In vitro study on histamine-induced cyclic adenosine monophosphate production in ulcer patients with different antisecretory responses to ranitidine.

Failure of acid suppression by H2 receptor antagonists has been observed in some patients with peptic ulcer diseases. The reasons for the drug resistance are unknown. In the present study, the effects of histamine and the H2 receptor antagonist ranitidine (CAS66357-35-5) on cyclic adenosine monophosphate (AMP) production was investigated using intact cells from gastric mucosal biopsies derived from patients with adequate (AR) and inadequate (IR) antisecretory response to ranitidine. The classification of AR and IR was performed by intragastric nocturnal pH-monitoring. Parietal cell content was increased in IR (14.5 +/- 5.3%; mean +/- SD) compared to AR (11.2 +/- 4.5%; p < 0.05). The histamine-induced cyclic AMP production was decreased in IR compared to AR whereas the EC50-values where similar (22-27 mumol/l). Inhibitory activity of ranitidine (Ki; 105-133 nmol/l) did not differ significantly in samples of both patient groups. Duration of clinical pretreatment with ranitidine did not affect the cyclic AMP production. These data suggest that the inadequate response may be rather due to lower H2 receptor density or non-competitive impairment of the receptor in gastric mucosal cells than to a decreased affinity of the antagonist to the receptor.