Glycoprotein IIB/IIIA-inhibition and microcirculatory alterations during experimental endotoxemia--an intravital microscopic study in the rat.
OBJECTIVE
Endothelial damage during early endotoxemia has been shown to be leukocyte-independent. Platelet-activating factor (PAF) and serotonin-receptor antagonism are known to reduce leukocyte-independent macromolecular leakage significantly, thereby focusing the field of interest to the platelets. We hypothesized that inhibition of the GP IIb/IIIa receptor, using the unspecific GP IIb/IIIa inhibitor abciximab, would reduce leukocyte-independent endothelial damage during early endotoxemia, and furthermore, that inhibition of the GP IIb/IIIa receptor with abciximab might improve microcirculatory disturbances, seen in a leukocyte-dependent animal model during endotoxemia.


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 experiment was divided into two parts. In the first part, we investigated the effects of the GP IIb/IIIa inhibitor abciximab on leukocyte-independent endothelial permeability during endotoxemia. In the second part of the experiment, we focused on the effects of the GP IIb/IIIa inhibitor abciximab on microcirculatory disturbances during endotoxemic states, without a modification of the leukocyte-endothelial interaction, putting the main emphasis again on endothelial permeability.


RESULTS
GP IIb/IIIa inhibition with abciximab resulted in a significant reduction of macromolecular efflux during leukocyte-independent endotoxemia. Both pretreatment with abciximab and post-treatment with abciximab reduced macromolecular leakage during leukocyte-dependent endotoxemia to values comparable to control values, and prevented an increase in leukocyte adherence, that has been reduced to values comparable to control values, too.


CONCLUSIONS
GP IIb/IIIa inhibition, using abciximab, protects against endothelial dysfunction and an increase in leukocyte adherence to the vascular wall during experimental endotoxemia. The protective properties of abciximab on microcirculation seemed to be leukocyte-independent.
Walther
Andreas
A
Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Andreas_Walther@med.uni-heidelberg.de
Czabanka
Marcus
M
Gebhard
Martha Maria
MM
Martin
Eike
E
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D002450:Cell Communication; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D019446:Endotoxemia / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology; D018715:Microscopy, Video; D010539:Permeability / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D014699:Venules / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000077284:Abciximab