1. Histamine stimulated the accumulation of total [3H]-inositol phosphates (IPn) in control HeLa cells with an EC50 of 3.7 +/- 0.7 microM in the presence of 10 mM LiCl. The maximum response to histamine after 15 min incubation was 43 +/- 5% over basal accumulation and occurred at a concentration of 1 mM histamine. 2. The histamine-induced IPn production in HeLa cells was confirmed as H1 receptor-mediated, since the H1 antagonist mepyramine (10(-6) M) inhibited the histamine response (10(-4) M) by 83 +/- 7%, whereas the H2 antagonist, ranitidine (10(-4) M), and H3 antagonist, thioperamide (10(-6) M), were ineffective. 3. Histamine (10(-4) M) pretreatment of HeLa cells for 30 min desensitized the subsequent histamine-induced IPn accumulation. The desensitized cells accumulated IPn in response to histamine with an EC50 of 1.7 +/- 0.7 microM after 15 min incubation. The maximum histamine-induced IPn accumulation at 10(-4) M was 19 +/- 5% over basal and was significantly lower (P < 0.03) than the maximum response in control cells. 4. The desensitization of histamine-induced IPn accumulation was time-dependent and, at a desensitizing histamine concentration of 10(-4) M, the half-maximal attenuation occurred after approximately 9 min and maximum desensitization was achieved by 15-20 min. The desensitization of the IPn accumulation was a reversible phenomenon and full recovery of the response occurred 150 min after the removal of the desensitizing histamine-containing medium. The half-time for the recovery of the histamine-induced response was estimated at 120 min. 5. Bradykinin stimulated IPn, accumulation in HeLa cells, and the ECm in control cells of 1.9 +/- 0.2 nM was not significantly different from the EC50 value from histamine-pretreated cells of 1.6 +/- 0.9 nM. The bradykinin response at 1 microM was 194 +/- 48% over basal IPn accumulation in control cells and this value was significantly different (P <0.04) from the 1 microM bradykinin-induced IPn accumulation in histamine pretreated HeLa cells of 143 +/- 38% over basal.6. NaF stimulated IP,, accumulation in control HeLa cells in a dose-related manner, with the maximum effect occurring at 15-20 mM. The EC50 value for NaF-stimulated IPn accumulation in control cells was 10.5 +/- 1.1 mm and the maximum response was 136 +/- 41% over basal after 20 min incubation. In histamine desensitized HeLa cells the EC50 value for NaF was 12.3 +/- 0.4 mM after 20 min stimulation,which was not significantly different from the value obtained in control cells. The maximum NaF stimulated IPn formation in desensitized cells of 68 +/- 23% over basal occurred at 15 -20 mM and was significantly lower (P<0.01) than that obtained in control cells.7. We show here that the acute histamine pretreatment of HeLa cells results in the desensitization of histamine H1 receptor-mediated IPn production. The desensitization was not restricted to the H1 receptor-mediated signal transduction pathway, but also includes both the bradykinin- and NaF mediated responses, supporting a heterologous desensitization mechanism. Our results are consistent with the site of attenuation being at or distal to the G-protein and the underlying mechanism being a slowed time-course for the production of inositol phosphates.