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.
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.
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