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(Circulation. 2006;114:1625-1632.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans

Ingibjörg J. Gudmundsdóttir, MD; Ian L. Megson, PhD; Jillian S. Kell, BSc; Christopher A. Ludlam, MD; Keith A.A. Fox, MD; David J. Webb, MD; David E. Newby, MD, PhD

From the Centre for Cardiovascular Science, University of Edinburgh, Edinburgh (I.J.G., J.S.K., C.A.L., K.A.A.F., D.J.W., D.E.N.), and Free Radical Research Facility, UHI Millennium Institute, Inverness (I.L.M.), UK.

Reprint requests to Dr Ingibjörg J. Gudmundsdóttir, Centre for Cardiovascular Science, University of Edinburgh, Chancellor’s Bldg, Royal Infirmary, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. E-mail Ingibjorg.Gudmunds{at}ed.ac.uk

Received May 5, 2006; revision received August 5, 2006; accepted August 8, 2006.

Background— Protease-activated receptor type 1 (PAR-1) has been proposed as the principal thrombin receptor in humans, although its actions in vivo have not been defined. The aim of the present study was to determine the direct vascular actions of PAR-1 agonism in humans.

Methods and Results— Dorsal hand vein diameter was measured by the Aellig technique in 14 healthy volunteers during local intravenous SFLLRN (PAR-1 agonist; 0.05 to 15 nmol/min) and SLIGKV (PAR-2 agonist; 1.6 to 160 nmol/min) infusions. The venous effects of SFLLRN were further assessed in the presence or absence of norepinephrine or the glycoprotein IIb/IIIa antagonist tirofiban. Forearm blood flow was measured by venous occlusion plethysmography in 16 volunteers during infusion of SFLLRN (1 to 50 nmol/min), SLIGKV (160 to 800 nmol/min), and the endothelium-dependent vasodilator bradykinin (100 to 1000 pmol/min). Platelet-monocyte binding (a sensitive measure of platelet activation) and plasma tissue plasminogen activator (tPA), plasminogen-activator inhibitor 1, and von Willebrand factor concentrations were measured at intervals throughout the study. SFLLRN caused dose-dependent venoconstriction (P<0.001) that was unaffected by norepinephrine or tirofiban co-infusion. In forearm resistance vessels, SFLLRN increased forearm blood flow (P<0.001), tPA release (P<0.001), and platelet-monocyte binding (P<0.0001) without affecting plasma plasminogen-activator inhibitor 1 or von Willebrand factor concentrations. SLIGKV caused venous (P<0.001) and arterial (P<0.01) dilatation without tPA release.

Conclusions— We have demonstrated that PAR-1 agonism causes platelet activation, venous constriction, arterial dilatation, and tPA release in vivo in humans. These unique and contrasting effects provide important insights into the physiological and pathophysiological role of thrombin in the human venous and arterial circulations.

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