Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo

J Am Coll Cardiol. 2008 Jul 1;52(1):33-9. doi: 10.1016/j.jacc.2008.04.003.

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 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.

MeSH terms

  • Adult
  • Biomarkers
  • Bradykinin / therapeutic use
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Female
  • Fibrinolysis* / drug effects
  • Forearm / blood supply
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Middle Aged
  • Nitroprusside / therapeutic use
  • Peptide Fragments / therapeutic use
  • Plasminogen Activator Inhibitor 1 / analysis
  • Plasminogen Activator Inhibitor 1 / immunology
  • Plethysmography
  • Receptor, PAR-1 / metabolism*
  • Receptors, Thrombin / drug effects
  • Research Design
  • Risk Factors
  • Smoking / adverse effects*
  • Smoking / blood
  • Smoking / metabolism*
  • Smoking / physiopathology
  • Thrombosis / blood
  • Thrombosis / etiology*
  • Thrombosis / metabolism
  • Thrombosis / physiopathology
  • Thrombosis / prevention & control
  • Tissue Plasminogen Activator / blood
  • Tissue Plasminogen Activator / metabolism*
  • Vasodilation* / drug effects
  • Vasodilator Agents / therapeutic use

Substances

  • Biomarkers
  • Peptide Fragments
  • Plasminogen Activator Inhibitor 1
  • Receptor, PAR-1
  • Receptors, Thrombin
  • Vasodilator Agents
  • thrombin receptor peptide (42-47)
  • Nitroprusside
  • Tissue Plasminogen Activator
  • Bradykinin