Rationale, Epidermal growth lactor receptor (EGF-R) is expressed in gastric mucosa, EGFRPs present in gastric mucosa ant~'or secretions such as EGF transforming growth facto> a (TGF-a), heparin-binding EGF-like growth lactor (HB-EGF), and amphiregulin activate tile EGF-R and contribute to gastric mucosal protection/repair In addition, increased EGFR signaling is implicated in the pathogenesis of Menetriere's disease (gastric mucosal hypertrophy and hypochlorhydria), Aim To determine the effect of EGF-RPs on gastric endocrine sea~tinn in rat and human, Methods. Rat and human thndic and antral segments were superfused and sst histamine, and gastrin measured RIA Results, In ratfundic segments, addition of EGF, TGF-c*, HB-EGF, and amphiregulin (0.1 pM to 0.1 p.M), each for 20minutes, caused a concentration-dependent increase in sst secretion (threshold: 1 pM; maximum: 33-48% above basal at 01 txM (P<0,01); EC:~,: 0.04-1 nM) and decrease in histamine secretion (threshold: 1 pM; maximum: 30-56% below basal at 0.1 IzM (P<0.01); EGo,: 001-05 nM). l.ikemse, in human fundic segments, EGF and TGF-a each caused a concentration-dependent increase in sst (threshold: 1 pM; maximum: 106-115% above basal at 01 ~M (P<0.001); EC50:0,1~0,9 nM) and decrease in histamine secretion (threshold: i pM; nmximum: 40-42% below basal at 01 p.M (P<0.01); ECs0:0.01-0.1 nM), Changes in histamine secretion reflected changes in sst secretion and could be abolished addition of sst antiserum In rat ano~I segmenls, ahhnugh each of the EGF-RPs caused a concentrationdependent increase in sst secretion (threshold: 1 pM; maximum: 38-53% above basal at 0,1 p.M: (P<0.001); EC,: : 0.03-4 nM), gastrin secret on remained unchanged. The results imply that EGF-RPs stimulated both sst and gastrin secretion, The gastrin response represents the net effect of direct stimulation and indirect inhibition sst; the effects cancel and gastrin secretion is uochanged. In support of this notion, in human antral segments, EGF and TGFer each stimulated both sst secretion (threshold: 0,1 pM; mammum: 174-215% above basal at 01 IxM (P<0.001); EC.~r 0.01-0.2 nM) and gastrin secretion (threshold: 0.1 pM; maximum: 300-350% above basal at 01 ~,M (P<0.C~31); ECs0: 0,01-0A nM). Conclusion. In human and rat stonaach, EGF-RPs: (1) inhibit acid secretion by stimulating sst and thus inhibiting histamine secretion in the fundus, and (2) enhance umcosal growth stimulating gastrin secretion in the antrmn.