Adrenomedullin stimulates somatostatin and thus inhibits histamine and acid secretion in the fundus of the stomach

Abstract

Adrenomedullin has recently been localized to enterochromaffin-like (ECL) and chief cells in the gastric fundus. It has been proposed that adrenomedullin may play a role in gastric mucosal defense and repair. In the present study, we have used the isolated, luminally perfused mouse stomach and superfused rat fundic segments to examine the effect of adrenomedullin on exocrine and endocrine secretion in this region of the stomach. Addition of adrenomedullin (1 pM to 1 μM) to the isolated mouse stomach caused a concentration-dependent decrease in acid secretion. The EC 50 value was 1.4×10 −9 and maximal inhibition of acid secretion was obtained at a concentration of 1 μM (31±4% below basal level, P<0.001). In rat fundic segments, superfusion with adrenomedullin (0.1 pM to 0.1 μM) caused a concentration-dependent increase in somatostatin secretion (EC 50, 1×10 −10) that was accompanied by a reciprocal decrease in histamine secretion (EC 50, 1.2×10 −11). Maximal stimulation of somatostatin secretion (60±5% above basal level, P<0.001) and inhibition of histamine secretion (50±5% below basal level, P<0.01) was obtained at a concentration of 0.1 μM. Changes in acid and histamine secretion induced by adrenomedullin reflected changes in somatostatin secretion and could be abolished by addition of somatostatin antibody. The axonal blocker, tetrodotoxin, also abolished the somatostatin and, consequently, the acid and histamine responses to adrenomedullin, implying that the effect of adrenomedullin on somatostatin secretion was mediated via activation of intramural neurons. We conclude that adrenomedullin, acting via intramural fundic neurons, stimulates somatostatin and thus inhibits histamine and acid secretion. This represents one mechanism by which adrenomedullin might enhance mucosal defense and repair.