title: Arginase depletes plasma l-arginine and decreases pulmonary vascular reserve during experimental pulmonary embolism.
abstract: The experiments test if experimental PE causes red blood cell hemolysis, arginase release and depletion of l-arginine and determine if arginase inhibition preserves l-arginine and improves pulmonary hemodynamics during PE. Experimental PE was induced in male Sprague-Dawley rats by infusing 25 μm microspheres (1.8 million/100 g body wt) in the jugular vein, producing moderate pulmonary hypertension. Pulmonary vascular resistance was estimated from the quotient of the right ventricular peak systolic pressure/cardiac output. Arterial plasma hemoglobin (ELISA), arginase activity (colorimetric assay) and l-arginine (high performance liquid chromatography) were determined. Arginase activity was inhibited by infusion of N-omega-hydroxy-nor-l-arginine (nor-NOHA, 400 mg/kg body wt, i.v.). Values are means ± s.e. Five hours of PE caused red blood cell hemolysis (15-fold increase in plasma hemoglobin) and release of arginase activity (2.7-fold increase). Plasma l-arginine concentration decreased significantly from 250 ± 20.6 to 118 ± 6.0 μmol/L (Control vs. PE) and estimated pulmonary vascular resistance increased 3-fold. Treatment with nor-NOHA prevented the depletion of plasma l-arginine (229 ± 15 μmol/L) and reduced the rise in pulmonary vascular resistance by 40%. In conclusion, experimental PE causes hemolysis, release of arginase activity, depletion of plasma l-arginine and increased estimated pulmonary vascular resistance. Inhibition of arginase activity preserves plasma l-arginine levels and improves estimated resistance, suggesting that the release of arginase during hemolysis contributes to the rise in estimated pulmonary resistance during experimental PE.
authors.affiliation: Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC 28203, USA. jwatts@carolinas.org
authors.forename: John A
authors.initials: JA
authors.lastname: Watts
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gellar
authors.forename: Mary-Beth K
authors.initials: MB
authors.lastname: Fulkerson
authors.forename: Sudeep K
authors.initials: SK
authors.lastname: Das
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kline
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008863:Microspheres; D011652:Pulmonary Circulation / Q000187:drug effects*; D011655:Pulmonary Embolism / Q000097:blood / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D006454:Hemoglobins; C404735:N(omega)-hydroxynorarginine; D019344:Lactic Acid; D001120:Arginine; D001119:Arginase