Endogenous tissue-type plasminogen activator andendothelial function in vivo. A clinical perspective
Abstract
Endogenous fibrinolysis is initiated by the glycoprotein tissue-type plasminogen activator (tPA), which is released from the vascular endothelium. Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of tPA. There is limited knowledge available on the local kinetics of active tPA in vivo, and no non-invasive method available for estimation of the endothelial tPA-release capacity in man. Many cardiovascular risk factors impair endothelial function and/or the capacity for tPA release, which may reduce the defense against formation of arterial clots. However, knowledge about the impact of age, coronary artery disease (CAD) and chronic heart failure (CHF) on tPA release is limited. The impact of these factors on stimulated tPA release was studied using the perfused-forearm model and different stimuli. The tPA response to exercise and its relationship with invasively determined endothelial tPA release was also investigated. The majority of tPA acutely released from the endothelium was found to remain free and active during its transit through the forearm tissue, in spite of great molar excess of PAI-1 over tPA. With increasing endothelial release rates, the relative increase in active tPA was proportionally greater than the increase in tPA protein. Neither plasma tPA nor PAI-1 levels at rest determined the capacity for endothelial tPA release. In healthy individuals, tPA release was up-regulated with age, while age had no impact on endothelium-dependent vasodilation. Optimally treated patients with CAD complicated by CHF had preserved capacity for tPA release and vasodilation. The exercise-induced tPA response could be used to predict the capacity for local desmopressin-stimulated release of tPA. This model may serve as a non-invasive method to investigate endothelial tPA release.In conclusion, the local availability of active tPA on the organ level is mainly determined by the release of tPA from the endothelium rather than the inflow of tPA or its inhibitors. The capacity for stimulated endogenous tPA release increases with age. Optimally treated patients with CAD and CHF have preserved vasomotor and fibrinolytic endothelial functions. Exercise-induced rise in venous plasma tPA is reproducible and may be used to non-invasively determine the capacity for endothelial tPA release in humans.
University
Göteborgs universitet/University of Gothenburg
Institution
Department of Medicine
Avdelningen för internmedicin
Disputation
Centralklinikens aula, Sahlgrenska universitetssjukhus/Östra, kl. 13.00
Date of defence
2004-02-06
View/ Open
Date
2004Author
Gudnason, Thorarinn 1964-
Keywords
tissue-type plasminogen activator
endothelial function
age
vasodilation
chronic heart failure
coronary artery disease
local regulation
perfused-forearm model
Publication type
Doctoral thesis
ISBN
91-628-5943-9