Endothelin-1 does not contribute to the release of tissue plasminogen activator in vivo in man

Objectives. Endothelin-l is a potent endothelium-derived vasoconstrictor pe ptide with autocrine and paracrine actions. Tissue plasminogen activator (t -PA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), are also released from the vascular endothelium and play a pivotal role in end ogenous fibrinolysis. We, therefore, examined the effects of exogenous and endogenous endothelin-l on t-PA and PAI-1 release in vivo in man. Design: Open investigative study. Setting: Clinical Research Centre, University of Edinburgh. Subjects: Fourteen healthy male volunteers, Interventions: Unilateral brach ial artery infusions of endothelin-l at 2.5 and 10 pmol/min, and the select ive endothelin type B (ETB) receptor antagonist, BQ-788, at 1 nmol/min. Main outcome measures: Blood flow and plasma fibrinolytic factors were meas ured in both forearms using venous occlusion plethysmography and venous blo od samples withdrawn from the antecubital fossae. Results: Endothelin-l caused a slow onset dose-dependent forearm vasoconstr iction (P<0.001) with a maximal reduction in blood flow of 40 +/- 4% and 63 +/- 3% at 2.5 and 10 pmol/min respectively. BQ-788 also caused a slow onse t reduction in forearm blood flow (P<0.001) reaching a maximum of 21 +/- 3% , However, BQ-788 and endothelin-l did not affect plasma concentrations of t-PA or PAI-1 in the venous effluent of the infused forearm, Conclusions: Despite sustaining significant vasoconstriction, neither endog enous nor exogenous endothelin-l influences the release of t-PA or PAI-I in the forearm vascular bed of man. This suggests that endothelin-l does not provide a major contribution to the regulation of endogenous fibrinolysis i n man. (C) Harcourt Publishers Ltd 1999.