STIMULATION OF PLASMINOGEN-ACTIVATOR INHIBITOR INVIVO BY INFUSION OF ANGIOTENSIN-II - EVIDENCE OF A POTENTIAL INTERACTION BETWEEN THE RENIN-ANGIOTENSIN SYSTEM AND FIBRINOLYTIC FUNCTION

Background. Recent clinical trial data indicate that the use of angiot ensin converting enzyme (ACE) inhibitors among patients with left vent ricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function. Methods and Resul ts. In four normotensive subjects and six hypertensive patients, we in vestigated whether infusion of angiotensin II (Ang II) affected circul ating levels of plasminogen activator inhibitor-1 (PAI-1), the most im portant physiological inhibitor of tissue-type plasminogen activator ( t-PA). Overall, mean levels of PAI-1 antigen increased significantly f rom 20.1 ng/mL before Ang II infusion to 36.0 ng/mL at the end of Ang II infusion (p = 0.008), whereas no change in PAI-1 was observed for c ontrol subjects infused with 5% dextrose (p=0.46). Among the normotens ive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng.kg-1.min-1, mean PAI-1 levels increased sequentially from 14 .7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p < 0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng.kg-1.min-1, PAI-1 levels increased from 23 .7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p=0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang I I appeared to have little effect on circulating levels of t-PA antigen . Conclusions. These in vivo data suggest that infusion of Ang 11 resu lts in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotens in system and thrombotic risk.