The effect of clonidine on gastric acid secretion was studied in the pylorus ligated stomach (Shay test) and in the perfused stomach of the rat. Clonidine produced biphasic (inhibitory and stimulatory) effects on gastric acid secretion. In the Shay test, clonidine produced only an inhibitory effect on spontaneous gastric acid secretion in a dose-dependent manner (ED50 = 0.042 mg/kg, intraduodenal administration). In the perfused stomach, clonidine in a dose range of 0.625 to 5 mg/kg i.p. slightly increased acid secretion. The secretion, induced by 5 mg/kg of clonidine, was antagonized by cimetidine (10 mg/kg i.p.) but was not affected by phentolamine. Clonidine, 1.25 mg/kg i.p., a dose which had only a slight stimulatory effect, enhanced histamine- and bethanechol-induced secretion. The enhancement of bethanechol-induced secretion was blocked by pretreatment with cimetidine, suggesting histamine H2 receptor stimulation by clonidine. After i.p. (1.25 mg/kg) or intracerebroventricular (i.c.v., 20 and 40 micrograms/kg) administration, clonidine antagonized 2-deoxy-D-glucose-induced acid secretion. Clonidine also inhibited secretion induced by vagal stimulation in anesthetized, vagi-sectioned rats. These results suggest that clonidine had both central and peripheral sites of action. The inhibitory effect on secretion induced by vagal stimulation was blocked by phentolamine (alpha-1 and alpha-2 adrenergic receptor blocker) but not by labetalol (which blocks alpha-1 but not alpha-2 receptors). It is proposed that the inhibitory effect of clonidine is due to its effect on presynaptic alpha-2 adrenergic receptors located on the postganglionic vagal fibers to the stomach. In summary, these data suggest that clonidine inhibited gastric acid secretion by both a central and a peripheral mechanism. As the dose was increased, clonidine also stimulated acid secretion by a stimulation of histamine H2 receptors.