REGULATION OF LOCAL TISSUE-TYPE PLASMINOGEN-ACTIVATOR RELEASE BY ENDOTHELIUM-DEPENDENT AND ENDOTHELIUM-INDEPENDENT AGONISTS IN HUMAN VASCULATURE

Objectives. This study sought to define the local regulation of vascul ar tissue type plasminogen activator (t-PA) release. Background. The v ascular endothelium, through the production of t-PA and plasminogen ac tivator inhibitor (PAI-1), is an important regulator of fibrinolysis. Plasma t-PA levels increase in response to adrenergic stimulation; how ever, it is unclear whether this increase is the result of systemic re flex responses or direct effects on the vascular endothelium. Methods. Forearm blood flow dose responses were generated to low doses of agon ist infused directly into the brachial artery in 15 normotensive men ( mean [+/- SE] age 28.9 +/- 2.2 years). Simultaneous arterial and venou s blood samples were drawn at baseline and in response to the intraart erial administration of isoproterenol (400 ng/min), methacholine (8 mu g/min) and sodium nitroprusside (SNP) (8 mu g/min). PAI-1 and t-PA an tigen levels were measured by enzyme-linked immunosorbent assay, and t he net release across the forearm was calculated. Results. Forearm pla sma flow increased significantly from baseline (1.4 +/- 0.2 ml/100 ml per min) after administration of isoproterenol, methacholine and SNP ( 9.7 +/- 1.9, 8.7 +/- 1.9 and 6.7 +/- 1.1 ml/100 ml per min, respective ly) (p < 0.001 by analysis of variance). Baseline net t-PA release (0. 7 +/- 0.3 ng/100 ml per min) increased significantly after administrat ion of isoproterenol (26.2 +/- 11.6 ng/100 ml per min, p = 0.005) and methacholine (15.3 +/- 5.5 ng/100 ml per min, p = 0.001) but not after administration of SNP (1.8 +/- 2.2 ng/100 ml per min, p = 0.84). Ther e was no net release of PAI-1 across the vascular bed. Conclusions. Ma rked, rapid local t-PA release occurred in response to isoproterenol, a beta adrenoceptor agonist, and methacholine, an endothelium dependen t nitric oxide agonist, in the human forearm, This effect was selectiv e and independent of the effects of shear stress due to increased flow because SNP induced similar increases in forearm blood flow without a ffecting t-PA release. Vascular t-PA release may be a potentially valu able tool for evaluating endothelial function in diseases associated w ith increased risk of thrombosis. (C) 1998 by the American College of Cardiology.