title: Endothelial dysfunction after arterial thrombosis is ameliorated by L-arginine in combination with thrombolysis.
abstract: OBJECTIVE
  To assess endothelial function after arterial thrombosis creation and after administration of a novel thrombolytic regimen in a new porcine model.
  
  
  METHODS
  Untreated arteries that had undergone thrombosis for 90 minutes were compared to arteries treated with tissue plasminogen activator (tPA, 4 mg) and a combination of tPA and L-arginine (L-arg; 600 mmol/L). External iliac artery luminal diameter was measured with use of duplex ultrasonography. Endothelial-dependent relaxation (EDR) and endothelial-independent relaxation (EIR) were measured with use of acetylcholine chloride (ACh) and sodium nitroprusside (NTP), respectively. Endothelial integrity was confirmed by scanning electron microscopy (SEM). Nitric oxide (NO) levels were determined with use of a chemiluminescent assay of its nitrite/nitrate metabolites (NO(x)).
  
  
  RESULTS
  After thrombosis, EDR was decreased (69% +/- 9.5; ACh = 15 micro g/min; n = 6). EDR remained unchanged after thrombolysis with tPA despite complete dissolution of thrombus (67% +/- 5.7; ACh = 15 micro g/min; n = 5). Thrombolysis with use of tPA coupled with L-arg resulted in an increase in EDR (95% +/- 4.9; ACh = 15 micro g/min; n = 5; P =.007). EIR was preserved in all groups, with uniform response to NTP. SEM analysis revealed intact endothelium in all groups. Local NO(x) levels were diminished after 90 minutes of thrombosis (49.3 micro mol/L vs 40.8 micro mol/L; P =.0002), but increased to 55.7 micro mol/L after thrombolysis with tPA and L-arg (P = NS).
  
  
  CONCLUSIONS
  Thrombus induces arterial dysfunction acutely without altering endothelial integrity. This dysfunction is ameliorated through regional administration of L-arg in combination with standard thrombolytic therapy, which increases local NO levels. This model allows the in-vivo study of thrombosis and alternative thrombolytic regimens. Regional enhancement of NO levels may prove to be an attractive adjunct in thrombolytic therapy.
authors.affiliation: Department of Vascular Surgery, Wilford Hall Medical Center, 2200 Bergquist Drive, Suite 1, Lackland Air Force Base, Texas 78236, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Davis
authors.forename: Delio P
authors.initials: DP
authors.lastname: Ortegon
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Kerby
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
authors.forename: Vikram S
authors.initials: VS
authors.lastname: Kashyap
mesh_terms: D000818:Animals; D001120:Arginine / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D009569:Nitric Oxide / Q000097:blood; D013552:Swine; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D009569:Nitric Oxide; D001120:Arginine; D010959:Tissue Plasminogen Activator