Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers

Lang, N. N. , Guðmundsdóttir, I. J., Boon, N. N., Ludlam, C. A., Fox, K. A. and Newby, D. E. (2008) Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers. Journal of the American College of Cardiology, 52(1), pp. 33-39. (doi: 10.1016/j.jacc.2008.04.003) (PMID:18582632)

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Abstract

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.

Item Type:Articles
Additional Information:Support was provided by Bristol-Myers Squibb Cardiovascular Prize Fellowship, United Kingdom (to Dr. Lang), the British Heart Foundation Junior Research Fellowship, United Kingdom (FS/05/028; to Dr. Guðmundsdóttir), and the British Medical Association Lansdell and Lawson Research Grant, United Kingdom.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Newby, Professor David and Lang, Dr Ninian
Authors: Lang, N. N., Guðmundsdóttir, I. J., Boon, N. N., Ludlam, C. A., Fox, K. A., and Newby, D. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier
ISSN:0735-1097
ISSN (Online):1558-3597
Published Online:24 June 2008

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