Binding of recipient natural antibodies to the endothelium of the graft, complement activation, endothelial cell activation, and microvascular thrombosis are major events in the hyperacute rejection of organ xenografts. The aim of this study was to investigate the effects of two new synthetic sulfated oligosaccharides (A and B) on the survival of discordant cardiac xenografts in the guinea pig-to-rat model. In untreated recipients, hyperacute rejection occurred in 5 min (median; range, 4-6 min) and immunohistological analysis of all the grafts revealed deposition of IgM and C3 along the endothelium. Administration of oligosaccharides A and B prior to revascularization prolonged the survival of xenografts in a dose-dependent manner, up to 113 min (median; range, 42-145 min) and 86 min (median; range, 35-108 min), respectively, when doses of 20 mg/kg were used. There were no bleeding complications. Histological examination of the rejected grafts showed a picture of hyperacute rejection, with no difference in IgM and C3 deposition as compared with the untreated animals. In cell culture experiments, the release of heparan sulfate from guinea pig cardiac endothelial cells induced by rat serum was inhibited by both saccharides in a dose-dependent manner. The results indicate that these new synthetic sulfated oligosaccharides are effective for prolongation of discordant xenograft survival, possibly by interfering with endothelial cell activation. Such substances may be of value in other xenotransplant combinations.