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Title: Bradykinin : vasomotor tone and endogenous fibrinolysis in man
Author: Witherow, Fraser N.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Bradykinin is a nonapetide released into plasma during the contact phase of blood coagulation. It has a wide variety of physiological effects including vasodilatation, tissue-type plasminogen activator (t-PA) release, inflammatory mediator, ischaemic preconditioning and vasculogenesis. It is inactivated in plasma by angiotensinconverting enzyme (ACE). Inhibition of this enzyme has been shown to be beneficial in a variety of cardiovascular disorders including heart failure and hypertension, and it is clear that this benefit is not due entirely to reduction in the bioavailability of angiotensin II. We hypothesised that • bradykinin is a vasodilator and stimulates endothelial t-PA release via a specific receptor and that this effect is augmented by ACE inhibition. • in patients with heart failure, bradykinin contributes to peripheral and systemic vascular tone during treatment with ACE inhibition. Forearm blood flow was measured using bilateral forearm plethysmography during intrabrachial drug infusion. Bilateral venous cannulae were inserted to perform blood sampling for estimation of plasma t-PA and plasminogen activator inhibitor 1 (PAI- 1) concentrations. Cardiac output was measured with pulmonary artery catheterisation. The novel peptide bradykinin receptor antagonist, B9340, was used to oppose the effects of bradykinin. Studies were performed in healthy volunteers • to demonstrate the pharmacodynamics of B9340 and to demonstrate the selectivity of B9340 in opposing bradykinin-induced t-PA release. • to demonstrate the safety and tolerability of systemic intravenous B9340 administration. Studies were performed in patients with heart failure • to demonstrate the effect of ACE inhibition on endothelial t-PA release. • to demonstrate the effect of bradykinin antagonism on peripheral and systemic vascular tone in patients treated with ACE inhibition and angiotensin receptor blockade. Results In healthy volunteers • 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. Intravenous systemic B9340 administration inhibited the local bradykinin-induced forearm vasodilatation in a dose-dependent manner. In patients with heart failure • bradykinin and substance P caused dose-dependent vasodilatation and release of t-PA from the infused forearm (p < 0.05). Long-term ACE inhibitor therapy caused an increase in forearm vasodilatation (p < 0.05) and t-PA release (p < 0.001) during bradykinin, but not substance P, infusion. • incremental doses of B9340 caused a dose-dependent reduction in forearm blood flow (p < 0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. • systemic intravenous B9340 administration resulted in greater mean arterial pressure, systemic vascular resistance, pulmonary arterial wedge pressure, and mean pulmonary arterial pressure during ACE inhibitor therapy compared with losartan therapy (p < 0.005, p < 0.07, p < 0.0001, and p < 0.05 respectively) or placebo infusion (p < 0.005 for all). We have shown that bradykinin is a potent vasodilator that stimulates endogenous t-PA release and that these effects are receptor specific and can be blocked by a bradykinin receptor antagonist. We have also shown that bradykinin does not contribute to peripheral or systemic vascular tone in health but does contribute to peripheral and systemic vascular tone in patients with heart failure treated with chronic ACE inhibition. We believe this suggests that many of the beneficial actions of ACE inhibition are mediated through bradykinin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available