title: The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine.
abstract: BACKGROUND
  Exercise to exhaustion and infusions of isoproterenol and phenylephrine were used to study interactions between plasminogen activator regulation and the control of regional blood flow in 10 healthy males.
  
  
  RESULTS
  Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibitor, and TPA/C1-inhibitor complex during the infusions and exercise were used to develop a comprehensive fluid-phase model of the circulatory regulation of fibrinolysis. alpha- and beta-adrenergic agonists increased TPA and UPA in plasma by different mechanisms: Phenylephrine decreased hepatic blood flow and thus clearance while isoproterenol stimulated increased secretion of TPA and UPA. Exercise to exhaustion increased TPA and UPA through a combination of increased secretion and decreased clearance. The time course of UPA and TPA release were similar, but the magnitude of their secretion responses differed. In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1. C1-inhibitor contributed equally with PAI-1 to TPA inhibition when active PAI-1 levels were low (20 to 50 pmol/L) but was less important when active PAI-1 levels were high.
  
  
  CONCLUSIONS
  We conclude that secretion, inhibition, clearance, and regional blood flow effects must all be taken into account when evaluating changes in plasminogen activator levels.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle 98195, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Chandler
authors.forename: W C
authors.initials: WC
authors.lastname: Levy
authors.forename: J R
authors.initials: JR
authors.lastname: Stratton
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism / Q000502:physiology; D003198:Computer Simulation; D015444:Exercise / Q000502:physiology*; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D008955:Models, Cardiovascular; D010656:Phenylephrine / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism* / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D003174:Complement C1 Inactivator Proteins; D017395:Plasminogen Activator Inhibitor 1; D010656:Phenylephrine; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D007545:Isoproterenol