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Title: The role of protease-activated receptor-1 in the human vasculature
Author: Guðmundsdóttir, Ingibjörg Jóna
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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Background: Thrombin is a powerful cardiovascular agonist and a vital link between thrombosis and inflammation. In addition to its role in the coagulation cascade, it directly activates platelets, inflammatory cells, endothelium and vascular smooth muscle. Proteaseactivated receptor-1 (PAR-1) has been proposed as the principal thrombin receptor in man although its actions in vivo have not been defined. The aim of this thesis was to determine the direct vascular actions of PAR-1 agonism in the human venous and arterial circulations. Objectives: The effects of PAR-1 activation on dorsal hand vein diameter were measured by the Aellig technique in healthy volunteers, compared with activation of the trypsin receptor PAR-2, and further assessed in the presence or absence of norepinephrine, the glycoprotein (GP)IIb/IIIa antagonist tirofiban, and endothelial denudation. In the arterial circulation, forearm blood flow was measured by venous occlusion plethysmography. Intra-arterial PAR-1 activating peptide was co-infused with tirofiban, and compared with PAR-2 activation and bradykinin infusion. Platelet-monocyte binding (a sensitive measure of platelet activation) and tissue plasminogen activator release (t-PA) were measured throughout. In subsequent studies, effects of inhibition of the endothelium-dependent vasodilators nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarisation factor (EDHF) on PAR-1 activation were assessed, as well as comparing the effects of PAR-1 activation in smokers and non-smokers. Methods: Activation of PAR-1 caused dose-dependent venoconstriction (P < 0.001) that was unaffected by norepinephrine or tirofiban co-infusion and endothelial denudation. In forearm resistance vessels, arterial PAR-1 activation increased forearm blood flow (P < 0.001), t-PA release (P < 0.001) and platelet-monocyte binding (PO.OOOl). Activation of PAR-2 caused venous (P < 0.001) and arterial (P < 0.01) dilatation without t-PA release or platelet activation. Although blockade of prostacyclin production had no effect, PAR-1 induced arterial vasodilatation was attenuated by inhibition of NO synthesis (PO.OOOl) and EDHF (PO.05), and abolished by their combination (PO.Ol). Smokers had impaired PAR-1 mediated vasodilatation and t-PA release. Results: We have, for the first time, demonstrated that PAR-1 agonism in vivo in man causes arterial dilatation, venoconstriction, platelet activation and t-PA release that is mediated through endothelium-dependent and independent pathways, and impaired in smokers. These unique and contrasting effects are of major physiological relevance to the regulation and resolution of intravascular thrombosis. These findings have implications for the development and therapeutic use of thrombin receptor antagonists and direct thrombin inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available