ABSTRACT
OBJECTIVES: To examine the microcirculatory changes in the rat tibial periosteum after hindlimb ischemia and reperfusion and to evaluate the effects of endothelin-A (ET-A) receptor antagonist therapy in this condition. The healing and functioning of vascularized bone autografts depend mainly on the patency of the microcirculation, and the activation of ET-A receptors may be an important component of the tissue response that occurs during ischemia-reoxygenation injuries. METHODS: Wistar rats were subjected to 1 hour of hindlimb ischemia and 3 hours of reperfusion. The periosteal microcirculation was visualized by intravital fluorescence microscopy. The leukocyte rolling and adherence in the postcapillary venules and the functional capillary density of the periosteum were determined. Two separate groups were treated with the selective ET-A receptor antagonist BQ 610 or the novel ET-A receptor antagonist ETR-p1/fl peptide at the onset of reperfusion. RESULTS: Reperfusion was accompanied by a significant decrease in functional capillary density and by an increase in the primary and secondary leukocyte-endothelial cell interactions. ET-A receptor inhibition reduced the leukocyte rolling and firm adherence and attenuated the decrease in functional capillary density in both treated groups. CONCLUSIONS: ET-1 plays a major role in microvascular dysfunction in the periosteum during reperfusion. The ET-1-ET-A receptor system might be an important target for tissue salvage therapy in transplantation surgery.
Subject(s)
Periosteum/blood supply , Reperfusion Injury/drug therapy , Animals , Cell Adhesion , Endothelium, Vascular/pathology , Hindlimb , Intercellular Signaling Peptides and Proteins , Leukocyte Rolling , Male , Mice , Microcirculation/drug effects , Microcirculation/pathology , Microscopy, Video , Oligopeptides/pharmacology , Peptides/pharmacology , Rats , Rats, Wistar , TibiaABSTRACT
BACKGROUND: Ischemia/reperfusion-induced polymorphonuclear neutrophil leukocyte (PMN) adhesion and extravasation are pivotal for the development of postinjury multiple organ failure. We hypothesized that the deleterious microcirculatory consequences of hemorrhagic shock (HS) could be altered by low-molecular-weight heparin (LMWH) therapy. Our aim was to investigate the effects of dalteparin sodium on leukocyte-endothelial cell interactions when LMWH treatment was initiated before HS or during resuscitation. METHODS: Anesthetized dogs underwent HS (40 mm Hg mean arterial pressure for 60 minutes) and resuscitation either with shed blood or with lactated Ringer's (LR) solution. LMWH or conventional heparin sodium pretreatment was administered subcutaneously before hemorrhage; or LMWH was given intravenously during resuscitation. Mesenteric postcapillary venules were observed by intravital video microscopy before and after HS, and 60 minutes, 120 minutes, and 180 minutes after resuscitation, and leukocyte rolling and firm adherence were determined. RESULTS: HS significantly increased PMN rolling and adhesion in the mesenteric microcirculation. LMWH, but not heparin sodium pretreatment, significantly inhibited both primary and secondary interactions. LMWH treatment was also effective when initiated during resuscitation. LMWH exerted the same inhibitory effect regardless of the type of resuscitation. CONCLUSION: LMWH treatment during resuscitation effectively inhibits PMN rolling and adhesion.
