q000188:drug therapy; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D011292:Premedication; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D011355:Prodrugs; D011687:Purines; D013481:Superoxides; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005492:Folic Acid; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat