Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo.
OBJECTIVE
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 mug/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 <or= 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.
Lang
Ninian N
NN
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. ninian.lang@ed.ac.uk
Gudmundsdóttir
Ingibjörg J
IJ
Boon
Nicholas A
NA
Ludlam
Christopher A
CA
Fox
Keith A
KA
Newby
David E
DE
D000328:Adult; D015415:Biomarkers; D001920:Bradykinin / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside / Q000627:therapeutic use; D010446:Peptide Fragments / Q000627:therapeutic use; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000276:immunology; D010991:Plethysmography; D044463:Receptor, PAR-1 / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000187:drug effects; D012107:Research Design; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use
D015415:Biomarkers; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D014665:Vasodilator Agents; C082835:thrombin receptor peptide (42-47); D009599:Nitroprusside; D010959:Tissue Plasminogen Activator; D001920:Bradykinin