title: Vascular arginase contributes to arteriolar endothelial dysfunction in a rat model of hemorrhagic shock.
abstract: BACKGROUND
  Hemorrhagic shock causes hypoperfusion of peripheral tissues and promotes endothelial dysfunction, which may lead to further tissue injury. Trauma increases extrahepatic activity of arginase, an enzyme which competes for l-arginine with nitric oxide synthase, and plays a key role in the development of endothelial dysfunction during aging, hypertension, and diabetes. However, the role of arginase in hemorrhage-induced endothelial dysfunction has not been studied. This study tests the hypothesis that arginase inhibition improves endothelial function after hemorrhage.
  
  
  METHODS
  Male Sprague-Dawley rats were implanted with indwelling arterial catheters for blood pressure measurements and blood removal. Awake animals were subjected to a 45% fixed volume controlled hemorrhage and blood pressure was monitored. Unbled rats served as controls. Skeletal muscle arterioles were isolated 24 hours after hemorrhage and cannulated in a pressure myograph system. To study endothelial function, arterioles were exposed to constant midpoint, but altered endpoint pressures, to establish graded levels of luminal flow and internal diameter was measured.
  
  
  RESULTS
  Hemorrhage lowered mean arterial pressure that spontaneously recovered to 78% and 88% of baseline in 2 hours and 20 hours, respectively. Vascular arginase II and blood glucose levels were elevated, whereas hemoglobin and insulin levels were decreased 24 hours after blood loss. In posthemorrhage arterioles, flow-induced dilation was abolished. Acute in vitro treatment with an inhibitor of arginase, N-hydroxy-nor-l-arginine, restored flow-induced dilation to unbled control levels. Similarly, the arginase and nitric oxide synthase substrate, l-arginine, but not the inactive isomer, d-arginine, restored flow-induced dilation.
  
  
  CONCLUSIONS
  These results indicate that arginase contributes to endothelial dysfunction in resistance vessels after significant hemorrhage.
authors.affiliation: Division of Trauma and Emergency Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Johnson
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.forename: Teresa
authors.initials: T
authors.lastname: Craig
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: John G
authors.initials: JG
authors.lastname: Myers
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Stewart
authors.forename: Fruzsina K
authors.initials: FK
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012771:Shock, Hemorrhagic / Q000201:enzymology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase