An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium.
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.
Newby
D E
DE
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Scotland, UK. D.E.Newby@ed.ac.uk
Wright
R A
RA
Ludlam
C A
CA
Fox
K A
KA
Boon
N A
NA
Webb
D J
DJ
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
D017395:Plasminogen Activator Inhibitor 1; D014665:Vasodilator Agents; D014841:von Willebrand Factor; D009599:Nitroprusside; D013373:Substance P; D005169:Factor VIII; D010959:Tissue Plasminogen Activator