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

Abstract

Objectives: Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide 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 endogenous fibrinolysis. We, therefore, examined the effects of exogenous and endogenous endothelin-1 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 brachial artery infusions of endothelin-1 at 2.5 and 10 pmol/min, and the selective endothelin type B (ET B) receptor antagonist, BQ-788, at 1 nmol/min. Main outcome measures: Blood, flow and plasma fibrinolytic factors were measured in both forearms using venous occlusion plethysmography and venous blood samples withdrawn from the antecubital fossae. Results: Endothelin-1 caused a slow onset dose-dependent forearm vasoconstriction ( 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 onset reduction in forearm blood flow ( P<0.001) reaching a maximum of 21 ± 3%. However, BQ-788 and endothelin-1 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 endogenous nor exogenous endothelin-1 influences the release of t-PA or PAI-1 in the forearm vascular bed of man. This suggests that endothelin-1 does not provide a major contribution to the regulation of endogenous fibrinolysis in man.