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CLINICAL RESEARCH: VASCULAR DISORDER

Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans

Ingibjörg J. Guðmundsdóttir, MRCP^_*, Ninian N. Lang, MRCP^_*,_*, Nicholas A. Boon, MD, FRCP, Christopher A. Ludlam, PhD, FRCP^_*, David J. Webb, MD, FRCP^_*, Keith A. Fox, FRCP, FESC^_* and David E. Newby, PhD, MRCP^_*

^_* Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
Department of Cardiology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Manuscript received August 17, 2007; revised manuscript received November 21, 2007, accepted December 17, 2007.

^_* Reprint requests and correspondence: Dr. Ninian N. Lang, Centre for Cardiovascular Science, The University of Edinburgh, Chancellor's Building, Edinburgh EH16 4SU, United Kingdom. (Email: ninian.lang{at}ed.ac.uk).

Objectives: The purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1 (PAR-1) activation in vivo in man.

Background: Thrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man.

Methods: Dorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the "NO clamp" (L-N^G-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively.

Results: Endothelial denudation did not affect PAR-1–evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition.

Conclusions: Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.

Abbreviations and Acronyms   ANOVA = analysis of variance   EDHF = endothelium-derived hyperpolarizing factor   L-NMMA = L-NG-monomethyl arginine citrate   NO = nitric oxide   PAI-1 = plasminogen activator inhibitor type 1   PAR = protease-activated receptor   PGI2 = prostacyclin   SNP = sodium nitroprusside   TEA = tetraethylammonium ion   t-PA = tissue-type plasminogen activator   vWF = von Willebrand factor

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