Medical Hypotheses 6: 919-927, 1980

SOMATOSTATIN - THE LONG LOST ANTRAL CHALONE

W. E. G .Thomas, University Department of Surgery, Bristol Royal Infirmary,

Bristol BS2 8HW, UK.

ABSTRACT

For many years the existence of an antral inhibitory hormone or chalone has been

controversial. Recent experimental findings however have suggested that there is an

antral inhibitory mechanism, active against gastrin release and gastrin stimulated acid

secretion, that is suppressed in an alkaline milieu and stimulated in an acid milieu.

Antral somatostatin possesses the characteristics necessary to fulfill this role, and these

findings have prompted the hypothesis that somatostatin plays a vital role in the

homeostasis of gastric acid secretion and is indeed the long lost antral chalone.

Key Words: chaione, gastrins, gastric juice, somatotropin release inhibiting hormone.

INTRODUCTION

A great deal of attention in the past has been focused on the presence or absence

of a gastric antral inhibitory hormone or chalone. Many workers have felt that

suppression of the release of gastrin by acid is the only inhibitory mechanism, while

others have advocated a specific chalone, which they claimed to have demonstrated

using divided antral pouch techniques or cross-circulation experiments. The results

have often been conflicting and in I974 Thompson (I) concluded that “it is not yet

possible to make a definitive statement on an antral chalone”. However recent

experiments (2-9) and the discovery of somatostatin in large quantities in the ‘D’ cells

of the antrum (IO) have again raised the possibility of a physiological inhibitor of

gastric acid secretion.

BACKGROUND

In considering a gastric inhibitory mechanism, attention soon focused on the

antrum after Woodward et al (II, 12) demonstrated that the acid response to either mechanical stimulation of the antrum or the introduction of liver homogenate to an

isolated antral pouch, could be markedly reduced by irrigating the antrum with

hydrochloric acid. This was soon confirmed by many others (l3-15), and this inhibitory

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effect of antral acidification was also seen in relation to insulin hypoglycaemia (16),

sham feeding (17), and the intestinal phase of gastric secretion (18).

The nature of this inhibition remained uncertain and indeed still is, although

three possible mechanisms have been postuIated:-

(i) acid reaction in the antrum causes cessation of the production or

release of gastrin;

(ii) inhibition is due to local neural reflex from the antrum;

(iii) acid eiicits the formation or release of a specific humoral inhibitor

or chalone from the antrum.

Many workers still feel that high acidity in the antrum suppressing the production or

release of gastrin is the only inhibitory mechanism (15,19) and since a reliable immuno-

assay for gastrin was introduced in 1970, this fall in serum gastrin with decreasing antral

pH has been clearly shown (20).

The exact mechanism of this suppression of gastrin release is also under debate as

some workers advocated a local neural mechanism (21) while others were unable to block

the inhibitory effect with local anaesthetic and thus refuted such a mechanism (22). It

is however now generally accepted that a fall in antral pH diminishes the formation or

release of gastrin, but many workers feel that this is not the only mechanism of antral

inhibition, and therefore have raised the possibility of an antral inhibitory hormone or

chal one.

The existence of an antral chalone or inhibitor has been the subject of a vast

amount of work but the results are conflicting . Intravenous infusion of gastric juice

from both humans (23) and dogs have been shown to have an inhibitory effect upon

acid secretion, and Hood et al (24) concluded that the antral mucosa was the probable

source of this inhibition. Interpretation of these results must take into consideration the

possibility that secretion may be affected by the presence of pyrogens, as many of these

dogs had rigors during infusions. However, support for active antral inhibition came

from Harrison et al (25) who divided the antrum and transplanted the distal half to the

colon and used the proximal half to restore continuity with the duodenum. They then

monitored Heidenhain pouch acid secretion and found that when the proximal antral

remnant was excised the acid secretion rose by 62% but fell back to basal levels when

the distal remnant was removed. They suggested therefore that the proximal remnant was

releasing an inhibitory substance. It was also found that this effect still persisted if the

proximal antral remnant was denervated (26), demonstrating that this mechanism was not under vogal control, although others have not been able to confirm these results (27).

Divided antral pouch techniques have also been used, one for the stimulation of

gastrin release ond the other for acidification in an endeavour to produce a humoral

inhibitory effect. However the results were conflicting with two groups of workers

producing evidence for its existence (14,28) and two against (13,29). because of these

obviously contradictory results, efforts have been made to demonstrate the existence or otherwise of this elusive chalone by means of cross-circulation experiments (30,3l).

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This concept was supported by Danhof (30) who found inhibition of spontaneous and

histamine induced acid secretion, when an intravenous injection of an extract of blood

draining acidified antra was administered to other dogs, Thompson et al (31) prepared

pairs of dogs with the donor dog being equipped with an isolated antral pouch and a

portal vein cannula, and the recipient being equipped with a Heidenhain pouch and an

inferior vena cava cannula. Cross-transfusions were then undertaken and the donor

dog’s antral pouch then irrigated with decinormal hydrochloric acid, This led to a

significant reduction of acid secretion from the Heidenhain pouch of the recipient dog

when the stimuli were food, acetylcholine or insulin hypoglycaemia. This also occurred

if the antrum was denervated, thus providing a further indication of a separate

inhibitory substance.

Recent experimental findings have further supported the existence of an antral

inhibitory hormone. It has been shown that antral distension in healthy subjects could

decrease acid production if the intra-gastric contents were kept acid (2). However

graded antral distension has also been shown to stimulate acid secretion in patients with

duodenal ulceration but not in healthy subjects (2,3). This differs from the canine

response to antral distension where this stimulus leads to a marked increase in a fundic

pouch secretion, although only a slight increase in serum gastrin (32). However, in

normal human subjects, antral distension with a I50 ml balloon inhibited the response to

pentagastrin by 20%, but not in patients with duodenal ulcers. This suggests that antral

distension elicits inhibitory as well as stimulatory mechanisms and it is interesting to

note that balloon distension of the antrum in man is not accompanied by an increased

release of gastrin (4). It is therefore conceivable that the inhibitory mechanism evoked

by antral distension not only inhibits the response to pentagastrin, but also suppresses

gastrin release. It appears to be more efficient in an acid milieu (5) and is suppressed

by alkalinisation of the antrum.

This concept is further supported by finding that alkaline duodenal reflux produces

functional effects in gastric secretion independently of changes in parietal cell

population. Surgically produced duodeno-gastric reflux causes hypersecretion of gastric

acid to a stimulus of pentagastrin (6), but not to histamine, and also an elevated and

prolonged gastrin response to a meal (7). These effects do not occur when bile alone is

diverted into the stomach, suggesting it is a function of the alkaline pancreatic juice.

This hypersecretion to pentagastrin that is produced by alkaline reflux, cannot be due to

a trophic effect of increased gastrin release, as there is no increase in the response to

histamine and no histological evidence of parietal cell hyperplasia. However a study of the kinetics of these secretory changes does suggest that the alkaline reflux may produce

these effects by suppressing a non-competitive inhibitory mechanism (8) that is active

against both gastrin release, and the sensitivity of the parietal cells to pentagastrin.

If one considers the possibility that these two inhibitory actions were the property of one

specific hormone, then it would appear that this postulated &alone would have to fulfil the following criteria:-

(i) it would have to be naturally occurring;

(ii) it would have to act as a non competitive inhibitor of gastrin

and pentagastrin;

921

(iii) it would not inhibit histamine at physiological doses;

(iv) it would inhibit the release of gastrin from the ‘G’ cells;

(v) its inhibitory activity would be activated in an acid milieu and

suppressed in an alkaline milieu.

A possible candidate hormone for this role is somatostatin. This has been shown to

suppress gastrin release (33) and to decrease parietal cell responsiveness to gastrin (34),

while portal venous blood levels of somatostatin rise with irrigation of the antrum at an

acid pH (35). It thus possesses the necessary characteristics for an antral chalone.

HYPOTHESIS

It is proposed that somatostatin, found in large quantities in the ‘D’ cells of the

gastric antrum, acts as an inhibitory hormone which is activated by an acid pH, thus

providing it with a physiological role in the homeostasis of gastric acid secretion and

allowing it to be a contender for the role of the long lost antral chalone.

DISCUSSION

Somatostatin (growth-hormone release-inhibiting hormone) is a cyclical

tetradecapeptide that was first isolated from the hypothalamus by Brazeau et al in I973

(36). More recently it has also been shown by immunocytochemicai techniques to be

present in the ‘D’ cells of the pancreas (37) and in the gastrointestinal tract (38).

Indeed the gastrointestinal tract contains more somatostatin than the brain with the

highest proportion being found in the antrum of the stomach (IO) where the ‘D’ cells are

found in the lamina propria and are clearly distinct from ‘G’ cells (38). Somatostatin

thus fulfils the first criteria in that it is a naturally occurring substance.

All known actions of somatostatin are inhibitory. It inhibits the release of growth

hormone (39,40) and thyroid stimulating hormone (39) from the anterior pituitary, also

insulin (40), and glucagon (40) from the pancreas. It is a strong inhibitor of pentagastrin

stimulated acid output (33,34) and the kinetics of this inhibition suggests that it acts as

a non-competitive inhibitor in that it decreases the calculated maximal acid output to

pentagastrin (Vmax), but does not significantly alter the dose rate of pentagastrin needed

for half maximal response (Km) (8). This method of action has also been confirmed by

Taborsky et al (41) for its inhibitory effects on the islet cells of the pancreas, where

somatostatin again appears to act in a non-competitive manner. It would therefore fulfil

the second criteria by being able to reproduce the inhibitory effect necessary to explain

the hypersecretion seen with alkaline duodeno-gastric reflux. Indeed a low dose infusion of somatostatin reduces the hypersecretory responses seen with duodenal reflux,

down to control levels (9). These findings are consistent with alkaline reflux suppressing

somatostatin activity, thus leading to an increased responsiveness of the parietal cells to

pentagastrin.

The third criteria is very difficult to assess, as it is impossible at this stage of our

knowledge of somatostatin to state what a “physiological dose” is. It appears to act locally, in a paracrine manner, and the ‘D’ cells have been shown to possess long

922

cellular extensions which would enhance its effect on neighbouring cells (42). It may

also affect the parietal cells by means of a local portal system of vessels in the

stomach (43), which may explain why many pouch techniques have failed to produce a

conclusive answer as to a chalone, because of disruption of this local vascular

arrangement. Systemic venous somatostatin levels are very much lower than portal

levels and the systemic levels may only represent overspill from local activity. However

any alteration in plasma levels or cellular granulation may act as indicators of such

activity, although this cannot be regarded as proven. The widespread distribution of

somatostatin throughout the body, further suggests that it acts locally, as release of

somatostatin in large quantities into the bloodstream may be disastrous because of its

many actions. Such a local action may again explain why it has been so difficult to

demonstrate antral inhibition, other than a decrease in gastrin release. It may be

argued that in double pouch experiments the local gastric portal system of vessels may be

disrupted, and although acidification of an antral pouch may release somatostatin, it

would be unable to reach certain target cells as it does not appear to be a general

circulating hormone. However, it may still display its other local action and suppress

the release of gastrin from neighbouring ‘G’ cells. However, whatever the exact

mechanism or manner of somatostatin activity, it is impossible to state what o

“physiological dose” may be. However, the amount of somatostatin activity that would

need to be suppressed to produce the hypersecretion of acid seen with alkaline reflux,

was found to be equivalent to an infusion of 0.25 ug kg-lh-l (8,9). This dose rate is

very much smaller than those used by other workers in this field, and although one cannot definitely call it “physiological”, it is low enough to suggest that this is a

possibility. Therefore, if one assumes that this may represent a physiological action of

somatostatin, then this dose rate produces no inhibition of histamine stimulated acid

secretion, and thus fulfils the third criteria.

The fourth criteria requires that somatostatin act by suppressing gastrin release

from the ‘G’ cells. This effect has been clearly demonstrated by several workers (8,33).

Moreover a low dose infusion of 0.25 ug kg-Lh-I somatostatin once again can be seen to

convert the elevated gastrin response to a meal seen with duodenal reflux down to almost

control levels (8).

The fifth criteria requires that somatostatin activity would be activated in an acid

milieu and suppressed in an alkaline milieu. Again this is extremely difficult to assess if its activity is purely local, as ‘D’ cell granulation and serum levels may not accurately

represent an indication of paracrine activity. However, there are certain indications that an alkaline pH in the antrum suppresses somatostatin release from ‘D’ cells.

Gustavson and Lundqvist (44) have shown that irrigating the antra of pigs with

bicarbonate led to a fall in portal blood somotostatin, and that this also occurred when ‘0x0’ was used for irrigation. Vcgal stimulation has also been shown to release somatostatin into the gastric lumen as long as the antrum remains at on acid pH (45).

However, an alkaline pH inhibits this release, thus suggesting that somatostatin release could well be inhibited by alkaline duodenal reflux, and thus fulfil the fifth criteria.

This is further supported by finding that portal venous blood levels of somatostatin rise

with irrigation of the antrum at an acid pH (35), with degranulation of antrol ‘D’ cells (46) showing that ‘D’ ccl Is respond to alteration in pH. These results and our present

923

knowledge of somatostatin and its characteristics, are therefore consistent with

somatostatin acting as an inhibitor of acid secretion that is suppressed by alkaline

duodenal reflux and activated by an acid milieu.

CONCLUSIONS

Somatostatin, a cyclical tetradecapeptide, is found in the ‘D’ cells of the antrum

in quite large quantities. It is a potent inhibitor of acid secretion when pentagastrin is

the stimulus, but a weak inhibitor when histamine is used, and also inhibits the release

of gastrin from ‘G’ cells. Alkalinisation of the antrum causes somatostatin levels to

fall in the portal venous blood, while acidification produces a rise. Somatostatin thus

possesses all the necessary characteristics to fulfil the role of an antral chalone that

would play a vital part in the homeostasis of gastric acid secretion.

ACKNOWLEDGEMENTS

This work was performed whilst a Bernard-Sunley Research Fellow at the Royal

College of Surgeons of England, and formed the basis of a M. S. Thesis for London

University. I am indebted to professors J. H.Wyllie and D.E.M.Taylor for their

helpful criticism and advice, and to Professor R.Y .Calne who provided facilities in the

Department of Surgery, Addenbrookes Hospital, Cambridge. The somatostatin was

kindly donated by Ayerst Laboratories.

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