on July 17, 2003
Published online before print July 17, 2003, doi: 10.1161/01.ATV.0000087142.99472.F6
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Submitted on May 22, 2003
Accepted on July 2, 2003
Bradykinin Receptor Antagonism and Endothelial Tissue Plasminogen Activator Release in Humans
Fraser N. Witherow ;
From Cardiovascular Research (F.N.W., K.A.A.F., D.E.N.) and the Department of Haematology (P.D., C.A.L.), University of Edinburgh, Royal Infirmary of Edinburgh; and the Department of Clinical Pharmacology (D.J.W.), University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
* To whom correspondence should be addressed. E-mail: d.e.newby{at}ed.ac.uk.
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.
Methods and 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.
Key words: bradykinin • blood flow • tissue plasminogen activator • receptor antagonism
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