Intravenous pentagastrin as a partial agonist of gastric secretion in man: evidence in favor of the existence of hormonal inhibitory sites.
The gastric secretory response to prompt intravenous injection of pentagastrin was investigated in 3 normal subjects and 3 patients with duodenal ulcer. The highest responses to pentagastrin and histamine were correlated. Intravenous pentagastrin in a dose of 0,5 mug per kg could thus achieve the same extent of discrimination between individuals with a 10-fold economy in dosage over subcutaneous pentagastrin. Sensitivity to pentagastrin, expressed in the D50, was higher in patients with duodenal ulcer. Unexpectedly, the highest response to intravenous pentagastrin was only 40% of the peak response to subcutaneous histamine. Accordingly, intravenous pentagastrin acted as a partial agonist with an efficacy of about 0.4. The effect of prompt injection of pentagastrin contrasted with the effect of slow intravenous infusion of pentagastrin, as well as with the effects of gastrin-17 given by either prompt injection or slow infusion. A model is proposed to account for these and related findings in other species. The secretory receptor for gastrin and its analogues is viewed as consisting of two sites: a high affinity stimulatory site and a low affinity inhibitory site. Partial agonism after prompt intravenous injection would result from blood and tissue transients which are successively too high (partially inhibitory) and low (stimulatory). The disparate effects of analogues and the differences between species would be determined by the relative affinities of the two sites. The overflow of stimulant into inhibitory sites would account for the reversal of response at high doses observed in numerous studies.
D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004381:Duodenal Ulcer / Q000378:metabolism; D005750:Gastric Juice / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D005755:Gastrins / Q000008:administration & dosage / Q000494:pharmacology; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D010418:Pentagastrin / Q000008:administration & dosage / Q000494:pharmacology*; D010434:Pepsin A / Q000378:metabolism; D011956:Receptors, Cell Surface; D013268:Stimulation, Chemical
D005755:Gastrins; D011956:Receptors, Cell Surface; D006632:Histamine; D010434:Pepsin A; D010418:Pentagastrin