Bradykinin receptor antagonism and endothelial tissue plasminogen activator release in humans.
OBJECTIVE
We sought to assess pharmacodynamic responses to the bradykinin antagonist B9340 and to determine the contribution of the endothelial bradykinin receptor to stimulated tissue plasminogen activator (t-PA) release in humans.


RESULTS
Bilateral forearm blood flow and plasma fibrinolytic variables were measured in 8 volunteers during 100 minutes of intrabrachial infusions of saline placebo, B9340 at 4.5 nmol/min, or B9340 at 13.5 nmol/min. On each occasion, intra-arterial bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min) were coinfused for 10 minutes at each dose. To assess the onset and offset of action, 6 additional subjects on 2 occasions received intra-arterial bradykinin (100 pmol/min) for 60 minutes with a coinfusion of either saline placebo or B9340 (13.5 nmol/min) for 12 minutes. During placebo infusion, bradykinin and substance P caused dose-dependent vasodilatation in the infused forearm (P<0.001). B9340 caused a dose-dependent inhibition of bradykinin-induced forearm vasodilatation and t-PA release (P<0.001) without affecting substance P-induced vasodilatation or t-PA release (P=NS). B9340 caused a reversible inhibition of bradykinin-induced vasodilatation (P<0.001) with a rapid onset and offset of action.


CONCLUSIONS
B9340 is a potent, reversible, and selective competitive receptor antagonist of bradykinin-induced vasodilatation and t-PA release in humans.
Witherow
Fraser N
FN
Cardiovascular Research, University of Edinburgh, University of Edinburgh, Royal Infirmary of Edinburgh, UK.
Dawson
Pamela
P
Ludlam
Christopher A
CA
Webb
David J
DJ
Fox
Keith A A
KA
Newby
David E
DE
D000328:Adult; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D012039:Regional Blood Flow / Q000187:drug effects; D012107:Research Design; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
C098525:B 9340; D065168:Bradykinin Receptor Antagonists; D010959:Tissue Plasminogen Activator; D001920:Bradykinin