In man histamine and muscarinergic mechanisms are essential mediators of 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 determine in healthy human volunteers (n = 14; 3 females, 11 males; age 23-28 years) the degree by which the specific histamine H2-receptor antagonist famotidine or the muscarinergic antagonist atropine block acid secretion in response to synthetic human gastrin (hG) (1-17). Famotidine 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 were injected i.v., and gastric secretions were collected via a nasogastric tube for the ensuing 60 min to assess basal secretion. Thereafter, hG (1-17) was infused for 60 min in randomized order at two different rates: 0.75 ng/kg/min resulting in postprandial plasma gastrin levels (55-66 pg/ml), and 1.5 ng/kg/min yielding supraphysiologic levels (110-136 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. Famotidine abolished basal acid secretion and completely blocked acid and volume secretion in response to both hG (1-17) doses. After injection of famotidine both hG (1-17) doses resulted in plasma levels exceeding those in controls by 18-27 pg/ml. A similar increase (14-16 pg/ml) was observed after famotidine injection without simultaneous hG (1-17) infusion indicating that this increase was due to the release of endogenous gastrin when the acid feedback inhibition was blocked by famotidine. To study a potential additional role of cholinergic mechanisms the effect of atropine (7 micrograms/kg i.m.) on hG (1-17)-induced acid secretion was 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 during infusion of hG (1-17) by 16-24 pg/ml. We conclude that in man histamine and muscarinic mechanisms are essential mediators of gastrin-stimulated acid secretion. The present data argue against a significant direct effect of gastrin alone on human parietal cells but rather support potentiating interaction with histamine and cholinergic mechanisms.
Zimmerhackl
B
B
Department of Medicine II, Technical University, Munich, Germany.
Wünsch
E
E
Classen
M
M
Schusdziarra
V
V
Schepp
W
W
D000328:Adult; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology*; D004435:Eating; D015738:Famotidine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D018727:Muscarinic Antagonists; D011897:Random Allocation
D005755:Gastrins; D006635:Histamine H2 Antagonists; D018727:Muscarinic Antagonists; D015738:Famotidine; C013550:gastrin 17; D001285:Atropine