Exercise to exhaustion and infusions of isoproterenol and phenylephrine were used to study interactions between plasminogen activator regulation and the control of regional blood flow in 10 healthy males. Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibitor, and TPA/C1-inhibitor complex during the infusions and exercise were used to develop a comprehensive fluid-phase model of the circulatory regulation of fibrinolysis. alpha- and beta-adrenergic agonists increased TPA and UPA in plasma by different mechanisms: Phenylephrine decreased hepatic blood flow and thus clearance while isoproterenol stimulated increased secretion of TPA and UPA. Exercise to exhaustion increased TPA and UPA through a combination of increased secretion and decreased clearance. The time course of UPA and TPA release were similar, but the magnitude of their secretion responses differed. In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1. C1-inhibitor contributed equally with PAI-1 to TPA inhibition when active PAI-1 levels were low (20 to 50 pmol/L) but was less important when active PAI-1 levels were high. We conclude that secretion, inhibition, clearance, and regional blood flow effects must all be taken into account when evaluating changes in plasminogen activator levels.