THE CIRCULATORY REGULATION OF TPA AND UPA SECRETION, CLEARANCE, AND INHIBITION DURING EXERCISE AND DURING THE INFUSION OF ISOPROTERENOL ANDPHENYLEPHRINE

Background Exercise to exhaustion and infusions of isoproterenol and p henylephrine were used to study interactions between plasminogen activ ator regulation and the control of regional blood flow in 10 healthy m ales. Methods and Results Experimental measurements of cardiac output, heart rate, tissue plasminogen activator (TPA), urokinase plasminogen activator (UPA), plasminogen activator inhibitor (PAI-1), C1-inhibito r, 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 increa sed TPA and UPA in plasma by different mechanisms: Phenylephrine decre ased hepatic blood flow and thus clearance while isoproterenol stimula ted increased secretion of TPA and UPA. Exercise to exhaustion increas ed TPA and UPA through a combination of increased secretion and decrea sed clearance. The time course of UPA and TPA release were similar, bu t tile magnitude of their secretion responses differed. In vivo, C1-in hibitor bound to TPA at a rate of 553 mol(-1) . s(-1). C1-inhibitor co ntributed equally with PAI-1 to TPA inhibition when active PAI-1 level s were low (20 to 50 pmo/L) but was less important when active PAI-1 l evels were high. Conclusions We conclude that secretion. inhibition, c learance, and regional blood flow effects must all be taken into accou nt when evaluating changes in plasminogen activator levels.