Circannual and Circa-Hemiannual Rhythms of Basal and Stimulated Gastric Secretion in Conscious Cats

Conscious cats equipped with a gastric fistula and a denervated Heidenhain pouch were submitted to weekly measurements of the basal and pentagastrin-stimulated gastric secretion for 1 to 14 years. Rhythms of basal secretion were documented in 37 cats for the group studies, in 25 cats only for the individual studies which required at least whole year data. Twelve-month or 6-month rhythms were detected for each variable studied, i.e. volume, acid, pepsin, fucose and uronic acid outputs in the group studies, with peaks for volume, acid and pepsin in Winter, peaks for uronic acid in Spring and Fall indicating different rhythms for oxyntic, chief and mucous cells. Individual studies detected rhythms in 25% of the analyses, and demonstrated male and female and cat to cat differences. Spectral analysis in 3 cats confirmed the differences in the individual rhythms with prominent peaks differing from 365 days in 50% of the cases. Chronopharmacological responses to pentagastrin were documented for volume, acid and pepsin outputs in 5 male and 6 female cats. Group analysis detected a Winter acrophase for volume and acid secretion and a Summer acrophase for pepsin secretion. Analysis of the stimulated response data showed interindividual variation but a higher percentage of detection for rhythms, i.e. 38% for all variables and 50% for pepsin secretion. Different rhythms in acid and pepsin secretion documented in individual studies could provide the basis of a better understanding of the discrepancies reported in the literature concerning the seasonal incidence of peptic ulcer disease.     

Small Bowel and Plasma Gastrin Rhythms in Cats

The purpose of this experiment was to study the possible role of the gastric antrum and small bowel in the rhythm(s) of plasma gastrin. The cat was used as the laboratory animal. Three groups of cats were provided with a gastric fistula for the study of gastric acid and plasma gastrin rhythms. The first group (N = 7) served as controls. A second group (N = 3) was antrectomized and later subjected to a 80% small bowel resection. Gastric acid secretions were collected every 30 min from 0800 to 2400. Blood samples for determination of gastrin were drawn every 2hr from 0800 to 2400. In control animals a circadian (i.e.<24hr) and 3 ultradian (i.e.<24 hr) rhythms were detected for acid output. In the antrectomized cats, circadian and ultradian rhythms were documented. After small bowel resection circadian and ultradian rhythms in gastric acid secretion were observed. For plasma gastrin, circadian and ultradian rhythms were found in the control cats. In the antrectomized cats no rhythms were observed. After small bowel resection an ultradian rhythm reappeared in these antrectomized cats. Removal of the antrum in the cat induces disappearance of circadian and ultradian rhythms of plasma gastrin but fails to modify the acid rhythms. Small bowel resection results in the reappearance of an ultradian rhythm for plasma gastrin and a shift in acrophase for the circadian rhythm in acid secretion.     

Small bowel and plasma gastrin rhythms in cats

The purpose of this experiment was to study the possible role of the gastric antrum and small bowel in the rhythm(s) of plasma gastrin. The cat was used as the laboratory animal. Three groups of cats were provided with a gastric fistula for the study of gastric acid and plasma gastrin rhythms. The first group (N = 7) served as controls. A second group (N = 3) was antrectomized and later subjected to a 80% small bowel resection. Gastric acid secretions were collected every 30 min from 0800 to 2400. Blood samples for determination of gastrin were drawn every 2 hr from 0800 to 2400. In control animals a circadian (i.e. approximately 24 hr) and 3 ultradian (i.e. less than 24 hr) rhythms were detected for acid output. In the antrectomized cats, circadian and ultradian rhythms were documented. After small bowel resection circadian and ultradian rhythms in gastric acid secretion were observed. For plasma gastrin, circadian and ultradian rhythms were found in the control cats. In the antrectomized cats no rhythms were observed. After small bowel resection an ultradian rhythm reappeared in these antrectomized cats. Removal of the antrum in the cat induces disappearance of circadian and ultradian rhythms of plasma gastrin but fails to modify the acid rhythms. Small bowel resection results in the reappearance of an ultradian rhythm for plasma gastrin and a shift in acrophase for the circadian rhythm in acid secretion.     

Circadian Rhythmicity of Acid Secretion and Electrical Function in Intact and Injured Rat Gastric Mucosa—The Relation of Timing to Ulcerogenesis

Alteration of electrical function in mammalian gastric mucosa is considered as an indicator of gastric barrier rupture. Measurements of transmucosal potential difference (PD) and electrical resistance (R) have documented such alterations to a variety of mucosal damaging agents. This study was designed to test whether the rat gastric mucosa exhibits circadian rhythms in acid secretion and electrical function and whether the damage produced by a mucosal acting agent (butyric acid) is also circadian-stage dependent. Mucosa was isolated from the gastric body of male rats standardized from birth to a light-dark regimen. Circadian rhythms of acid secretion and PD and R with acrophases during the dark hours were documented. Administration of butyric acid produced circadian-stage dependent damage with an acrophase also during the dark-phase span. Thus, in this experimental model, measurements of electrical function represented a poor index of gastric mucosal susceptibility to damaging agents. The authors discuss the possibility that rhythms other than those related to electrical function may better define mucosal vulnerability to ulcerogenesis.     

Circadian Rhythmicity of Acid Secretion and Electrical Function in Intact and Injured Rat Gastric Mucosa—The Relation of Timing to Ulcerogenesis

Alteration of electrical function in mammalian gastric mucosa is considered as an indicator of gastric barrier rupture. Measurements of transmucosal potential difference (PD) and electrical resistance (R) have documented such alterations to a variety of mucosal damaging agents. This study was designed to test whether the rat gastric mucosa exhibits circadian rhythms in acid secretion and electrical function and whether the damage produced by a mucosal acting agent (butyric acid) is also circadian-stage dependent. Mucosa was isolated from the gastric body of male rats standardized from birth to a light-dark regimen. Circadian rhythms of acid secretion and PD and R with acrophases during the dark hours were documented. Administration of butyric acid produced circadian-stage dependent damage with an acrophase also during the dark-phase span. Thus, in this experimental model, measurements of electrical function represented a poor index of gastric mucosal susceptibility to damaging agents. The authors discuss the possibility that rhythms other than those related to electrical function may better define mucosal vulnerability to ulcerogenesis.     

Neurotensin inhibition of gastric exocrine secretions in the cat

The gastric exocrine inhibitory activities of neurotensin were characterized in conscious cats prepared with gastric fistulae. Neurotensin was a potent inhibitor of pentagastrin-stimulated pepsin secretion (ID50, approx. 0.3 mumol . kg-1 . h-1) but was approximately 60 times less potent against acid secretion. Neurotensin did not significantly reduce submaximal histamine-stimulated acid or pepsin secretions. the total 2 h acid and pepsin outputs in response to insulin-hypoglycaemia were not reduced by neurotensin, although the peak 15-min outputs were reduced. The reduction in peak secretion was possibly related to neurotensin antagonism of the ability of insulin to lower blood glucose concentrations. Neurotensin alone was not hyperglycaemic when given as an intravenous infusion. Two C-terminal fragments of neurotensin, the dodecapeptide and nonapeptide, inhibited pentagastrin-stimulated pepsin secretion, but were less potent than neurotensin. The observations with the C-terminal fragments indicate that the major determinants of gastric exocrine inhibitory activity of neurotensin reside in its C-terminal; this agrees with observations on other biological activities of neurotensin. The reduced potency of the dodecapeptide indicates the importance of the N-terminal pyroglutamyl residue for full gastric exocrine inhibitory activity.     

The effect of secretin on pentagastrin-stimulated secretion of gastric pepsin and acid in rats.

Rats with chronic gastric fistulas were stimulated for 12 or 24 h with constant intravenous infusion of pentagastrin. When secretin was also infused for the last half period of the experiment, respectively, 6 or 12 h, the volume of gastric secretion and HCl output were significantly reduced but the concentration of pepsin was significantly increased. The dissociated effect of secretin on gastric acid and pepsin secretion reported previously in man, dog and cat was also found in the rat.     

Cyclic hexa- and pentapeptide somatostatin analogues with reduced gastric inhibitory activity

The gastric inhibitory activity of cyclic hexa- and pentapeptide analogues of somatostatin was investigated in conscious cats with gastric fistulae. Gastric acid and pepsin secretions were stimulated by pentagastrin. Cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe) showed no inhibition of acid secretion at molar doses up to 50-times the ID50 for somatostatin. This peptide inhibited pepsin secretion at the highest dose (50 micrograms kg-1 hr-1), and its potency is approximately 0.005 compared with somatostatin (1.0). Cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) inhibited acid (approximately 50%) and pepsin (approximately 85%) secretions, but the inhibition was not dose-related being similar with doses of 10 to 50 micrograms kg-1 hr-1. The cyclic pentapeptide, cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr), was inactive in the dose range studied, with a potency less than 0.01. Cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] has been described as a somatostatin antagonist with respect to inhibition of growth hormone, insulin and glucagon release in rats [2]. Up to 60-fold molar excesses of this peptide failed to antagonise the inhibitory activity of somatostatin in the stomach. The results demonstrate that residues outside the central 6-11 region of somatostatin are very important for its gastric activity. The lack of gastric antagonistic activity of the pentapeptide antagonist indicates that these residues are likely to be involved in receptor recognition/binding.     

Gastric secretion in dogs following three day fasting and resumed feeding

The investigation into the influence of a three-day starvation on the gastric secretion in dogs with Pavlov pouches stimulated by meat, histamine and pentagastrin, was carried out. A 72-hour starvation did not change the summary volume of the gastric juice, debit of the gastric acid, and quantity of pepsin. At the same time the starvation decreased the average rate of gastric juice secretion, gastric acid and pepsin secretion in response to histamine and decreased the pepsin secretion in response to pentagastrin. In this way re-feeding enhanced the average rate of gastric juice secretion and gastric acid secretion on 3-day and pepsin on 5-day in response to meat. The average rate of gastric juice secretion increased on the 5-day after refeeding in response to histamine and the average rate of gastric juice, gastric acid and pepsin secretion in response to pentagastrin.     

Structure-activity studies with cholecystokinin on gastric secretion in the cat

The influence of the position of the sulphate group in CCK on its gastric acid and pepsin stimulating activities was investigated in conscious cats with gastric fistulae. In Boc-CCK7, substitution of tyrosine-SO₃H by ε-hydroxynorleucine-SO₃H, an aliphatic amino acid approximating the length of tyrosine, enhanced acid secretory potency, whilst similar substitution by serine-SO₃H reduced potency, possibly due to the serine residue holding the sulphate group closer to the peptide backbone. Desulphation of Ser-CCK6 reduced acid secretory potency indicating that the known loss of potency upon desulphation of CCK-like peptides is not wholly dependent upon the presence of tyrosine residue in position 7. Sulphated CCK-like peptides are partial agonists of pepsin secretion, and desulphation confers full agonist activity. Analogues of CCK with serine or ε-hydroxynorleucine substituting for tyrosine, whether sulphated or not, showed full agonist activity in stimulating pepsin secretion. These data suggest the presence of the aromatic tyrosine residue, as well as sulphation, to be a necessary prerequisite for pepsin partial agonist activity in CCK-like peptides.     

Inhibitory effect of sorbin on pepsin secretion in conscious cats and rabbits

Sorbin, a 153 amino acid polypeptide isolated from porcine upper small intestine and its shortest synthetic derivative, the C-terminal heptapeptide (C7-sorbin), substituted by D alaninamide in the last position (D7-sorbin), have proabsorptive and antisecretory effect in the different parts of the intestine. We showed that labeled C7-sorbin accumulated not only in the enterocytes and the enteric nervous system but also in the gastric chief cells in the rat. The chief cell secretion of pepsin was then studied in two other species, the cat and the rabbit, simultaneously with the acid secretion of parietal cells. Lipase secretion was studied in the rabbit because lipase is exclusively secreted by the upper cells of the fundic glands, which do not secrete pepsin. The animals were equipped with a gastric fistula, fully innervated, and a Heidenhain pouch, vagally denervated, during a continuous perfusion of pentagastrin (PG) 2 microg/kg. h and vasoactive intestinal peptide (VIP) 4 microg/kg. h. D7-sorbin (100 pmol/kg. h) inhibited cat and rabbit pepsin secretion from the innervated gastric fistula secretion and from the cat denervated Heidenhain pouc secretion, but was without effect on acid secretion and lipase secretion. These data indicate that the inhibitory effect of sorbin is specific on chief cells because the acid parietal cell secretion in both species and lipase upper cell secretion of the fundic glands, in the rabbit, are not implicated.     

Temporal relationships of 21 physiological variables in horse and sheep

Daily or circadian oscillation has been documented in a variety of physiological and behavioral processes. Although individual variables have been studied in great detail, very few studies have been conducted on the temporal relationships between the rhythms of different variables. It is not known whether the circadian pacemaker generates each and every rhythm individually or whether most rhythms are simply derived from a few clock-controlled rhythms. As a first step in elucidating this issue, 21 physiological variables were recorded simultaneously in horse and sheep. The results indicated that, in both species, different variables exhibit different degrees of daily rhythmicity and reach their daily peaks at different times of the day. The variables exhibiting strongest rhythmicity were locomotor activity, rectal temperature, and plasma concentrations of melatonin and glucose. Comparison of rhythmicity and acrophase in the various rhythms allowed inferences to be made about mechanisms of causation.     

Comparison of the gastric exocrine inhibitory activities and plasma kinetics of somatostatin-28 and somatostatin-14 in cats

The gastric exocrine inhibitory activities of somatostatin-28 (SS-28) and somatostatin-14 (SS-14) were determined in conscious cats prepared with gastric fistulae. Gastric acid and pepsin secretions were stimulated with pentagastrin. Expressed in terms of exogenous doses, SS-14 (ID50: 1.49 nmol . kg-1 . h-1) was 3.4 times more potent than SS-28 (ID50: 5.12 nmol . kg-1 . h-1) as an inhibitor of gastric acid secretion. Similarly SS-14 (ID50: 0.25 nmol . kg-1 . h-1) was 3.8 times more potent than SS-28 (ID50: 0.96 nmol . kg-1 . h-1) as an inhibitor of pepsin secretion. Expressed in terms of circulating plasma concentration measured by radioimmunoassay, SS-14 (ID50: H+, 232 and pepsin 73 pM) was 8-9 times more potent than SS-28 (ID50: H+, 2112 and pepsin, 611 pM) as an inhibitor of gastric exocrine secretions. The plasma immunoreactive half-life of SS-28 (6.1 min) was double that for SS-14 (2.4 min) possibly due to a slower theoretical metabolic clearance rate of the larger peptide (30 and 87 ml . kg-1 . min-1, respectively). Both peptides had similar apparent distribution volumes (SS-14, 306 and SS-28, 263 ml . kg-1). As judged by gel chromatography of plasma samples, there was no evidence for the conversion of SS-28 to SS-14 in vivo. The reduced activity of SS-28, compared with SS-14, against gastric exocrine secretions contrasts with its more potent effects in the pituitary and pancreas.     

Evidence against prostaglandin-mediation of somatostatin-inhibition of gastric secretions

The inhibitory activities of somatostatin and PGE2 against pentagastrin-stimulated gastric acid and pepsin secretions were investigated, with and without pretreatment with the cyclooxygenase inhibitor indomethacin, in conscious cats prepared with gastric fistulae. Somatostatin was a potent inhibitor of acid secretion in both vagus intact and vagotomized animals, and its effect was not diminished by indomethacin pretreatment. Somatostatin inhibition of pepsin secretion was diminished after indomethacin, but a similar effect was noted with exogenous PGE2, suggesting a mechanism unrelated to inhibition of prostaglandin synthesis. It is concluded that there is no evidence to implicate endogenous prostaglandins in somatostatin inhibition of feline gastric exocrine secretions.     

Somatostatin,prostaglandin E2 and atropine inhibition of the gastric actions of bombesin in the dog

Bombesin, acetylcholine, prostaglandins and somatostatin are all thought to be involved in the regulation of gastrin release and gastric secretion. We have studied the effects of low doses of atropine, 16-16(Me)₂-prostaglandin E₂ (PGE₂) and somatostatin-14 on bombesin-stimulated gastrin release and gastric acid and pepsin secretion in conscious fistula dogs. For reference, synthetic gastrin G-17 was studied with and without somatostatin. Bombesin, in a dose-related manner, increased serum gastrin, which in turn stimulated gastric acid and pepsin secretion in a serum gastrin, concentration-dependent manner. Somatostatin inhibited gastrin release by bombesin as well as the secretory stimulation by G-17; the combination of sequential effects resulted in a marked inhibition of bombesin-stimulated gastric acid and pepsin secretion. PGE₂ also strongly inhibited gastrin release and acid and pepsin secretion. Atropine had no significant effect on gastrin release, but greatly inhibited gastric secretion. Thus somatostatin and PGE₂ inhibited at two sites, gastrin release and gastrin effects, while atropine affected only the latter.     

Effect of somatostatin on the secretin-induced gastric secretions of pepsin and mucus in cats

The effect of somatostatin 14 on gastric stimulation produced by secretin was determined in 6 conscious cats equipped with a gastric fistula and a denervated fundic pouch. Somatostatin strongly inhibited the basal and secretin-induced pepsin secretion. It did not, however, inhibit the secretin-induced mucus secretion, even though it decreased the basal mucus secretion. During somatostatin administration, the secretagogue effect of secretin on mucus secretion might be dissociated from its stimulatory action on pepsin secretion.     

Structure-activity studies with somatostatin: the role of tryptophan in position 8

The gastric acid and pepsin inhibitory activities of 21 analogues of somatostatin, the majority modified at position 8, were determined in conscious cats in order to examine the importance of Trp8 for the activity of somatostatin. Pepsin secretion stimulated by pentagastrin was 5 times more sensitive, compared with the acid secretion, to inhibition by somatostatin. All the analogues showed similar differential sensitivity, indicating a similar specificity of somatostatin receptors involved in the inhibition of these two secretions. Halogenated-Trp8 analogues of somatostatin were only equipotent or slightly more active than somatostatin against gastric secretion in the cat, whilst these analogues are up to 30 times more potent against growth hormone release in the rat, indicating a different specificity of the two groups of receptors. Studies with the position 8 modified analogues suggest that the electron density of the aromatic nucleus of Trp8 may be relatively unimportant in determining the gastric inhibitory activity, whilst it can be concluded that the role of Trp8 in somatostatin depends to a large extent on the indole NH group. The precise role of Trp8 in somatostatin could be an involvement in the binding of somatostatin to its receptors, or involvement in forming the biologically active conformation of somatostatin.     

Gastric secretion and gastrin under progressive doses of somatostatin-14 and -28 administered intraperitoneally to the rat

The actions of progressive doses of intraperitoneally (IP) administered somatostatin-14 (SS-14) and -28 (SS-28) on gastric secretion (acid, pepsin) and mucosal blood flow (MBF) were studied in conscious gastric fistula rats both under basal conditions and under additional administration of pentagastrin. Also, somatostatin-like immunoreactivity was measured in aortal blood in all groups as well as aortal gastrin levels under basal conditions. IP infusion of equimolar doses of SS-14 and SS-28 resulted in an equal and dose-dependent inhibition of basal as well as pentagastrin-stimulated gastric acid secretion. MBF was reduced by either peptide both in the basal and pentagastrin experiments. Under basal conditions pepsin secretion was significantly increased by infusion of SS-14 at the higher doses, by infusion of SS-28 only at the intermediate dose (3.1 nmole kg-1.hr-1). In the pentagastrin experiments, low and intermediate doses of SS-14 tended to lower pepsin outputs but the highest dose of SS-14 stimulated pepsin secretion, whereas SS-28 had no effect on pepsin. Administration of SS-28 inhibited gastrin only at the highest dose (12.3 nmole kg-1.hr-1), and SS-14 had no influence at all on gastrin. After IP infusion of both peptides, plasma SLI rose dose-dependently under basal and stimulated conditions. Gel chromatography indicated an in-vivo conversion of SS-28 to SS-14 or intermediate fragments. It is concluded that SS-14 and SS-28 delivered by IP infusion, inhibit basal and stimulated gastric acid equally in the rat without suppressing gastrin. The mechanism underlying SS-mediated pepsin stimulation is unknown.     

The influence of a new prostaglandin E2 analogue (FCE 20700) on gastric acid and pepsin secretion in the dog.

The effects of FCE 20700, a new prostaglandin E₂ analogue, on gastric acid and pepsin secretion stimulated by different secretagogues were studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucose were simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF was not significantly affected. It is concluded that FCE 20700 possesses a weak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion.     

Effect of feeding frequency on the daily rhythms of acidic digestion in a teleost fish (gilthead seabream)

Gilthead seabream is a fish species of great importance in Mediterranean aquaculture, attracting many studies on nutrition and chronobiology, although nothing is known about the effect of feeding frequency on the daily rhythms of the gastric digestion process. In this article, we investigated daily rhythms in stomach fullness, gastric and intestine pH, as well as pepsin activity and expression of pepsinogen and proton pump in juvenile fish under three different feeding protocols: (A) one daily meal at 9:00, (B) two daily meals at 9:00 and 17:00 and (C) continuous feeding during the daytime. The results revealed that feeding protocol affected significantly the rhythm of gastric pH and the pepsin activity pattern. The gastric pH exhibited significant daily rhythms in the three cases with the acrophase located at night in the regimes A and B and during daytime, in the regime C. In the regimes A and B, the pepsin activity peaked few hours after the meals, although the afternoon meal in B produced a higher peak. In the regime C, the peak occurred in the middle of the feeding period. Lowest total pepsin activity was observed in regime A, and the highest activity with the regime C. In contrast, the pepsinogen gene expression remained low along the daily cycle, with an expression peak just before or after the morning meal in regimes A and C, respectively. The proton pump gene expression was also practically constant with a peak right after the morning meal in the regime C. On the other hand, intestinal pH showed a postprandial increase after the first morning meal in all the three treatments, recovering the resting values in the dark period. Two meals and continuous feeding allowed a better and prolonged gastric digestion and consequently the juveniles exhibited better growth with the same daily ration of food. In short, while the gastric digestion pattern is mainly driven by pH changes induced by the time of food ingestion, the regulation of the intestinal digestion seems to be more independent of the feeding protocol.