Interactions of tissue-type plasminogen activator with plasma inhibitors and their pharmacologic implications.
To delineate interactions of infused tissue-type plasminogen activator (t-PA) with inhibitors in plasma and their impact on fibrinolytic activity, serial plasma samples from patients with acute myocardial infarction and from normal rabbits given infusions of t-PA were assayed for t-PA antigen, activity of "fast acting" plasminogen activator inhibitor (PAI-1), and the presence and nature of t-PA-inhibitor complexes. In patients, endogenous t-PA circulated predominantly as a 100 kilodalton (kDa) complex with PAI-1, as verified by immunoprecipitation. During infusions, t-PA circulated not only as free t-PA (55 kDa) but also in complexes with PAI-1 (100 kDa), alpha 2-antiplasmin (110 kDa), and C1-esterase inhibitor (170 kDa). After termination of infusions, levels of free t-PA declined, while inhibitor complexes remained prominent. Free PAI-1 activity, assayed spectrophotometrically, was markedly elevated in the 24 hr interval after infusion of t-PA in 47% of patients with infarction. The specific activity of t-PA during infusions was 0.4 IU/ng or greater. However, during the 3 hr interval after infusions in patients, specific activity declined in association with prominence of t-PA complexes, predominantly with PAI-1. Infusions of t-PA in normal rabbits did not result in reactive increases in PAI-1 activity or in the t-PA-PAI-1 complex. After infusions, t-PA was associated predominantly with alpha 2-antiplasmin and C1-esterase inhibitor rather than PAI-1. t-PA inhibitor complexes were seen despite immediate acidification of whole blood, indicating that they were present in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
D000368:Aged; D000818:Animals; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D005260:Female; D005342:Fibrinolysis; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy*; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors; D015849:Plasminogen Inactivators; D011817:Rabbits; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000378:metabolism
D003174:Complement C1 Inactivator Proteins; D006023:Glycoproteins; D015849:Plasminogen Inactivators; D000979:alpha-2-Antiplasmin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator