Selective serotonin-receptor antagonism and microcirculatory alterations during experimental endotoxemia

Background. Endothelial damage contributes greatly to the high mortality in septic shock. Recent experiments from our laboratory with the GP IIb/ IIIa-antagonist abciximab describe a dominating role for platelets as mediators of endothelial dysfunction during endotoxemia. In many inflammatory conditions, serotonin is released by activated platelets into the circulation. Therefore, we investigated the effects of serotonin-receptor antagonism using methysergide and ketanserin (KET) on microcirculatory alterations during endotoxemia. Material and methods. In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline 60 and 120 min after the start of the experiment. The experiments were separated into a pretreatment and a posttreatment part. In each part, rats were randomized into four groups. Animals In the treatment groups received either methysergide (MET) or KET. Endotoxin-challenged animals without MET or KET treatment served as a control group. Results. Pretreatment as well as posttreatment with MET or KET is effective in maintaining venular wall shear rate, reducing leukocyte-endothelial interaction, and reducing macromolecular efflux during endotoxemia. Conclusions. Serotonin-receptor antagonism with MET or KET represents a promising new therapy option to restore the microcirculation during endotoxemia. (c) 2007 Elsevier Inc. All rights reserved.