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The Interaction of Histamine with Gastrin and Carbamylcholine on Oxygen Uptake by Isolated Mammalian Parietal Cells

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The Interaction of Histamine with Gastrin and Carbamylcholine on Oxygen Uptake by Isolated Mammalian Parietal Cells The Interaction of Histamine with Gastrin and Carbamylcholine on Oxygen Uptake by Isolated Mammalian Parietal Cells Andrew H. Soll J Clin Invest. 1978;61(2):381-389. https://doi.org/10.1172/JCI108948. Research Article Using oxygen uptake as an index of the physiological response of isolated parietal cells, the interactions between histamine and gastrin and between histamine and carbamylcholine and the effects of atropine and metiamide on these interactions have been studied. Parietal cells were isolated from canine fundic mucosa by sequential exposure of separated mucosa to collagenase and EDTA. In previous studies carbamylcholine, isobutyl methyl xanthine, gastrin, and histamine have each been shown to increase oxygen uptake by these cells. Isobutyl methyl xanthine greatly enhanced the histamine effect. Carbamylcholine was inhibited by atropine but not by metiamide, histamine was inhibited by metiamide but not by atropine, and gastrin was inhibited by neither, suggesting that each of these agents has a direct action on the parietal cell. In the present studies, potentiating interactions between histamine and carbamylcholine and between histamine and gastrin have been demonstrated. Against a histamine (0.1 and 1 μM) plus isobutyl methyl xanthine (0.1 mM) background, the dose for 50% response for gastrin was approximately 1 nM, and the maximal response was obtained at 0.1 μM. When added to these combinations of stimulants, metiamide and atropine retained their respective specificities against stimulation by histamine and carbamylcholine, in that responses were inhibited to the level that was seen when the component of the pair that was not inhibited was given alone. The […] Find the latest version: https://jci.me/108948/pdf The Interaction of Histamine with Gastrin and Carbamylcholine on Oxygen Uptake by Isolated Mammalian Parietal Cells ANDREW H. SOLL, Veterans Administration Wadsworth Hospital Cen ter, Los Angeles, California 90073, and the University of California at Los Angeles School of Medicine, Los Angeles, California 90024 A B ST RA CT Using oxygen uptake as an index of the histamine plus carbamylcholine produced maximal physiological response of isolated parietal cells, the responses that were greater than the maximal response interactions between histamine and gastrin and be- to histamine alone further supports the hypothesis that tween histamine and carbamylcholine and the effects of these agents each have direct actions on parietal cells. atropine and metiamide on these interactions have These observations are not consistent with the been studied. Parietal cells were isolated from canine hypothesis that histamine is the sole mediator for the fundic mucosa by sequential exposure of separated effects of other secretagogues. Furthermore, the inhibi- mucosa to collagenase and EDTA. In previous studies torv effects of atropine and metiamide on the specific carbamylcholine, isobutyl methyl xanthine, gastrin, cholinergic and histaminic components of the interac- and histamine have each been shown to increase tions that occur between secretagogues provide a oxygen uptake by these cells. Isobutyl methyl xanthine possible explanation for the apparent lack of specificity greatly enhanced the histamine effect. Carbamyl- of these agents on in vivo acid secretion. choline was inhibited by atropine but not by metiamide, histamine was inhibited by metiamide but not by atropine, and gastrin was inhibited by neither, INTRODUCTION suggesting that each of these agents has a direct action Histamine, gastrin, and cholinergic agents each stimu- on the parietal cell. In the present studies, potentiating lated oxygen consumption by dispersed parietal cells interactions between histamine and carbamylcholine prepared from canine fundic mucosa (3). Parietal cells and between histamine and gastrin have been appeared to largely account for these increases in demonstrated. Against a histamine (0.1 and 1 ,M) plus oxygen consumption. Based upon the correlation of isobutyl methyl xanthine (0.1 mM) background, the acid secretion and oxygen consumption in in vitro dose for 50% response for gastrin was approximately 1 studies with amphibian mucosa and with an ex vivo nM, and the maximal response was obtained at 0.1 AM. stomach preparation (3), the increases in oxygen When added to these combinations of stimulants, consumption by the isolated parietal cells were taken as metiamide and atropine retained their respective evidence of stimulation of the parietal cell acid specificities against stimulation by histamine and secretory mechanisms. In this previous study, data was carbamylcholine, in that responses were inhibited to obtained suggesting that the parietal cells have separate the level that was seen when the component of the pair receptors for each of these agents, since histamine was that was not inhibited was given alone. inhibited by metiamide but not by atropine, carbamyl- The observation that histamine plus gastrin and choline was inhibited by atropine but not by This work was presented, in part, at the meeting of the metiamide, and gastrin was inhibited by neither American Gastroenterological Association, 22 to 27 May 1976, atropine nor metiamide (3). These results, however, are Miami, Fla. (1) and the First International Symposium on in apparent conflict with in vivo studies of acid secre- Gastrointestinal Hormones, 5 to 8 October 1976, Asilomar, tion in which atropine inhibits the actions of histamine Calif. (2). (4-6) and gastrin (5, 7), as well as acetylcholine, Dr. Soll is the recipient of a Research Associateship from the Veterans Administration. and in which H2-histamine antagonists inhibit the Receivedfor publication 7June 1977 and in revisedform 22 actions of gastrin (8-12) and cholinergic agents (13, 14), September 1977. as well as histamine. This apparent nonspecificity of The Journal of Clinical Investigation Volume 61 February 1978 *381 -389 381 inhibitors may be the result of the sequential action of mean basal oxygen uptake for crude and enriched cell fractions secretagogues with, for example, gastrin releasing (3). mucosal histamine and histamine in turn acting directly In previous studies (3), the phosphodiesterase inhibitor IMX was found to markedly enhance the response to upon the parietal cell. H2-blockers would then interfere histamine, and in the present studies this agent was included with the histamine mediation of gastrin action. A at 0.1 mM in all incubations in which histamine was used second possibility is that the H2-antagonists and unless otherwise noted. anticholinergic agents may block receptors other than for histamine and acetylcholine, respectively, thus RESULTS interfering with the receptor binding of presumably unrelated agents. Alternatively, endogenous mucosal Histamine-gastrin interactions. Gastrin (natural histamine and (or) acetylcholine may be released hog heptadecapeptide gastrin, 0.1 ,M) which alone spontaneously in the basal state and may interact with produced a 12% increase in oxygen uptake above basal other secretagogues on the parietal cell. The apparent (3), markedly enhanced the response to histamine. This lack of specificity of H2-antagonists and anticholiner- combination of 0.1 ,uM gastrin with 10 ,uM histamine gics would then reflect specific inhibition of the produced a response in nine consecutive preparations histaminic and cholinergic components of these in- that was 157 + 8.2% (mean +SE) of the maximal teractions. In the present study, with oxygen uptake as increment above basal produced by histamine, with a an index of the physiological response of dispersed range from 114.7 to 191.5% and the difference statisti- parietal cells, the interactions between histamine and cally significant by the t test for paired values gastrin and between histamine and cholinergic agents, (P <0.01). In each of these nine preparations the and the effects of atropine and metiamide on these response to the combination of histamine plus gastrin interactions, were examined. was greater than the sum of the responses to the The findings of these studies are compatible with a individual agents, and this difference was statistically model based upon interaction of secretagogues at the significant by the paired t test (P <0.01). In four parietal cell in which the inhibitory actions of an- preparations, the effect of 0.1 ,uM gastrin upon the ticholinergics and H2-receptor antagonists against dose-response relation to histamine was studied, and combinations of stimulants can be explained by their enhancement by gastrin was evident at histamine respective removal of the cholinergic and histaminic concentrations from 0.1 uM to 0.1 mM (Fig. 1). This components of these interactions. 200 CRUDE m METHODS ENRICHED a w Cells were prepared from canine fundic mucosa which was cnz 150O completely separated from submucosa and then incubated in basal essential medium with crude collagenase III (Worth- w ington Biochemical Corp., Freehold, N.J., 0.75 mg/ml), fol- lowed by incubation in the same medium with 1-2 mM I100 ,} WITHOUT G- 17 EDTA, and then returned to the collagenase containing -J medium. These methods and the methods for determining oxygen uptake and for data analysis have been detailed j 50 previously (3). The present studies were done both on crude mucosal cell fractions and on enriched parietal cell fractions 0 obtained with the Beckman elutriator rotor (Beckman Instru- A0 ments, Inc., Fullerton, Calif.) (3). G-R 0.1 I I, M Olim 0.1 LM - H The data are expressed as the percentage of the maximal 6 (M) increment
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