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.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%.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.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.