We examined the validity of the high K⁺ condition, widely used as a model to investigate the mechanism of acid secretion, employing isolated rabbit gastric glands. When Na⁺ in the nutrient solution was replaced with K⁺, the acid secretion monitored by the accumulation of ¹⁴C-aminopyrine increased K⁺-concentration-dependently. Stimulation of carbachol or dbcAMP was also greatly enhanced by K⁺. The responses to forskolin, phorbol ester, gastrin and submaximal dose of histamine were potentiated in the high K⁺ condition, but the responses to isobutylmethylxanthine, calyculin A and the maximal dose of histamine were not. The augmented response to carbachol was not dependent on [Ca²⁺]_o. Replacement of Na⁺ with any other ions, including Rb⁺, Cs⁺, Li⁺, tetramethylammonium and choline, increased the basal aminopyrine ratio. Most of these ions were also effective in enhancing the response to dbcAMP, but failed to augment the effect of carbachol. Replacement of Na⁺ with K⁺, Rb⁺, Cs⁺ and Li⁺ transiently elicited acid secretion in the isolated mouse whole stomach. These results suggest that the high K⁺ is not a simple model for the direct activation of the proton pump, but the augmentation consists of two components, i.e., the combined effects of low Na⁺ and high K⁺. The former augments basal and cAMP-stimulated acid production, whereas the latter augments acid production by any agonist except calyculin A.