Methysergide attenuates leukocyte-independent plasma extravasation during endotoxemia.
OBJECTIVE
During endotoxemia, the early endothelial damage has been shown to be leukocyte independent. Therefore, it was the aim of our study to investigate the role of serotonin in mediating leukocyte-independent microvascular permeability during endotoxemia. Microvascular permeability was determined after inhibition of the L-selectin mediated leukocyte adherence by fucoidin and after inhibition of serotonin effects by the serotonin (5HT)-receptor antagonist methysergide.


METHODS
In male Wistar rats, leukocyte rolling, leukocyte adherence, and macromolecular leakage were determined in mesenteric postcapillary venules using intravital microscopy. After pretreatment with the serotonin-receptor antagonist methysergide, animals in the FUCO/ETX/5HT-ANT group received a continuous infusion of endotoxin. Animals in the FUCO/ETX group underwent the same procedure but received saline 0.9% instead of methysergide. In both groups, leukocyte adherence was prevented by administration of fucoidin. Animals in the saline group received volume-equivalent saline 0.9%.


RESULTS
In the endotoxin-challenged groups, fucoidin prevented leukocyte rolling and reduced leukocyte adherence to values comparable to saline group. In the FUCO/ETX group, macromolecular leakage increased significantly, starting at 60 minutes. Values in the saline group increased slightly, being significant at 120 minutes, whereas vascular permeability remained unchanged in the FUCO/ETX/5HT-ANT group. Differences in macromolecular leakage between the FUCO/ETX-group versus the FUCO/ETX/5HT-ANT group and the saline group were significant at 120 minutes. Differences in macromolecular leakage between the FUCO/ETX/5HT-ANT group and the saline group were not significant.


CONCLUSIONS
The leukocyte-independent endothelial damage during early endotoxemia can be inhibited efficiently by the 5-HT-receptor antagonist methysergide, indicating that serotonin plays an important role in that pathophysiology.
Walther
A
A
Department of Anesthesiology, University of Heidelberg, Heidelberg, Germany.
Yilmaz
N
N
Schmidt
W
W
Bach
A
A
Gebhard
M M
MM
Martin
E
E
Schmidt
H
H
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D019446:Endotoxemia / Q000503:physiopathology*; D006439:Hemodynamics; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D008784:Methysergide / Q000494:pharmacology*; D010949:Plasma / Q000502:physiology*; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*
D011134:Polysaccharides; D012702:Serotonin Antagonists; C007789:fucoidan; D008784:Methysergide