The effects of histamine and histamine antagonists on bile flow have been studied using the cholecystectomized conscious sheep. Histamine stimulated bile flow in a dose-dependent manner (D50 = 15.7 micrograms/h per kg). Free water and HCO3-output were increased after intravenous histamine infusion. With histamine at 120 mg/h per kg, there was a 41.0 (s.d. = 4.6)% and 38.7 (s.d. = 4.2)% (n = 6) increase in bile volume and HCO3-output respectively. Bile salt concentration was decreased after intravenous histamine, but net bile salt secretory rate remained unchanged. There was no change observed in the molar ratios of bile salts: phospholipids: cholesterol. Total lipids were decreased from 2.2 (s.d. = 0.3) to 1.60 (s.d. = 0.4) g/dl (n = 6). The corrected lithogenic index did not change significantly. 14C-Erythritol clearance also increased during histamine infusion in a dose-dependent manner but did not correspond to increments in bile flow. The histamine H1-receptor antagonist, diphenhydramine 0.05-1.0 mg/h per kg did not alter histamine stimulated bile flow. The H2-receptor antagonists, cimetidine (0.5-4 mg/h per kg) and ranitidine (0.05-0.5 mg/h per kg) progressively reversed the histamine-induced choleresis. Maximum inhibitory effect was attained at 2.0 and 0.25 mg/h per kg for cimetidine and ranitidine, respectively. At these levels, variation of intravenous infusion of histamine did not result in competitive displacement of the inhibitory response by either cimetidine or ranitidine. Moreover, concomitant infusion of diphenhydramine at 1.0 mg/h per kg potentiated the inhibitory effect of cimetidine or ranitidine on histamine-induced choleresis. Histamine increases the bile salt independent component of hepatic bile flow.(ABSTRACT TRUNCATED AT 250 WORDS)