Effects of subulcerogenic doses of cysteamine (100 mg/kg s.c.) and propionitrile (5 mg/kg) on alkaline secretion by duodenal surface epithelium and pH at the surface of this mucosa were assessed in duodenum of anesthetized rats. Alkaline secretion was titrated in situ, using segments of duodenum just distal to the Brunner's glands area and devoid of pancreatic HCO3-. Surface pH was measured by advancing pH-sensitive microelectrodes from the luminal solution to the epithelial cell surface. Proximal duodenum from bullfrogs was used to study effects of cysteamine on alkaline secretion in vitro. Cysteamine caused an increase in alkaline secretion in the rat during the first hour after administration, but rates after 5 and 20 h were the same as in controls and cysteamine (1 mg/ml) had no effect on secretion in vitro. Neither in vitro nor in vivo did cysteamine affect the rise in alkaline secretion in response to exogenous prostaglandin E2 (and dibutyryl-cyclic adenosine monophosphate). Luminal acid is a potent stimulant of duodenal mucosal alkaline secretion. By delayed (5 h) actions, both cysteamine and propionitrile inhibited the rise in alkaline secretion in response to a 5-min exposure to luminal acid with pH 2.00 in the rat. Cysteamine also depressed the ability of this mucosa to maintain a high rate of alkaline secretion during sustained exposure at pH 2.00 but had no such effect at pH 5.00. The former resulted in acidification of the pH gradient at the mucosal surface. Cysteamine is thus probably without effect on the HCO3- secretory process itself but impairs the ability of the duodenal mucosa to respond to acid. Inhibition of mechanisms mediating this response may contribute to the duodenal ulcerogenic actions of cysteamine and propionitrile.