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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 30 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 ~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.
Abbreviations:
LPS (lipopolysaccharide), Mr (relative molecular mass), PA-inhibitor (fast-acting inhibitor of tissue-type plasminogen activator), t-PA (tissue-type plasminogen activator)To read this article in full you will need to make a payment
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Article info
Publication history
Accepted:
April 1,
1986
Received:
May 20,
1985
Footnotes
☆Supported by grants from the Geconcerteerde Onderzoeksactie and from the Nationale Loterij.
Identification
Copyright
© 1986 Published by Elsevier Inc.