IN MAN HISTAMINE AND MUSCARINERGIC MECHANISMS ARE ESSENTIAL MEDIATORSOF ACID-SECRETION IN RESPONSE TO SYNTHETIC HUMAN GASTRIN (1-17)

It is still controversial whether gastrin stimulates acid secretion by interacting with specific gastrin receptors on parietal cells or via endogenous mediators, e.g., histamine. Therefore, it was our aim to de termine in healthy human volunteers (n = 14; 3 females, 11 males; age 23-28 years) the degree by which the specific histamine H2-receptor an tagonist famotidine or the muscarinergic antagonist atropine block aci d secretion in response to synthetic human gastrin (hG) (1 - 17). Famo tidine was deliberately administered at a supramaximal dose (40 mg i.v . bolus) to reliably block any and all effects of endogenous histamine on the parietal cells. After an overnight fast famotidine or saline w ere injected i.v., and gastric secretions were collected via a nasogas tric tube for the ensuing 60 min to assess basal secretion. Thereafter , hG (1-17) was infused for 60 min in randomized order at two differen t rates: 0.75 ng/kg/min resulting in postprandial plasma gastrin level s (55-66 pg/ml), and 1.5 ng/kg/min yielding supraphysiologic levels (1 10-136 pg/ml). Both rates increased basal acid secretion (meq/10 min) from 0.5 +/- 0.2 to 3.8 +/- 0.6 and 4.7 +/- 0.5, respectively. Famotid ine abolished basal acid secretion and completely blocked acid and vol ume secretion in response to both hG (1-17) doses. After injection of famotidine both hG (1-17) doses resulted in plasma levels exceeding th ose in controls by 18-27 pg/ml. A similar increase (14-16 pg/ml) was o bserved after famotidine injection without simultaneous hG (1-17) infu sion indicating that this increase was due to the release of endogenou s gastrin when the acid feedback inhibition was blocked by famotidine. To study a potential additional role of cholinergic mechanisms the ef fect of atropine (7 mug/kg i.m.) on hG (1-17)-induced acid secretion w as examined. Atropine reduced basal acid secretion from 0.8 +/- 0.1 to 0.1 +/- 0.08 meq/15 min. Similarly, the response to 0.75 ng/kg/min hG (1-17) was reduced by 72.9% Basal gastrin release was not altered by atropine which, however, tended to increase serum gastrin levels durin g infusion of hG (1-17) by 16-24 pg/ml. We conclude that in man histam ine and muscarinic mechanisms are essential mediators of gastrin-stimu lated acid secretion. The present data argue against a significant dir ect effect of gastrin alone on human parietal cells but rather support potentiating interaction with histamine and cholinergic mechanisms.