The effect of histamine on cyclic AMP levels in rat granulation tissue was examined. Granulomas formed by subcutaneous implantation of formalin-soaked filter paper disks were used as granulation tissue. Histamine injection (5 mg/kg i.p.) produced a significant increase in the cyclic AMP levels. Administration of either burimamide or mepyramine blocked the cyclic AMP increase induced by histamine. Propranolol reversed the cyclic AMP increase by adrenaline but partially blocked a similar effect of histamine. Quinidine slightly but insignificantly potentiated the cyclic AMP increase induced by injection of either histamine or adrenaline. When histamine (1 mM) was added concomitantly with theophylline (1 mM) to the incubation medium in which the chopped granulation tissue was immersed, cyclic AMP levels in the granulation tissue significantly increased compared to the addition of theophylline alone. Metiamide (1 mM) completely blocked the cyclic AMP increase caused by histamine, while mepyramine (1 mM) partially blocked this histamine effect. These results suggest the presence of histamine H(2)-receptors on the cells of granulation tissue and a major role of these receptors in the increase in cyclic AMP caused by histamine, although some extent of involvement of H(1)-receptors is also suggested.