INHIBITION OF ONE-CHAIN AND 2-CHAIN FORMS OF HUMAN TISSUE-TYPE PLASMINOGEN-ACTIVATOR BY THE FAST-ACTING INHIBITOR OF PLASMINOGEN-ACTIVATOR INVITRO AND INVIVO

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  • 1 July 1986
    • journal article
    • research article
    • Vol. 108  (1) , 53-59
Abstract
The inhibition of one-chain and two-chain molecular forms of human tissue-type plasminogen activator (t-PA) by the fast-acting inhibitor of plasminogen activator (PA-inhibitor) present in plasma was studied in vitro and in vivo in rabbits. In vitro, both one-chain and two-chain forms of t-PA were neutralized very rapidly in rabbit plasma with high levels of PA-inhibitor. The rate constant of the interaction between two-chain t-PA and PA-inhibitor was estimated to be 3.107 L/mol/sec. The presence of CNBr-digested fibrinogen, which mimics the effect of fibrin on the activation of plasminogen by t-PA, did not influence the rate constant. Moreover, PA-inhibitor-rich plasma inhibited in a very similar way in vitro thrombolysis by one-chain or two-chain t-PA incorporated into the clot. Injection of one-chain or two-chain t-PA into rabbits with increased levels of PA-inhibitor, induced by endotoxin, resulted in very rapid inhibition of t-PA activity. Within 20 seconds after injection, no residual free t-PA could be demonstrated. Gel filtration analysis showed that the disappearance of t-PA activity was associated with the generation of t-PA-PA-inhibitor complex with an apparent Mr of 100,000. This enzyme-inhibitor complex, like free t-PA, was cleared from the circulation with a half-life of .apprx. 2 minutes, mainly via the liver. It is concluded that PA-inhibitor neutralizes one-chain and two-chain molecular forms of t-PA in plasma at very similar rates, both in vitro and in vivo. In this respect, the PA-inhibitor of plasma is different from that isolated from placenta tissue.