Witherow Fraser N, Dawson Pamela, Ludlam Christopher A, Webb David J, Fox Keith A A, Newby David E
Cardiovascular Research, University of Edinburgh, University of Edinburgh, Royal Infirmary of Edinburgh, UK.
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1667-70. doi: 10.1161/01.ATV.0000087142.99472.F6. Epub 2003 Jul 17.
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.
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.
B9340 is a potent, reversible, and selective competitive receptor antagonist of bradykinin-induced vasodilatation and t-PA release in humans.
我们试图评估对缓激肽拮抗剂B9340的药效学反应，并确定内皮缓激肽受体对人体刺激组织纤溶酶原激活物（t-PA）释放的作用。
在8名志愿者的双侧前臂进行100分钟的肱动脉内输注生理盐水安慰剂、4.5 nmol/min的B9340或13.5 nmol/min的B9340，期间测量双侧前臂血流量和血浆纤溶变量。每次输注时，每种剂量的动脉内缓激肽（30至3000 pmol/min）和P物质（4至16 pmol/min）共输注10分钟。为了评估作用的起效和消退，另外6名受试者在2次实验中接受动脉内缓激肽（100 pmol/min）输注60分钟，并与生理盐水安慰剂或B9340（13.5 nmol/min）共输注12分钟。在安慰剂输注期间，缓激肽和P物质在输注的前臂引起剂量依赖性血管舒张（P<0.001）。B9340引起缓激肽诱导的前臂血管舒张和t-PA释放的剂量依赖性抑制（P<0.001），而不影响P物质诱导的血管舒张或t-PA释放（P=无显著性差异）。B9340引起缓激肽诱导的血管舒张的可逆性抑制（P<0.001），作用起效和消退迅速。
B9340是一种强效、可逆且选择性的竞争性受体拮抗剂，可抑制人体缓激肽诱导的血管舒张和t-PA释放。
