Bradykinin Receptor Antagonism and Endothelial Tissue Plasminogen Activator Release in Humans

Abstract

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 (PϽ0.001). B9340 caused a dose-dependent inhibition of bradykinin-induced forearm vasodilatation and t-PA release (PϽ0.001) without affecting substance P-induced vasodilatation or t-PA release (PϭNS). B9340 caused a reversible inhibition of bradykinin-induced vasodilatation (PϽ0.001) with a rapid onset and offset of action. radykinin is an endogenous, vasoactive, nonapeptide mediator involved in many physiologic processes. It is cleaved from high-molecular-weight kininogen during the contact phase of blood coagulation, 1 resulting in endothelium-dependent vasodilatation and stimulation of tissue plasminogen activator (t-PA) release from human endothelial cells. 2 It has a brief duration of action (plasma half-life of 15 to 30 seconds) owing to its rapid degradation by several enzymes, principally angiotensin-converting enzyme (ACE). Bradykinin appears to contribute to the vascular effects of ACE inhibitor therapy in hypertension 3 and heart failure. 4 Bradykinin receptor antagonists have been developed from peptide analogues of bradykinin. The most widely used bradykinin receptor antagonist is HOE-140, or icatibant, which demonstrates high selectivity for the B 2 receptor. Recently, a third-generation synthetic peptide antagonist of bradykinin, B9340, has been synthesized. It has a similar chemical structure to HOE-140 and differs by replacement of the ␣-(2-indanyl)glycine at position 7 of the molecule with a tetrahydroisoquiniline-3-carboxylic acid moiety. In comparison with HOE-140, B9340 retains similar potency of inhibition at the bradykinin B 2 receptor (median inhibitory concentration [IC 50 ] of 0.158 nmol/L for both) but has greater inhibition at the B 1 receptor (IC 50 of 1000 nmol/L and 7.9 nmol/L for HOE-140 and B9340, respectively). 5 The purpose of this study was to assess pharmacodynamic responses to the novel bradykinin antagonist B9340 and to determine the contribution of the endothelial bradykinin receptor to stimulated t-PA release in vivo in humans. To assess the selectivity of B9340, we compared the vasomotor and fibrinolytic responses of bradykinin with those of s...

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

“…13 The major new finding of the present study is related to the mechanisms underlying bradykinin-stimulated tPA release in humans. As reported previously, 24,25 bradykinin induces a significant increase of tPA release in healthy subjects. This effect is specific and not flow dependent, because it was not detected when infusion of the endothelium-independent relaxing compound sodium nitroprusside was used in the same experimental conditions.…”

Endothelium-Derived Hyperpolarizing Factor Mediates Bradykinin-Stimulated Tissue Plasminogen Activator Release in Humans

“…16, 17, 22 We now demonstrate that in addition to stimulating vasodilation, bradykinin stimulates t-PA release that is completely abolished by K + ca channel inhibition. 6, 34 …”

Influence of a Novel Inhibitor (UM8190) of Prolylcarboxypeptidase (PRCP) on Appetite and Thrombosis

“…In the FeCl3-induced carotid artery thrombosis model PRCP gt g mice displayed a shortened time to arterial occlusion, and enhanced plasma thrombin generation, consistent with a hypercoagulable state. Since BK causes an induction of tissue plasminogen activator (tPA, a clot dissolving enzyme) [56], it is also tempting to speculate that α-kallikrein through BK generation protects normal endothelial cell morphology against thrombotic disorders by promoting tPA generation. However, whether PRCP, an upstream regulator of kallikrein is involved in the generation of tPA under pathologic conditions in in vitro and animal remains unknown.…”