Time- and dose-related regional fluxes of tissue-type plasminogen activator in anesthetized endotoxemic pigs.
BACKGROUND
Acute endotoxinemia elicits an early fibrinolytic response. This study analyzes the effects of the dose and duration of endotoxin infusion on arterial levels of tissue-type plasminogen activator (tPA) and pulmonary, mesenteric and hepatic plasma tPA fluxes.


METHODS
Pigs were randomized to receive an acute, high-dose (for 6 h, n=13, high ETX) or a prolonged, low-dose (for 18 h, n=18, low ETX) infusion of endotoxin or saline vehicle alone (for 18 h, n=14, control). All animals were fluid resuscitated to maintain a normodynamic circulation. Systemic and regional blood flows were measured and arterial, pulmonary arterial, portal and hepatic venous blood samples were analyzed to calculate regional net fluxes of tPA. Plasma tumor necrosis factor (TNF-alpha) levels were analyzed.


RESULTS
Mesenteric tPA release and hepatic uptake increased maximally at 1.5 h in ETX groups related to dose. Maximal mesenteric tPA release [high ETX 612 (138-1185) microg/min/kg, low ETX 72 (32-94) microg/min/kg, median+/-interquartile range] and hepatic tPA uptake [high ETX -1549 (-1134 to -2194) microg/min/kg, low ETX -153 (-105 to -307) microg/min/kg] correlated to TNF-alpha levels. Regional tPA fluxes returned to baseline levels at 6 h in both ETX groups and also remained low during sustained low ETX. No changes were observed in control animals.


CONCLUSIONS
Endotoxemia induces an early increase in mesenteric tPA release and hepatic tPA uptake related to the severity of endotoxemia. The time patterns of changes in mesenteric and hepatic tPA fluxes are similar in acute high-dose endotoxemia and sustained low-dose endotoxemia.
Nyberg
A
A
Department of Anaesthesiology and Intensive Care, Sahlgrenska University Hospital, Göteborg, Sweden.
Jakob
S M
SM
Seeman-Lodding
H
H
Porta
F
F
Bracht
H
H
Bischofberger
H
H
Jern
C
C
Takala
J
J
Aneman
A
A
D000771:Anesthesia, Intravenous; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000097:blood* / Q000503:physiopathology; D004926:Escherichia coli; D005260:Female; D005342:Fibrinolysis; D005440:Fluid Therapy; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries; D010949:Plasma; D011651:Pulmonary Artery; D011897:Random Allocation; D034421:Sus scrofa; D013610:Tachycardia / Q000097:blood / Q000209:etiology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D010959:Tissue Plasminogen Activator