A kinetic model of the circulatory regulation of tissue plasminogen activator during exercise, epinephrine infusion, and endurance training.
A computer simulation of the circulatory system was used to kinetically model secretion, inhibition, and clearance of tissue plasminogen activator (t-PA) during three different processes that increase active t-PA levels: epinephrine infusion, exercise, and endurance training. Infusion of epinephrine stimulated an increase in t-PA secretion that was proportional to the plasma epinephrine concentration. In addition, epinephrine infusion increased hepatic blood flow and t-PA clearance, thus slowing the increase of plasma t-PA levels. During exercise, t-PA levels increased due both to increased t-PA secretion and to decreased clearance secondary to reduced hepatic blood flow. The increase in t-PA secretion during exercise was directly proportional to the epinephrine concentration in blood with the same ratio of t-PA secretion to epinephrine as found during epinephrine infusion, suggesting that increased plasma epinephrine during exercise was the primary stimulus for t-PA secretion. Lastly, the simulation predicted that 6 months of endurance training produced a decrease in resting plasminogen activator inhibitor type 1 (PAI-1) secretion, resulting in less t-PA inhibition and an overall increase in active t-PA after training. Accurate analysis of the regulation of active t-PA levels in blood required simultaneous modeling of t-PA and PAI-1 secretion, hepatic clearance, and inhibition of t-PA by PAI-1.
Chandler
W L
WL
Department of Laboratory Medicine, University of Washington, Seattle 98195.
Levy
W C
WC
Veith
R C
RC
Stratton
J R
JR
D003198:Computer Simulation; D004837:Epinephrine / Q000097:blood / Q000494:pharmacology*; D015444:Exercise / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008102:Liver Circulation / Q000187:drug effects; D008954:Models, Biological; D010807:Physical Endurance / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator; D004837:Epinephrine