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Gastrin-Histamine Sequence in the Regulation Of 698 Gut, 1991, 32, 698-701 Gastrin-histamine sequence in the regulation of gastric acid secretion Gut: first published as 10.1136/gut.32.6.698 on 1 June 1991. Downloaded from H L Waldum, A K Sandvik, E Brenna, H Petersen The importance of the vagal nerves in the however, does not affect histamine release.'9 We regulation ofacid secretion has been known since have also shown that both somatostatin2' and the Pavlov,' and in 1905 Edkins postulated the prostaglandin E1 analogue misoprostolF' inhibit existence of the antral hormone gastrin.' In 1920 gastrin induced histamine release and acid Popielsky described stimulation of gastric acid secretion as well as histamine stimulated acid secretion by histamine.3 Thus, the three major secretion. Moreover, gastrin stimulated acid acid secretagogues acetylcholine (from the vagal secretion and histamine release are heavily nerves), gastrin, and histamine have been known dependent on the extracellular calcium concen- for a long time. While vagal activity is regulated tration, in contrast to histamine stimulated acid via afferent vagal nerves as well as by the central secretion which is unaffected." Stimulation of nervous system, gastrin release is stimulated by the vagal nerves resulted in a release ofhistamine peptones in the gastric juice4 and is inhibited by in insufficient amounts to explain completely the acid.5 Gastrin release is also modulated by the stimulation of acid secretion.'" The muscarinic- 1 vagal activity,6 possibly via gastrin releasing agonist McN-A-343 stimulates acid secretion peptide.7 Somatostatin, which reaches the without affecting histamine release, thus gastrin producing G cells via the endocrine as suggesting that the muscarinic receptor on the well as the paracrine pathways, also inhibits parietal cell, but not on the histamine producing gastrin release.8 cell, is of the M- 1 type. "9 Curiously, gastrin The regulation of histamine release, on the releasing peptide slightly stimulates acid other hand, was almost completely unknown secretion while concomitantly inhibiting until recently. In the 60s, Kahlson et al showed histamine release.22 This effect is attenuated by that food, and especially exogenous gastrin, somatostatin antiserum, suggesting that somato- reduced the content of histamine in the oxyntic statin release could explain the inhibitory effect mucosa while stimulating the key enzyme in of gastrin releasing peptide on histamine http://gut.bmj.com/ histamine synthesis, histidine decarboxylase, release.22 Using different histamine receptor thus indicating that histamine release is an agonists and antagonists, we were also able to important step in the stimulation of acid show that histamine release is inhibited by a secretion.9 In fact, MacIntosh"0 and Code" had modified H2 receptor.23 previously suggested that the other secreta- The regulation of acid secretion in the rat is gogues stimulated acid secretion by releasing illustrated in Figure 2. According to our results, histamine. Later on, Ekblad described the therefore, it is not necessary to postulate the on September 26, 2021 by guest. Protected copyright. stimulation ofhistamine release by acetylcholine presence of a gastrin receptor on the rat parietal in amphibian oxyntic mucosa.'2 In a recent cell to explain the stimulation ofacid secretion by review Black and Shankley analysed the dose gastrin. The specific trophic effect of gastrin on response curves for different secretagogues alone the histamine producing enterochromaffin like or with a histamine 2 blocker, and concluded cells also makes it highly likely that these have a that cholinergic stimulation releases histamine. '" gastrin receptor.24 It should be stressed that there Using isolated vascularly perfused rat stomach,'4 generally seems to be a close relation between the we were able to show that gastrin evokes an stimulation of function and growth.25"27 The immediate and dose dependent histamine moderate general tropic effect of gastrin on the release."' We had previously studied the relation oxyntic mucosa may be mediated by substances between the concentration of gastrin and released from the enterochromaffin like cell such histamine, and acid secretion and showed that as the postulated gastrocalcin2' or histamine gastrin does not augment maximal histamine itself.29 stimulated acid secretion.'6 By comparing the effect ofgastrin on acid secretionand the resulting concentration of histamine in the gastric venous Species differences? drainage'5 with the acid secretory response to In the rat, there is obviously no need for a gastrin Department of Medicine and Institute of Cancer histamine infusion,'6 it is evident that the acid receptor on cells other than the enterochromaffin Research, University stimulatory effect of gastrin may be explained like cells to explain the gastrin induced Hospital, Trondheim, solely by the release of histamine (Fig 1). There stimulation ofacid secretion and mucosal growth. Norway H L Waldum was no significant difference between the The rat has been claimed to be an odd species A K Sandvik histamine release at the two highest gastrin with regard to the regulation of gastric acid E Brenna concentrations (Fig 1), and in a later study'7 secretion.3` In that species histamine has been H Petersen using dextran instead of albumin as colloid," reported to be a poor gastric acid secretagogue.3' Correspondence to: Dr H Waldum, Department of both acid secretion and histamine release It is true that in conscious rats histamine seems to Medicine, University reached maximum at a gastrin concentration of produce a lower maximal acid secretion than Hospital, N-7006 Trondheim, Norway 520 pmolIl. In these studies we used the phos- gastrin.3' 32 In the totally isolated vascularly per- Accepted for publication phodiesterase inhibitor isobutyl methylxanthine fused rat stomach, however, histamine is 3 August 1990 (IBMX) to augment the acid secretion. IBMX, appreciably more efficient than gastrin.'6 This Gastrin-histamine sequence in the regulation ofgastrc acidsecretion 699 70- well as from carcinoid tumours in man.39 Penta- gastrin has also been reported to induce a release 60 -0 3 ofhistamine into the gastric lumen and the blood E Gut: first published as 10.1136/gut.32.6.698 on 1 June 1991. Downloaded from m in duodenal ulcer patients.w0 A specific trophic 50 effect ofgastrin on the enterochromaffin like cell - is also found in man.4142 Therefore, there is no 40- doubt that the enterochromaffin like cells in 30- many species produce histamine and that these cells have gastrin receptors. 0 200 As already stated, there is within each species an inverse relation between the histamine forming capacity of the oxyntic mucosa and the 0 acid Before E o histamine secretagogue potency.9 r/' . 0- considering the role of histamine in the stimu- w 0 1d0 1000 0 100 1000 lation of acid secretion, therefore, one has to Q. Gastrin-17 , (1012mo1/1) Gastrin -17 (10-12mol/l) know the histamine potency in that particular 00 species. On isolated parietal cells and isolated glands from rodent oxyntic mucosa, gastrin <160- alone has been reported to have no" or only a faint," effect on acid secretion as evaluated by aminopyrine uptake. It should be remembered 120- that histamine has a low potency in these species.9 In the dog on the other hand, where histamine is 80- a rather potent secretagogue,945 gastrin was found to have a weak stimulatory effect on the aminopyrine uptake of the enriched parietal cell 40- fraction.45 Cimetidine did not inhibit this slight increase in aminopyrine uptake.45 The author 0O commented, however, because of the small 0 0.01 0.1 1 10 100 1000 response to gastrin and the relatively wide Histamine (10-6mo1/I) standard errors, small inhibitory effects by cime- Figure 1: The effect ofgastrin on acid secretion and histamine release into the venous drainage tidine could have been missed.45 Moreover, even of the isolated vascularly perfused rat stomach compared with the effect of histamine on acid in this relatively pure parietal cell fraction, secretion in the same model. (Figure takenfrom resultsfrom references 14 and 15.) cimetidine inhibited the stimulatory effect of http://gut.bmj.com/ IBMX suggesting residual histamine in the medium.45 It should also be remembered that discrepancy in results between conscious rats and vascularly perfused isolated rat stomachs Low pH Food may be explained by the extragastric toxic effects of high concentrations of histamine. In fact, in conscious rats the selective H2 receptor agonist, on September 26, 2021 by guest. Protected copyright. dimaprit, was found to produce a higher maximal acid secretion than histamine and, in contrast to histamine, did not cause a reduction in acid secretion with higher doses.32 In the rat, how- G-cell ever, the parietal cell sensitivity for histamine is low,'633 explaining why histamine cannot be administered in vivo to that animal in doses that would produce maximal acid secretion. The low potency of histamine in the rat is compensated for by the high histamine forming capacity in Ca+ that species.9 Kahlson et al convincingly showed ?ceptor that there is a close inverse interspecies relation Vagal nerves between the histamine forming capacity and the Enterochromaffin - (acetylchol ine) sensitivity towards histamine.9 This histamine like cell forming capacity does not correlate with the total oxyntic mucosal histamine content.934 On the other hand, the histamine forming capacity ofthe oxyntic mucosa in a species is closely correlated Somatostatin . with the density of the enterochromaffin like cells but not the mast cells.935 In spite of this, the mast cell has been regarded as the source of the M-1 receptor d histamine that takes part in the regulation ofacid secretion. No physiological stimulus, however, Parietal cell has been shown to influence the histamine release from the mast cells.37 Furthermore, histamine has now been found in enterochromaffin like cells in most species, including dog and man.35 As in the rat, gastrin HF releases histamine from the canine stomach,38 as Figure 2: RegXulation ofacid secretion in the rat.
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