In the discordant guinea pig (GP)-to-rat combination, heart xenografts are hyperacutely rejected. The aim of the present study was to demonstrate that a donor-species-specific extracorporeal liver hemoperfusion can prolong survival of discordant heart xenografts and to specify the role of non-parenchymal cells. GP hearts were grafted into Brown Norway rats (group 1) In group 2, heart xenografting was carried out immediately after a 15-min GP hemoperfusion. In group 3, Kupffer cells of the GP liver were blockaged by intravenous injection of dextran sulfate (4 mg/100 g) 30 min before hemoperfusion. In group 4, Kupffer cells of the liver were activated by intravenous injection of muramyl dipeptide (MDP; 500 micrograms/250 g) 24 h before hemoperfusion. Lymphocytotoxic antibodies were detected according to a complement-dependent antibody assay. A donor-specific liver hemoperfusion can delay hyperacute rejection of heart xenografts (67.6 +/- 47.1 min in group 2 versus 8.0 +/- 2.4 min in group 1; p < 0.01) and reduce the level of lymphocytotoxic antibodies. Deposits of immunoglobulins and complement were significant on the hemoperfused liver and moderate on the transplanted heart. In group 3, after blockade of Kupffer cells with dextran, heart xenograft survival was less prolonged (31.8 +/- 8.2 min) and the decrease in antibody levels was not significant and associated with moderate deposits of immunoglobulins and complement on the hemoperfused liver and significant deposits on heart xenografts. In group 4, after stimulation of Kupffer cells by MDP, a significant decrease in antibody levels was present, and significant deposits were observed. These results show that donor-specific liver hemoperfusion can prolong the survival of discordant heart xenografts and support the hypothesis that nonparenchymal liver cells play a major role by absorption of preformed antibodies and complement.