alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Necrosis

CY1503, an analogue of sialyl-Lewisx, is an inhibitor of the selectin adhesion molecules. CY1503 has been found to limit myocardial infarct size in canine and feline models. However, the effect of CY1503 on the "no-reflow" phenomenon is still unknown. Anesthetised rabbits were subjected to 30 min of coronary artery occlusion and 4 h of reperfusion. Protocol 1: after 27 min of ischemia, rabbits were randomised to an iv bolus of either CY1503 (30 mg/kg) (n=9) or saline (n=9). Protocol 2: rabbits were randomly given two iv boluses of CY1503 (30 mg/kg) (n=6) or saline (n=6), administered after 10 and 25 min of ischemia. Protocol 3: after 27 min of ischemia rabbits were randomly given an iv bolus of CY1503 (30 mg/kg) (n=6) and infusion of 20 mg/kg over 4 h or saline bolus+infusion (n=6). Regional myocardial blood flow (RMBF) was assessed after 30 min and 4 h of reperfusion. The risk zone (RZ) was assessed by blue dye and the necrotic zone (NZ) by tetrazolium staining. RMBF: protocol 1: RMBF in the RZ was 2.19+/-0.33 v 2. 34+/-0.34 ml/g/min in CY1503 and controls at 30 min (P=0.75), and 0. 43+/-0.07 v 0.41+/-0.08 at 4 h of reperfusion (P=0.85). The corresponding results for protocol 2 were 1.77+/-0.29 v 1.53+/-0.34 at 30 min (P=0.61) and 0.53+/-0.16 v 0.91+/-0.55 at 4 h (P=0.53). RMBF in RZ in protocol 3 were 1.52+/-0.25 v 1.32+/-0.20 at 30 min (P=0.56) and 0.30+/-0.05 v 0.29+/-0.09 (P=0.90) after 4 h of reperfusion. The RZ was similar in both groups in all protocols. The NZ/RZ ratio was comparable in the CY1503 and control group in all three protocols (0.32+/-0.04 v 0.37+/-0.06, 0.37+/-0.08 v 0.33+/-0. 07, and 0.51+/-0.05 v 0.38+/-0.05 in protocols 1, 2, and 3, respectively). CY1503 did not limit infarct size or prevent the "no-reflow" phenomenon in the rabbit.

Topics: Animals; Cats; Cell Adhesion; Dogs; E-Selectin; Gangliosides; Heart; L-Selectin; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Neutrophils; Oligosaccharides; P-Selectin; Rabbits; Radionuclide Imaging; Sialyl Lewis X Antigen; Species Specificity

We investigated the role of adhesion molecules in the early phase of reperfusion following cold ischemia. Livers of male Lewis rats were preserved for 0 h (group A) or 24 h in University of Wisconsin (UW) solution without additives (group B) or in UW solution with anti-ICAM-1 antibody (group C) or anti-E-selectin-1, SLe(x) and SLe(a) antibodies (group D). The livers were then reperfused with diluted rat whole blood (DWB; groups A and B). DWB containing anti-ICAM-1 and LFA-1 antibodies (group C) or DWB containing anti-L-selectin, SLe(x) and SLe(a) antibodies (group D). The reperfusion was performed at 37 degrees C for 1 h at 5 cm H2O of perfusion pressure. During reperfusion, hepatic microcirculation was assessed by monitoring portal and peripheral tissue blood flow. Bile production was significantly reduced in group B livers compared with those in group A. Anti-ICAM-1 and LFA-1 antibodies failed to improve hepatic microcirculation, whereas anti-LECAM-1, SLe(x) and SLe(a) antibodies significantly improved the microcirculation. Bile production in group C and D livers was comparable to that in group B livers. Preservation for 24 h significantly increased the release of TNF-alpha from 0.207 to 43.7 pg/g per hour during reperfusion. Monoclonal antibodies to the adhesion molecules did not suppress the release of TNF-alpha in groups C and D. Histological examination demonstrated a lack of leukocyte infiltration or thrombus in hetapic microvessels. The extent of hepatocyte necrosis did not differ among groups B, C, and D. We conclude that the microcirculatory disturbance in the early phase of reperfusion occurs as a result of the tethering of leukocytes through the interaction of the selectin family and their ligands, and that the ICAM-1-LFA-1 pathway is not involved in this step. The lack of improvement in bile production with antibodies to the selectin family and their ligands strongly suggests that other mechanisms participate in the deterioration of hepatic function.

Topics: Adenosine; Allopurinol; Animals; Antibodies, Monoclonal; Antibody Specificity; Bile; CA-19-9 Antigen; Cell Adhesion; Cold Temperature; E-Selectin; Glutathione; Insulin; Intercellular Adhesion Molecule-1; Ischemia; L-Lactate Dehydrogenase; L-Selectin; Leukocytes; Liver; Lymphocyte Function-Associated Antigen-1; Male; Microcirculation; Necrosis; Oligosaccharides; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Inbred Lew; Reperfusion; Reperfusion Injury; Sialyl Lewis X Antigen; Tumor Necrosis Factor-alpha