title: An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium.
abstract: The effects on blood flow and plasma fibrinolytic and coagulation parameters of intraarterial substance P, an endothelium dependent vasodilator, and sodium nitroprusside, a control endothelium independent vasodilator, were studied in the human forearm circulation. At subsystemic locally active doses, both substance P (2-8 pmol/min) and sodium nitroprusside (2-8 microg/min) caused dose-dependent vasodilatation (p <0.001 for both) without affecting plasma concentrations of PAI-1, von Willebrand factor antigen or factor VIII:C activity. Substance P caused local increases in t-PA antigen and activity (p <0.001) in the infused arm while sodium nitroprusside did not. At higher doses, substance P increased blood flow and t-PA concentrations in the noninfused arm. We conclude that brief, locally active and subsystemic infusions of intraarterial substance P cause a rapid and substantial local release of t-PA which appear to act via a flow and nitric oxide independent mechanism. This model should provide a useful and selective method of assessing the in vivo capacity of the forearm endothelium to release t-PA acutely.
authors.affiliation: Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Scotland, UK. D.E.Newby@ed.ac.uk
authors.forename: D E
authors.initials: DE
authors.lastname: Newby
authors.forename: R A
authors.initials: RA
authors.lastname: Wright
authors.forename: C A
authors.initials: CA
authors.lastname: Ludlam
authors.forename: K A
authors.initials: KA
authors.lastname: Fox
authors.forename: N A
authors.initials: NA
authors.lastname: Boon
authors.forename: D J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005169:Factor VIII / Q000032:analysis; D005342:Fibrinolysis; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014665:Vasodilator Agents; D014841:von Willebrand Factor; D009599:Nitroprusside; D013373:Substance P; D005169:Factor VIII; D010959:Tissue Plasminogen Activator