When hepatic stellate cells (Ito cells, fat-storing cells) were incubated with adrenomedullin, they underwent relaxation as monitored by the silicone-rubber membrane method; 43%, 65% and 87% of stellate cells relaxed 5, 10 and 20 min, respectively, after addition of 10(-6) M adrenomedullin. Adrenomedullin also triggered the dissociation of F-actin and induced transformation of stellate cells to dendritic cell-like structure. When incubated with 10(-6) M of adrenomedullin for 30 min, cellular levels of cAMP increased from the basal value of 10.2 +/- 1.4 to 107 +/- 2.8 pmol/2 x 10(5) cells without affecting cGMP levels. The reaction occurred dose-dependently and was inhibited by an antagonist of calcitonin gene-related peptide. Adrenomedullin had negligible effects on DNA and protein synthesis in proliferating stellate cells. Thus, adrenomedullin is a potent relaxing peptide to hepatic stellate cells and may contribute to the regulation of sinusoidal microcirculation.