Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.
1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress.
Bult
H
H
University of Antwerp, Division of Pharmacology, Wilrijk, Belgium.
Heiremans
J J
JJ
Herman
A G
AG
Malcorps
C M
CM
Peeters
F A
FA
D000818:Animals; D001794:Blood Pressure; D003167:Complement Activation; D003182:Complement C5 / Q000378:metabolism; D015936:Complement C5a; D004285:Dogs; D004727:Endothelium / Q000502:physiology; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009929:Organ Size; D011863:Radioimmunoassay; D012701:Serotonin / Q000378:metabolism*; D013931:Thromboxanes / Q000378:metabolism
D003182:Complement C5; D013931:Thromboxanes; D012701:Serotonin; D015936:Complement C5a; D011464:Epoprostenol