(Circulation. 1999;99:1411-1415.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Endothelial Dysfunction, Impaired Endogenous Fibrinolysis, and Cigarette Smoking
A Mechanism for Arterial Thrombosis and Myocardial Infarction
From the Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital (D.E.N., C.L., D.J.W.), and the Departments of Cardiology (D.E.N., R.A.W., C.L., K.A.A.F., N.A.B.) and Haematology (C.A.L.), University of Edinburgh, Royal Infirmary, Edinburgh, Scotland, UK. Dr Wright is now at the Department of Cardiology, The Ayr Hospital, Ayr, Scotland, UK.
Correspondence to Dr D.E. Newby, Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, Scotland, UK. E-mail d.e.newby{at}ed.ac.uk
Background—Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P–induced tPA release in vivo in humans.
Methods and Results—Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively.
Conclusions—Cigarette smoking causes marked inhibition of substance P–induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity.
Key Words: plasminogen activators • endothelium • endothelium-derived factors • blood flow
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