Histamine produced a time-dependent (half-life: 20 min at 37 degrees C), temperature-dependent (no effect at 20 degrees C) and homologous desensitization of histamine H2 receptor activity (H2 R) in HGT-1 cells. Maximal and half-maximal desensitization were respectively observed at 10(-5) and 2 X 10(-7) M histamine. Decline of responsiveness in intact cells was related to a remarkable loss in histamine efficacy (from 15- to 2-fold stimulation in control and treated cells). The affinity of the H2R for histamine (EC50 = 10(-5) M) did not change during desensitization. Paradoxically, histamine treatment is associated with increased [3H] histamine binding capacity in intact HGT-1 cells, and no change in H2 receptor antagonist binding ([3H]-tiodine and [3H]-SKF 93479). Desensitization process was preferentially mimicked by H2 receptor agonists (impromidine greater than histamine greater than AET greater than PEA) and preferentially reversed by simultaneous addition of H2 receptor antagonists (cimetidine greater than DPH). We suggest that the desensitization of H2R activity by histamine presented here may be involved in the pathophysiological regulation and pharmacological control of gastric cell function in man.