title: Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation.
abstract: BACKGROUND
  The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy.
  
  
  OBJECTIVE
  We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation.
  
  
  METHODS
  To study the effect on these 2 end-points of inhibiting eNOS with intracoronary L-nitro arginine methyl ester (L-NAME; 1 mg/kg/day), infused with an osmotic pump for 30 days, we used a porcine model of heterotopic heart transplantation with pre-operative immunologic typing, to permit slow rejection without the need for immunosuppression. The endothelium-dependent relaxations of allografted coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump, and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. We evaluated intimal thickening using a semi-quantitative scale (0-4+ grading).
  
  
  RESULTS
  A significant decrease in relaxations to serotonin (5-HT) occurred in allografted arteries infused directly with L-NAME compared with allografted arteries from swine receiving 5-HT, and relaxations in the latter were decreased compared with those of swine receiving the vehicle and native coronary arteries (p < 0.05). We found no significant differences in endothelium-dependent relaxations to bradykinin among coronary rings from all groups. We observed a significant increase in the prevalence and severity of intimal thickening in allografted coronary arteries infused with L-NAME compared with allografts not infused (p < 0.05), which had significantly more intimal thickening compared with native coronary arteries (p < 0.05).
  
  
  CONCLUSIONS
  These results demonstrate that inhibiting the NO pathway worsens the endothelial dysfunction caused by rejection after heart transplantation and accelerates the intimal thickening process, leading to graft coronary vasculopathy. Strategies designed to preserve endothelial integrity and function of the endothelial NO pathway should be used to prevent graft coronary vasculopathy.
authors.affiliation: Department of Surgery, Montreal Heart Institute, Montréal, Québec, Canada.
authors.forename: Louis P
authors.initials: LP
authors.lastname: Perrault
authors.forename: Olivier
authors.initials: O
authors.lastname: Malo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bidouard
authors.forename: Nicole
authors.initials: N
authors.lastname: Villeneuve
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vilaine
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000818:Animals; D003324:Coronary Artery Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D016027:Heart Transplantation / Q000009:adverse effects*; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007263:Infusions, Parenteral; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester