gastrins and spiroglumide

A gastrin receptor antagonist, CR2194 (spiroglumide), was used to explore the physiological role of gastrin in regulating gastric acid secretion in humans.. The effect of CR2194 on inhibition of gastrin-stimulated acid output was evaluated in a four-period crossover study. Each subject received intravenous doses of 1, 2.5 or 7.5 mg kg-1 h-1 CR2194 or saline (control) followed by graded increasing doses of gastrin (6.4-800 pmol kg-1 h-1). Secondly, the effect of CR2194 on meal-stimulated intragastric acidity was evaluated by infusing either saline (control) or CR2194 (7.5 mg kg-1 h-1) before and after food ingestion.. Acid secretion was dose-dependently inhibited by CR2194. With CR2194, acidity was significantly reduced in the pre-meal and post-prandial period (P < 0.01 and 0.002 respectively), and the integrated gastrin response was augmented to 8.0 +/- 1.4 ng mL-1 240 min compared with 1.5 +/- 0.8 ng mL-1 240 min in the control experiment (P < 0.01). Finally, acid secretion in response to sham feeding was significantly reduced: 15.9 +/- 0.9 mmol 90 min-1 in the control experiment compared with 2.8 +/- 0.9 mmol 90 min-1 during CR2194 infusion (P < 0.05).. Gastrin receptor blockade with CR2194 alters gastric acid secretion in response to food ingestion or to sham feeding. The results support a physiological role for gastrin in regulating acid secretion in humans.

Topics: Adult; Food; Gastric Acid; Gastrins; Humans; Hydrogen-Ion Concentration; Keto Acids; Male; Middle Aged; Postprandial Period; Receptors, Cholecystokinin; Spiro Compounds; Time Factors

Topics: Animals; Benzamides; Carbachol; Dogs; Fistula; Gastric Acid; Gastric Mucosa; Gastrins; Histamine; Keto Acids; Muscle, Smooth; Pentagastrin; Pentanoic Acids; Rats; Receptors, Cholecystokinin; Spiro Compounds; Stereoisomerism; Stomach

The antigastrinic activity, in vivo, of CR 2194 (R-4-(3-chlorobenzamido)-5-(8-azaspiro[4.5]decan-8-yl) -5-oxo pentanoic acid) was assessed in various animal species. CR 2194 antagonized pentagastrin-stimulated gastric acid secretion in the rat (ID50 = 11 mg/kg i.v.), dog (ID50 = 5.9 mk/kg i.v. or 28.8 mg/kg os) and cat (ID50 = 15.5 mg/kg i.v.). CR 2194, in the cat, inhibited both competitively and non-competitively the gastric acid secretion stimulated with increased doses of pentagastrin, with a pA2 of 4.89. In the rat and in the dog the antagonism seemed to be non-competitive and the respective pD'2 calculated were 4.54 and 4.42. The interaction of CR 2194 with the gastrin receptors appeared reversible, as demonstrated by the return to normal values of the acid output after the conclusion of the i.v. infusion, during pentagastrin continuous stimulation in the dog. The antigastrin activity was specific: CR 2194 was unable to antagonize the gastric acid secretion stimulated by carbachol or histamine in the rat up to the dose of 100 mg/kg. CR 2194 was effective to antagonize the gastric acid secretion stimulated by gastrin release after meal ingestion in the Heidenhain pouch dog model. The ID50 calculated was 2.89 mg/kg after oral administration. All these characteristics make CR 2194 an important compound in the investigation of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.

Topics: Animals; Binding, Competitive; Cats; Dogs; Eating; Gastric Acid; Gastric Fistula; Gastric Mucosa; Gastrins; Keto Acids; Male; Pentagastrin; Perfusion; Rats; Rats, Sprague-Dawley; Spiro Compounds