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Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans.

Abstract：

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.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Gudmundsdóttir IJ,Lang NN,Boon NA,Ludlam CA,Webb DJ,Fox KA,Newby DE

doi

10.1016/j.jacc.2007.12.047

subject

Has Abstract

pub_date

2008-05-06 00:00:00

pages

1749-56

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(08)00694-3

journal_volume

pub_type

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Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans.