In liver grafts that will fail as a result of storage injury, reperfusion activates Kupffer cells. Overproduction of tumor necrosis factor by activated Kupffer cells may cause primary graft nonfunction, multiple organ failure and, eventually, death of graft recipients. Carolina rinse solution, adenosine, nisoldipine, pentoxifylline and prostaglandin E1 reduce graft failure from storage/reperfusion injury. To test the hypothesis that these agents act by suppressing cytokine release by activated Kupffer cells, we assessed the effect of each drug on tumor necrosis factor released from cultured rat Kupffer cells stimulated with lipopolysaccharide. Adenosine, nisoldipine and prostaglandin E1 each suppressed lipopolysaccharide-stimulated tumor necrosis factor release. The adenosine A2 receptor agonists. 5-n-ethylcarboxamidadenosine, 2-chloro-adenosine and R-phenylisopropyl adenosine also blocked tumor necrosis factor release in a potency suggestive of A2 receptor activity. Xanthine amine congener, a specific A1 receptor antagonist, failed to reverse the suppression by adenosine of tumor necrosis factor release, whereas CGS15943A, an A2 receptor antagonist, did reverse suppression by adenosine and 5-n-ethylcarboxamidadenosine. CGS15943A had no effect on suppression of lipopolysaccharide-stimulated tumor necrosis factor release by nisoldipine or prostaglandin E1. Dibutyryl-cyclicAMP also suppressed tumor necrosis factor release. Adenosine, 5-n-ethylcarboxamidadenosine, prostaglandin E1 and pentoxifylline increased cyclicAMP levels in cultured Kupffer cells, but nisoldipine did not.(ABSTRACT TRUNCATED AT 250 WORDS)