Direct vascular effects of protease-activated receptor type 1 agonism in vivo in humans.
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.


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.
Gudmundsdóttir
Ingibjörg J
IJ
Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. Ingibjorg.Gudmunds@ed.ac.uk
Megson
Ian L
IL
Kell
Jillian S
JS
Ludlam
Christopher A
CA
Fox
Keith A A
KA
Webb
David J
DJ
Newby
David E
DE
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000328:Adult; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology*; D002320:Cardiovascular Physiological Phenomena; D005260:Female; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D044463:Receptor, PAR-1 / Q000819:agonists* / Q000502:physiology*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology; D013917:Thrombin / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014841:von Willebrand Factor / Q000032:analysis
D009842:Oligopeptides; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D014662:Vasoconstrictor Agents; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; C082835:thrombin receptor peptide (42-47); D014841:von Willebrand Factor; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D010959:Tissue Plasminogen Activator