The effects of the cyclo-oxygenase inhibitors indomethacin and piroxicam have been investigated on histamine- and dibutyryl cyclic AMP-induced acid secretion in the rat isolated gastric mucosa. The relative potencies of a number of prostanoids as inhibitors of histamine-induced acid secretion were determined in an attempt to classify the prostaglandin receptor mediating this response. Indomethacin (8 X 10(-9) - 2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) potentiated the secretory responses elicited by histamine. This effect might be due to inhibition of the biosynthesis of antisecretory prostanoids. Indomethacin (2.7 X 10(-6) M) and piroxicam (3 X 10(-6) M) also potentiated the secretory response to dibutyryl cyclic AMP, but since prostaglandin E2 (PGE2, 10(-5) M) did not inhibit this secretory response, the mechanism of the potentiation may differ from that of histamine. The potency of the thromboxane mimetic U-46619 as an inhibitor of histamine-induced acid secretion was markedly reduced in the presence of indomethacin, suggesting that U-46619 may release endogenous antisecretory prostanoids. In the presence of indomethacin (2.7 X 10(-6) M) all the prostanoids tested produced concentration-related inhibitions of histamine-induced gastric acid secretion. PGE-analogues were the most potent compounds, the rank order of potency being 16, 16 dimethyl PGE2 greater than PGE2 greater than PGF2 alpha greater than U-46619 greater than PGD2 greater than PGI2. This order of potency is very similar to that obtained in smooth muscle preparations containing 'EP' receptors, suggesting that this receptor type also mediates inhibition of histamine-induced acid secretion in the rat.