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Endocrinology Vol. 140, No. 2 603-608
Copyright © 1999 by The Endocrine Society

ARTICLES

Developmental Regulation of Gastric Somatostatin Secretion in the Sheep1

Brendan J. Grabau, Yana Zavros, Kenneth J. Hardy and Arthur Shulkes

Department of Surgery, University of Melbourne, Austin and Repatriation Medical Center, Melbourne, Victoria 3084, Australia

Address all correspondence and requests for reprints to: Prof. Arthur Shulkes, Department of Surgery, University of Melbourne, Austin and Repatriation Medical Center, Melbourne, Victoria 3084, Australia. E-mail: shulkes{at}austin.unimelb.edu.au


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Gastric somatostatin (SRIF) regulates gastric acidity by inhibiting gastric acid and gastrin secretion. SRIF secretion is increased by gastric acidity and also directly by regulators of gastric acid secretion such as gastrin. This direct effect has not been described in the developing animal, nor have the roles of intermediaries such as histamine and gastric acidity been defined. The present study aimed to establish the regulatory role of gastrin and histamine during development on SRIF secretion and also to determine whether the effects of gastrin and histamine are independent of gastric pH. Pentagastrin and histamine were infused on separate occasions into fetal sheep, newborn lambs, and 28-day-old lambs. To determine the roles of endogenous histamine and gastric pH, ranitidine (a histamine-2 receptor antagonist) and omeprazole (a H+/K+ ATPase inhibitor) were coinfused with the agonists. Plasma SRIF and gastrin concentrations were measured by RIA. Pentagastrin stimulated SRIF secretion in the fetus after 131 days of gestation (term is 147 days), whereas stimulation by histamine was effective only after birth. The SRIF stimulatory effect of pentagastrin in 28-day-old lambs was abolished by ranitidine, which also reduced this effect in the adult sheep. This inhibitory effect of ranitidine was shown to be a result of blockade of stimulatory H2 receptors, because in the adult blockade of acid secretion with omeprazole failed to attenuate the response of histamine. These results indicate that in the fetus, gastrin receptors, but not histamine receptors, are functionally involved in the stimulation of SRIF secretion. After birth, both gastrin and histamine stimulate SRIF, but the effect of gastrin is mediated at least in part by the release of endogenous histamine. These responses occur independently of changes in gastric acidity, supporting the concept of a direct negative feedback between SRIF and gastrin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GASTRIN is a stimulant of gastric acidity, and gastric acid, in turn, inhibits gastrin secretion (1, 2). A major component of this regulatory negative feedback loop is somatostatin (SRIF). Somatostatin (SRIF) inhibits gastric acid secretion directly at the parietal cell (1, 2) and indirectly by reducing the release of gastric acid secretagogues. These secretagogues include histamine from enterochromaffin-like cells (3, 4, 5, 6) and gastrin from antral G cells (7, 8, 9).

Gastrin stimulates gastric acid, and until recently it was thought that an increase in gastric luminal acidity was the main stimulant for SRIF secretion (1, 9, 10, 11). However, gastrin stimulated SRIF secretion from isolated fundic cultured D cells (12, 13), isolated perfused stomach (14), and also in vivo, even when changes in gastric acidity were prevented by the proton pump inhibitor omeprazole (15). This suggests that gastrin can act independently of gastric acidity on gastric SRIF release. The argument supporting a regulatory role for gastrin on gastric D cells has been strengthened by the identification of gastrin receptors on D cells in the antrum and fundus of dogs, guinea pigs, and rats (16, 17). Moreover, infusion of gastrin caused an increased secretion of SRIF into the venous blood draining from the fundus and antrum of regionally cannulated adult sheep, and the increase in SRIF release was also reflected in peripheral plasma samples (18). We proposed that the stimulatory effect of gastrin on SRIF secretion is mediated in part by the release of histamine, as coinfusion of gastrin with the histamine H2 receptor antagonist ranitidine was significantly less than the response to gastrin alone (18). However, these studies could not rule out the possibility that the modulating effect of ranitidine on SRIF secretion was on gastric acidity rather than on histamine release.

It is important to dissect out the role of histamine on gastric SRIF secretion because there is no agreement about whether histamine has a stimulatory or an inhibitory effect on SRIF secretion. Vuyyuru et al. (19, 20) reported that histamine exerts an inhibitory effect on the secretion of SRIF from superfused antral and fundic segments. This inhibitory effect of histamine was proposed to be mediated by an inhibitory histamine H3 receptor. Although the inhibitory effects of histamine H3 receptor agonists have been demonstrated in vivo on the secretion of gastric acid and histamine release (21, 22, 23, 24, 25), histamine-mediated inhibition of SRIF secretion has not been demonstrated in vivo. In fact, infusions of histamine or H2 antagonists to dogs and man suggest that histamine is a stimulant of SRIF. However, it is not resolved whether this stimulatory effect of histamine is direct (26, 27) or indirect by an increase in acid secretion (28, 29). We tested this by infusing histamine and omeprazole (a parietal cell proton pump inhibitor) simultaneously.

Demonstrations of the regulation of gastric SRIF secretion by gastrin have been confined to adult in vitro and in vivo animal models (12, 13, 15, 30). There are no reported studies that examine the regulation of SRIF release by gastrin in the fetus or newborn. Progressive hypergastrinemia is observed in ovine (31, 32) and human (33, 34) fetuses, yet expected increases in the secretion of gastric acid and SRIF are small, indicating that feedback regulatory mechanisms governing fetal acid secretion are not present, are underdeveloped (35), or are inhibited. Nevertheless, gastric acid can be stimulated in fetal sheep by exogenous infusions of gastrin and histamine at 115–125 days gestation (31), and SRIF has been reported to inhibit ovine fetal gastrin secretion (36), suggesting that gastrin, histamine, and SRIF receptors are functional.

This study has three aims: 1) to evaluate whether gastrin mediates the secretion of gastric SRIF via the release of histamine, 2) to determine whether histamine regulates gastric SRIF independently of gastric pH, and 3) to determine the developmental profile of gastric SRIF regulation by gastrin and histamine.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Merino-Corriedale cross-pregnant ewes (30–45 kg) of known gestational age and adult sheep of either sex were housed on site at the departmental animal house. Food was withheld for 24 h before surgery, but water was provided ad libitum. Vascular cannulation was performed on fetal sheep from approximately 108 days gestation (term is 145–147 days). Under general anesthesia, polyethylene cannulas were inserted into the carotid artery (for blood sampling) and jugular vein (for infusion) of the fetus and into the jugular vein of the ewe as described previously (36). The fetal cannulas were exteriorized via a flank incision in the ewe. A 5- to 7-day recovery was allowed before experimental procedures. Adult sheep, neonatal lambs, and older lambs also had cannulas inserted into both jugular veins. One cannula was directed toward the heart for infusion of test substances, whereas the other was directed toward the head for blood sampling.

Experimental design
Fetuses, lambs, and adults were given, in random order, an infusion of histamine (David Bull Laboratories, Inc., Mulgrave, Australia) diluted in saline or pentagastrin (Sigma Chemical Co., Castle Hill, Australia) dissolved in dimethlysulfoxide and 0.1 M NH4HCO3 and then saline. Two or 3 days were allowed between infusions. Blood samples of 4 ml were taken as indicated below; fetal sampling was performed using a sterile technique.

Fetal experiments
The age groups for fetal experiments were less than 131 days and more than 131 days. A significant decrease in gastric pH was observed in ovine fetuses from approximately 131 days gestation (20). The rate of infusion for fetal experiments was 4 ml/h.

Pentagastrin. Pentagastrin at 30 µg/h was infused into the jugular vein of fetuses in both age groups for 1 h. Blood samples were collected from the fetal carotid artery at -20 and 0 min, at 20-min intervals during the 1-h infusion, and at 20 min postinfusion.

Histamine. Histamine at 300 µg/h was infused into fetuses in the more than 131-day-old group and was not tested in the less than 131-day-old group. Blood samples were obtained as described for the fetal pentagastrin infusion.

Lamb and adult experiments
Newborn lambs aged 2–5 days (neonates) and lambs aged 28–30 days were used in the experiments. Newborn lambs were infused at 4 ml/h, the 28- to 30-day-old lambs were infused at 6 ml/h, and adult sheep were infused at 20 ml/h.

Pentagastrin. Lambs were infused with pentagastrin at 30 µg/h, and the adult sheep were infused at 10 µg/kg·h for 2 h.

Pentagastrin plus ranitidine to lambs and adults. To determine whether pentagastrin stimulated SRIF through the release of histamine, 28- to 30-day-old lambs were infused with ranitidine (Zantac, Glaxo Australia, Boronia, Australia) for 1 h preceding the pentagastrin infusion, and this was continued during the subsequent 1 h of pentagastrin treatment. Ranitidine was administered as a bolus dose of 0.5 mg/kg followed by an infusion of 1.5 mg/kg·h. A similar protocol was used for adult sheep, except that ranitidine alone and ranitidine plus pentagastrin were each infused for 2 h. This dose of ranitidine blocks basal and stimulated gastric acid secretion in sheep (15, 18).

Histamine. Lambs were infused with histamine at 300 µg/h for 1 h, whereas adult sheep were infused with 60 µg/kg·h histamine for 2 h.

Histamine plus omeprazole or histamine plus ranitidine infusion to adults. To determine whether the stimulating effect of histamine was mediated by the consequential increase in gastric acidity, histamine was infused alone and together with omeprazole. After a 20-min basal period, omeprazole (Astra Pharmaceuticals, Sydney, Australia; 0.65 mg/kg) dissolved in saline-0.1% BSA (wt/vol) was administered as a bolus and then infused (0.90 mg/kg·h) for 120 min at a rate of 20 ml/h. At 120 min, histamine (60 µg/kg·h) was added to omeprazole treatment, and the infusion was continued for a further 120 min. To ensure that the effect of histamine was mediated by H2 receptors, the experiment was repeated with ranitidine (0.50 mg/kg bolus, 1.5 mg/kg infusion) used instead of omeprazole. These doses of omeprazole and ranitidine block basal and stimulated gastric acid secretion in sheep (15, 18, 31).

RIA
Amidated gastrin concentrations were measured in plasma by RIA using previously characterized gastrin antiserum 1296 (36). Antibody 1296 recognizes all amidated COOH-terminal gastrin fragments greater than the pentapeptide. Cross-reactivity with glycine-extended gastrin, cholecystokinin amide, or pentagastrin was negligible. The minimum assay detection limit was 0.2 fmol/ml, the calculated ID50 was 0.92 ± 0.05 fmol/tube, and the intra- and interassay variations were less than 2% and less than 11%, respectively. Plasma SRIF was measured after ethanol extraction using antiserum 8402, which recognizes both SRIF-14 and SRIF-28 equally (37). The ID50 was 6.7 ± 2.4 fmol/tube, and the intra- and interassay variations were less than 5% and less than 12% respectively.

Calculations and statistical analysis
Results are expressed as the mean ± SEM. The area under the plasma gastrin and SRIF concentration-time curves was calculated as described previously (18). A paired t test was used to compare basal SRIF output with output during the 60-min stimulation period. A one-way ANOVA procedure with an all pairwise multiple comparison test procedure (Tukey’s test) was used to test for significant differences in the 60-min plasma SRIF or gastrin output between age groups receiving different treatments. A similar procedure was used to test statistical differences among histamine-treated, histamine- plus ranitidine-treated, and histamine- plus omeprazole-treated sheep. Statistical differences between the pentagastrin-treated and the pentagastrin- plus ranitidine-treated groups were compared with paired t test. P < 0.05 was considered significant.

Ethical approval
Ethical approval for all experiments was obtained from the Austin and Repatriation Medical Center animal ethics committee.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Integrated SRIF and gastrin outputs after 60-min infusion of pentagastrin or histamine
Figure 1AGo summarizes the 60-min integrated output of SRIF during pentagastrin or histamine infusion in all age groups. Pentagastrin had no significant effect on SRIF output in the less than 131-day-old fetuses. In the more than 131-day-old fetuses, pentagastrin significantly stimulated SRIF output (P < 0.05) with larger SRIF responses in the neonate, lamb, and adult. Fetuses less than 131 days of age were not infused with histamine because preliminary experiments with fetuses older than 131 days indicated that infusion of histamine had no effect on SRIF output. A significant increase in SRIF secretion in response to histamine infusion was first observed in the neonate and was maintained in the lamb and adult.



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  		Figure 1. A, Integrated output of plasma SRIF for all age groups after 60-min infusion of pentagastrin or histamine. B, Integrated output of plasma gastrin for all age groups after 60-min infusion of pentagastrin or histamine. Significantly different from baseline (by paired t test): *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are expressed as the mean ± SEM. n, Number of animals.

 
Figure 1BGo shows the integrated output of gastrin during the 60-min infusions of pentagastrin and histamine in all age groups. A significant decrease from baseline values was observed in the adult infused with histamine (P < 0.05). In contrast to the fall in gastrin after histamine infusion, there was no measurable inhibitory effect of elevated SRIF secretion on gastrin secretion in the different age groups after pentagastrin infusion. The absence of such an effect can be explained by cross-reactivity between pentagastrin and gastrin antibody 1296, which is approximately 0.1%.

In pairwise multiple comparisons tests, the adult pentagastrin-SRIF response was significantly greater than those in the other pentagastrin-treated age groups (P < 0.05), except for the 28-day-old lamb and all histamine-treated animals. The outputs of gastrin from different age groups and treatments were not significantly different.

Infusion of ranitidine and pentagastrin to lambs and adult sheep
Figure 2AGo shows the plasma SRIF concentration in 28-day-old lambs infused with pentagastrin alone for 2 h, and Fig. 2BGo shows the plasma concentration of SRIF in lambs treated with ranitidine for 1 h followed by a combination of ranitidine and pentagastrin for the second hour. Treatment with pentagastrin alone increased SRIF concentration more than 2-fold over the basal concentration within 20 min, from 81 ± 15 to a maximum of 165 ± 49 pmol/liter, and this was sustained for the entire 2 h of infusion. Ranitidine blocked any stimulatory effect of the subsequent pentagastrin infusion (Fig. 2BGo). Pentagastrin administration to adult sheep produced a larger increase in SRIF (from 24 ± 2 to a maximum of 122 ± 11 pmol/liter) compared with that in the 28-day-old lambs. As summarized in the integrated outputs, ranitidine only partially blocked pentagastrin-stimulated SRIF secretion in adult sheep compared to that in lambs where complete blockade was observed (Fig. 3Go).



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  		Figure 2. A, Plasma SRIF concentration in 28-day-old lambs during infusion of pentagastrin alone for 2 h. B, Plasma SRIF concentration in 28-day-old lambs during infusion of ranitidine for 1 h, followed by a combination of ranitidine plus pentagastrin for 1 h. n, Number of animals.

 


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  		Figure 3. Integrated output of plasma SRIF in adult sheep and 28-day-old lambs during the infusion of pentagastrin or pentagastrin plus ranitidine. Significantly different from baseline (by paired t test): *, P < 0.05; **, P < 0.01. Pentagastrin plus ranitidine is significantly reduced compared with pentagastrin alone (by Tukey’s test): #, P < 0.05. Data are expressed as the mean ± SEM. n, Number of animals.

 
Plasma gastrin was unchanged during the pentagastrin infusion, but increased during the ranitidine plus pentagastrin infusion from 15 ± 9 to 52 ± 24 pmol/liter at 20 min, 69 ± 20 pmol/liter at 40 min, and 42 ± 19 pmol/liter at 60 min, reflecting the absence of inhibitory effect of SRIF.

Infusion of histamine plus omeprazole or histamine plus ranitidine to adult sheep
Histamine alone increased plasma SRIF from 18 ± 3 to 46 ± 10 pmol/liter (Fig. 4AGo). This response was not modified by the addition of omeprazole, whereas coinfusion of histamine with ranitidine markedly reduced SRIF secretion (Fig. 4BGo). The results are also presented as the integrated output and show that omeprazole had no significant effect on histamine-stimulated output, whereas ranitidine reduced histamine-stimulated SRIF output by 80% (Fig. 5Go).



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  		Figure 4. A, Plasma SRIF concentrations in adult sheep infused with histamine alone for 2 h. B, Plasma concentrations of SRIF in adult sheep after the infusion of histamine in combination with ranitidine or omeprazole.

 


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  		Figure 5. Integrated output in adult sheep of plasma SRIF after 2 h of infusion of histamine alone, histamine combined with ranitidine, and histamine combined with omeprazole. Significantly different from baseline (by paired t test): **, P < 0.01. The output of SRIF is significantly reduced after the infusion of histamine plus ranitidine compared with histamine alone or histamine plus omeprazole (by Tukey’s test): #, P < 0.05. Data are expressed as the mean ± SEM. n, Number of animals.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study has determined an in vivo developmental pattern for the regulation of gastric SRIF secretion by gastrin and histamine. Regulation of SRIF secretion by gastrin and histamine develops at different stages, as pentagastrin stimulates the secretion of SRIF in the fetus, whereas histamine is inactive until after birth. By 28 days after birth, the effect of gastrin is dependent on histamine release, whereas in the adult sheep, gastrin stimulated SRIF secretion is only partially dependent on histamine. Gastrin and histamine act on the D cell, independent of acid status, and the histamine effect is mediated by a stimulatory H2 receptor.

Gastrin and histamine are stimulants of gastric acid secretion, and it has long been argued that the consequential increase in luminal acidity is responsible for the increase in SRIF secretion (1, 10, 11). In turn, SRIF inhibits further gastric acid secretion, either by a direct effect on the parietal cell (1, 3) or through an indirect effect by inhibiting the secretion of gastrin and histamine (3, 4, 5, 6, 9). However, direct effects of gastrin on gastric SRIF secretion both in vitro and in vivo have been reported (13, 15, 26). In the case of histamine, the in vitro data from one laboratory suggest that the release of gastric histamine inhibits SRIF secretion via an H3 receptor (19, 20). All other studies conclude that histamine is stimulatory, although whether this is direct or via an increase in gastric acidity has not been resolved (26, 27, 28, 29). For instance H2 antagonists inhibit postprandial SRIF secretion in dogs, and this was claimed to be independent of changes in gastric acidity (26, 27). However, Greenberg et al. (29) found that omeprazole was just as effective as H2 antagonists in inhibiting histamine-stimulated SRIF in dogs, and Lucey et al. (28) concluded that cimetidine inhibited the postprandial increase in plasma SRIF in normal subjects by reducing postprandial gastric acid secretion. In the present study we showed that the stimulatory effect of histamine on SRIF secretion in adult sheep occurred in the presence of omeprazole, which would prevent any change in gastric acidity (15, 18, 31). This extends and complements our previous work, which established that gastrin could regulate SRIF by an acid-independent mechanism (15). The stimulatory effect of histamine appears to be confined to the fundic part of the stomach (18), consistent with the presence of histamine-containing enterochromaffin-like cells in this region (38).

A number of in vitro and in vivo studies have shown that gastrin-stimulated gastric acid secretion is mediated by the release of endogenous histamine (24, 25, 39, 40, 41, 42). However, this does not seem to apply to the immature animal, because in the rat pup the acid secretory response to pentagastrin occurs before the histamine system is functional (43). In the ovine fetus pentagastrin stimulated gastric acidity from 115 days of gestation, and this was usually several days before a positive response to histamine (31). The present study indicates that a similar pattern, although somewhat delayed, exists for the secretion of SRIF, with the response to pentagastrin occurring before histamine. The effect of pentagastrin on SRIF secretion was observed by 131 days gestation, whereas histamine was without effect until after birth. The reason for this differential in maturation between D and parietal cells remain to be determined. Even though the mechanism of SRIF release appears to be immature in the fetus, exogenous SRIF is effective in inhibiting gastrin and pancreatic polypeptide release in the fetal sheep (36).

The requirement for histamine as an intermediary for gastrin-stimulated SRIF secretion increases as the animal matures, similar to the requirements for histamine in acid secretion. Thus, in the 28-day-old lamb, histamine stimulated SRIF, and the H2 antagonist, ranitidine, abolished the stimulatory effect of pentagastrin on SRIF secretion. This indicates that in the neonatal lamb, gastrin-stimulated SRIF secretion is via the intermediary release of histamine, a finding in direct contrast with fetal data, where only a direct effect of gastrin could be demonstrated. The absence of a SRIF response to pentagastrin combined with ranitidine infusion may be caused by the inhibition of acid secretion by ranitidine (1, 10, 11, 12). However, when adult sheep were infused with a combination of histamine and omeprazole or pentagastrin and omeprazole (15), the SRIF response was not affected. Increasing or decreasing gastric acidity has little effect on peripheral plasma SRIF in the sheep (44). It therefore seems likely that the direct effects of gastrin or histamine, independent of the concurrent gastric pH, are being observed.

The direct effect of pentagastrin on the D cell that was present in the fetus and absent in the 28-day-old lamb reappeared in the adult sheep. The same experiment, using coinfusion of pentagastrin with ranitidine in adult sheep, only partly reduced the pentagastrin-alone response to SRIF secretion. The appearance, disappearance, and then reappearance of a pentagastrin-mediated effect are similar to the sensitivity of acid secretion to pentagastrin observed in rats when there is a fetal maturation phase followed after birth by a phase of insensitivity and then normal sensitivity in the adult (45). The factors responsible for variations in histamine dependence for gastrin-stimulated SRIF secretion have not been resolved. Basal circulating SRIF and gastrin are nearly 4-fold higher in lambs than in adults (37), suggesting that reduced sensitivity to gastrin in the lamb is an adaptive regulatory mechanism to high circulating gastrin concentrations. These mechanisms may include a desensitization to gastrin or down-regulation of gastrin receptors at the D cell.

The present work has established that gastrin and histamine are direct stimulants of gastric SRIF secretion. Gastrin has histamine-dependent and histamine-independent effects on SRIF secretion, related to the stage of animal maturation. A similar phenomenon has been noted with the regulation of parietal cell function by gastrin and histamine. The results are consistent with the hypothesis of a regulatory pathway linking gastrin to SRIF and serving to restore SRIF secretion and to modulate gastrin-stimulated acid secretion (15). The mechanism for triggering the switches between histamine dependence and independence is unknown. Identification of the presence and function of histamine and gastrin receptors in the fetal stomach will be an important first step in determining these triggers. These studies are currently in progress.


   Acknowledgments
 
Antibody 8402 raised against SRIF and antibody 1296 raised against gastrin-amide were provided by Center for Ulcer Research and Education/UCLA/Digestive Diseases Center Antibody/RIA Core. We thank Ms. H. Wong and Dr. J. Walsh for the donation of these antibodies. Omeprazole was donated by Astra Pharmaceuticals (Sydney, Australia). The excellent technical assistance of Sister Josephine Baker and Ms. Karen Jehn is gratefully acknowledged.


   Footnotes
 
1 This work was supported by the National Health and Medical Research Council of Australia and NIH Grant DK-41301. Back

Received July 9, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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