tPA regulates pulmonary vascular activity through NMDA receptors

Tissue-type plasminogen activator (tPA) is a potent fibrinolytic enzyme used to treat acute coronary artery obstruction. However, tPA has shown limited utility in other disorders caused by thrombotic vascular occlusion, such as pulmonary embolism. We found that tPA caused dose-dependent effects on t...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2011-09, Vol.301 (3), p.L307-L314
Main Authors: Nassar, Taher, Bdeir, Khalil, Yarovoi, Serge, Fanne, Rami Abu, Murciano, Juan-Carlos, Idell, Steven, Allen, Timothy Craig, Cines, Douglas B, Higazi, Abd Al-Roof
Format: Article
Language:English
Subjects:
Animals
Capillary Permeability - drug effects
Endothelium, Vascular - drug effects
Enzymes
Humans
Lungs
Male
Mice
Mice, Inbred C57BL
Phenylephrine - pharmacology
Pulmonary arteries
Pulmonary Artery - drug effects
Pulmonary Artery - physiology
Pulmonary Embolism
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - physiology
T cell receptors
Tissue Plasminogen Activator - administration & dosage
Tissue Plasminogen Activator - pharmacology
Vasoconstriction - drug effects
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Summary:Tissue-type plasminogen activator (tPA) is a potent fibrinolytic enzyme used to treat acute coronary artery obstruction. However, tPA has shown limited utility in other disorders caused by thrombotic vascular occlusion, such as pulmonary embolism. We found that tPA caused dose-dependent effects on the contractility of pulmonary arterial rings that may affect its effectiveness as a thrombolytic agent. At low concentrations (1 nM), tPA stimulated pulmonary vascular contraction in response to phenylephrine, whereas at higher concentrations (20 nM) tPA inhibited pulmonary arterial contractility and promoted pulmonary vascular permeability through an interaction between its "docking site" and N-methyl d-aspartate receptor type 1 (NMDA-R1) expressed by pulmonary arteries. A hexapeptide derived from plasminogen activator inhibitor type 1 that blocked the docking site of tPA, but not its catalytic activity, inhibited its interaction with NMDA-R1, abolished inhibition of pulmonary artery contractility, attenuated vascular permeability, and facilitated fibrinolysis in a murine model of pulmonary embolism. Similar outcomes were seen using a tPA variant that lacks the docking site but retains catalytic activity. These data suggest that it is feasible to attenuate the deleterious extrafibrinolytic effects of tPA and improve its benefit:risk profile in the management of pulmonary embolism.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00429.2010