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CLINICAL RESEARCH: VASCULAR MEDICINE

Marked Impairment of Protease-Activated Receptor Type 1-Mediated Vasodilation and Fibrinolysis in Cigarette Smokers

Smoking, Thrombin, and Vascular Responses In Vivo

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

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

Manuscript received January 7, 2008; revised manuscript received March 25, 2008, accepted April 2, 2008.

^_* 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: We sought to test the hypothesis that cigarette smoking adversely alters protease-activated receptor type 1 (PAR-1)-mediated vascular effects in vivo in humans.

Background: Distinct from its role in the coagulation cascade, thrombin exerts its major cellular and cardiovascular actions via PAR-1. The activation of PAR-1 causes endothelium-dependent arterial vasodilation and the release of endogenous fibrinolytic factors.

Methods: Forearm blood flow was measured with venous occlusion plethysmography in 12 cigarette smokers and 12 age- and gender-matched nonsmokers during intrabrachial infusions of PAR-1–activating-peptide (SFLLRN; 5 to 50 nmol/min), bradykinin (100 to 1,000 pmol/min), and sodium nitroprusside (2 to 8 µg/min). Plasma tissue plasminogen activator (t-PA) and plasminogen-activator inhibitor 1 antigen and activity concentrations were measured throughout the experiment.

Results: All agonists caused dose-dependent increases in forearm blood flow (p < 0.0001 for all). Although bradykinin and sodium nitroprusside caused similar vasodilation, SFLLRN-induced vasodilation was attenuated in smokers (p = 0.04). Smokers had modest reductions in bradykinin-induced active t-PA release (reduced by 37%, p = 0.03) and had a marked impairment of SFLLRN-induced t-PA antigen (p = 0.02) and activity (p = 0.006) release, with a 96% reduction in overall net t-PA antigen release. The use of SFLLRN also caused similar (p = NS) increases in inactive plasminogen-activator inhibitor 1 in both smokers and nonsmokers (p 0.002 for both).

Conclusions: Cigarette smoking causes marked impairment of PAR-1–mediated endothelial vasomotor and fibrinolytic function. Relative arterial stasis and near abolition of t-PA release will strongly promote clot propagation and vessel occlusion. These findings suggest a major contribution of impaired endothelial PAR-1 action to the increased atherothrombotic risk of cigarette smokers.

Key Words: smoking • thrombosis • fibrinolysis • blood flow • endothelium

Abbreviations and Acronyms   ANOVA = analysis of variance   EDHF = endothelium derived hyperpolarizing factor   NO = nitric oxide   PAI-1 = plasminogen activator inhibitor type 1   PAR = protease-activated receptor   t-PA = tissue-type plasminogen activator   vWF = von Willebrand factor

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J. Am. Coll. Cardiol. 2008 52: A32. [Full Text] [PDF]