Gastric Fistula Cats Research Articles

YM022, a highly potent and selective CCKB antagonist inhibiting gastric acid secretion in the rat, the cat and isolated rabbit glands.

We investigated the effects of the novel CCKB/gastrin antagonist YM022 on gastric acid secretion in vivo and in vitro, compared to CI-988 and L365,260 as reference antagonists. In the anaesthetized rat, pentagastrin-induced stimulation of gastric acid secretion was dose-dependently and up to 100% inhibited by i.v. administration of YM022 with an ID50 of 0.009 +/- 0.0006 mumol/kg h in comparison to 0.6 +/- 0.03 and 3.40 +/- 0.05 mumol/kg h for CI-988 and L-365,260, respectively. In the gastric fistula cat, i.v. administration of YM022 produced a similar inhibitory effect with an ID50 of 0.02 mumol/kg in comparison to 1.6 and 2.5 mumol/kg for CI-988 and L-365,260, respectively. Furthermore, bolus injection of 0.6 mumol/kg YM022 produced 100% inhibition within 30 min and 85% inhibition was still observed after 3 h. In the isolated rabbit gastric glands, CCK8-stimulated 14C-aminopyrine uptake was inhibited according to the following rank order of potency: YM022 (IC50 = 0.0012 microM) > > CI-988 (IC50 = 0.2 microM) > > L365,260 (IC50 = 2.8 microM). Unlike with L365,260, no influence of CI-988 and YM022 on histamine-stimulated acid output was shown in this study. Thus, YM022 is a highly potent and selective gastric CCKB/gastrin receptor antagonist and has a long-lasting inhibitory effect on gastric acid secretion.

Evidence that histamine H3 receptors are involved in the control of gastric acid secretion in the conscious cat.

In an attempt to assess the role of histamine H3 receptors in the control of gastric acid secretion, the effects of the selective histamine H3 receptor agonist, (R) alpha-methylhistamine and antagonist, thioperamide were evaluated in the conscious gastric fistula cat under basal conditions and against different stimuli. (R) alpha-methylhistamine (0.05-0.2 mumol/kg/h) was ineffective against spontaneous and dimaprit-induced acid secretion; it also did not reduce significantly pentagastrin-induced acid output, but caused a dose-dependent (0.05-0.1 mumol/kg/h) and significant inhibition of the acid response to 2-deoxy-D-glucose. Thioperamide (0.02-0.04 mumol/kg/h) did not modify spontaneous acid secretion, whereas it evoked a significant enhancement of the acid response to submaximal doses (50 mg/kg i.v.) of 2-deoxy-D-glucose. Thioperamide completely reversed the inhibitory effect of (R) alpha-methylhistamine against 2-deoxy-D-glucose-induced secretion, while leaving unaffected the inhibition induced by somatostatin. These data suggest that histamine H3 receptors may be involved in the control of acid secretion stimulated by indirectly acting secretagogues.

Increased parietal cell sensitivity after chronic treatment with ranitidine in the conscious cat

The sensitivity of histamine H2 receptors of the gastric mucosa after one month treatment with ranitidine, administered daily (5 mg/kg i.m.), was checked in 5 conscious cats provided with gastric fistula. Basal acid secretion as well as the acid response to the H2 agonist dimaprit (60 micrograms/kg/hr) were studied before and at different periods after cessation of ranitidine treatment (1, 3, 7 and 14 days). Control experiments were carried out in 5 gastric fistula cats which received daily physiological saline for one month. Basal acid secretion in treated animals increased significantly (p less than 0.05) from 0.04 +/- 0.002 to 0.24 +/- 0.05 mEq H+/10 min. Also the response to dimaprit increased significantly (p less than 0.05) from 0.49 +/- 0.08 to 0.86 +/- 0.12 mEq H+/10 min. Seven days after cessation of treatment, both basal and stimulated secretion returned to pretreatment levels. In control cats no significant difference was noticed in basal and stimulated secretion at the beginning and at the end of the study.

Antisecretory activity of omeprazole in the conscious gastric fistula cat: Comparison with famotidine

The antisecretory activity of the H+/K+ ATPase inhibitor omeprazole was studied in the conscious gastric fistula cat in comparison with the H 2-blocker famotidine. Omeprazole caused a dose-dependent inhibition of the dimaprit-induced acid secretion, being approximately fivefold less potent than famotidine (intravenous ID 50s were 0·34±0·03 and 0·067±0·015 μmol/kg for omeprazole and famotidine, respectively). Omeprazole caused a non-competitive inhibition of the dose-response curve to dimaprit, whereas famotidine induced a parallel shift to the right without depressing the maximum response. Conversely from famotidine, the antisecretory effect of omeprazole was found to be dependent on the acid secretory state of the stomach, the effect being more evident when the compound was administered at the plateau of acid secretion. The inhibitory effect of omeprazole was very long lasting (25% inhibition was still present 24 h after administration of the drug) whereas that of famotidine was overcome by dimaprit infusion within 3–4 h. The antisecretory effect of omeprazole concerned to the same extent the volume and the acid concentration of the gastric juice, whereas famotidine reduced mainly the volume. When the stimulus was represented by pentagastrin the intravenous ID 50 values were 0·57±0·03 and 0·088±0·015 μmol/kg for omeprazole and famotidine, respectively. From the above data it may be concluded that the antisecretory profile of omeprazole differed markedly from that of famotidine, independently from the potency and the efficacy of the two drugs.

Influence of urea-equivalent groups in position 5 of 2-amino, 2-(1-aminoethylidenamino) and 2-guanidino thiazole derivatives on H2-receptor antagonist activity in gastric fistula cat

A series of thiazole derivatives, in which a side-chain with different urea-equivalent groups was introduced in position 5 of the heterocycle, have been tested as inhibitors of dimaprit-induced gastric acid and pepsin secretion in the gastric fistula cat. By comparing the in vivo and the previously reported in vitro activity of these compounds, we can note a very close parallelism not only in the quality of their action but also in the estimates of pA2 values. These data support an interdependence between the molecular substructures and the affinity for the H2-receptor.

Inhibitory effect of famotidine on cat gastric secretion.

The inhibitory effect of the novel H2 receptor antagonist famotidine was studied in conscious gastric fistula cats against dimaprit-induced hypersecretion, in comparison with ranitidine. On the secretory plateau induced by dimaprit (2 mumol kg-1 h-1) famotidine (0.05-0.2 mumol kg-1 i.v.) exerted a dose-dependent inhibitory effect, being approximately 4.5 times as potent as ranitidine (ID50 values were 0.067 +/- 0.015 and 0.30 +/- 0.025 mumol kg-1 for famotidine and ranitidine, respectively). No significant differences were found between the two drugs, as for the time-course of the inhibitory effect. Famotidine (0.01-0.32 mumol kg-1 h-1) caused a parallel displacement of the dose-response curve to dimaprit to the right, without reducing the maximum response to the stimulant, thus behaving as a competitive antagonist, like ranitidine. pA2 values for famotidine and ranitidine were 7.95 and 6.92, respectively. In the same range of doses famotidine dose-dependently reduced also the secretory response to histamine. From these data it was concluded that famotidine is a potent histamine H2 receptor antagonist in the cat gastric mucosa; moreover, conversely from "in vitro" data, the antagonism was surmountable even at the highest doses tested. In vivo experiment, therefore, did not reveal any particular feature of this compound, apart from the undoubtedly high potency, in comparison with other members of the family.

Gastric acid response to pentagastrin and gastrin-releasing peptide in conscious cats.

The mammalian counterpart to bombesin, gastrin-releasing peptide (GRP), is considered to stimulate gastric acid secretion by release of endogenous gastrin. The present study was carried out to examine if GRP has a stimulatory action on acid secretion in addition to that produced by released gastrin. In 4 gastric fistula (GF) and Heidenhain pouch (HP) cats, 160 pmol X kg-1 X h-1 i.v. GRP produced a GF and HP acid response that amounted to 22 and 13%, respectively, of the maximal acid response to pentagastrin, with no rise in serum gastrin concentration. GRP significantly increased the maximal acid response to pentagastrin in the GF but not in the HP. These results suggest that GRP stimulates acid secretion in cats also by an action not related to the release of gastrin. This action is greater in the presence of vagal innervation.

Action of the new H2-antagonist, DA 4577, on different in vitro and in vivo preparations.

The new H2-antagonist, 4(5)-(4- isopropylaminomethyleniminophenyl )-imidazole (compound marked DA 4577), was tested for its activity on different in vitro preparations and also in the conscious cat. Its effect was compared with that of some new H2 antagonists. Two sets of experiments were performed: in the first, concerning the specific H2-receptor antagonism, DA 4577 was found to be extremely potent on the guinea-pig papillary muscle and on the human atrium stimulated by histamine (pA2 = 8.24 and 8.60 respectively). Compound DA 4577 was also found very active in inhibiting histamine-induced acid secretion from the isolated rat fundus (pA2 = 7.37) and on the dimaprit-induced gastric secretion in conscious gastric fistula cats (ID50 = 0.39 mumol kg-1 h-1). In the second set of experiments, concerning effects independent of the H2-receptor blockade (side effects of the molecule), compound DA 4577 was found to be devoid of negative inotropic effect on the human atrium in the absence of histamine stimulation; in this respect it behaved like cimetidine or ranitidine but unlike oxmetidine which showed a constant negative inotropic effect even at concentration 10 times lower than those of DA 4577. Furthermore DA 4577 was ineffective in modifying gastrointestinal motility in vitro in concentrations up to 3 X 10(-4) M, conversely from ranitidine (which stimulated motility) and oxmetidine (which inhibited motility). On the whole DA 4577 appeared to be a very potent and selective H2 antagonist which, unlike other members of the family, is devoid of non-specific effect on human atrium and on motility of the gastrointestinal tract of different animal species.

Stimulated gastric prostaglandin output, and the effect of inhibition of prostaglandin synthetase, in the conscious cat.

1. In the conscious gastric fistula cat there was no correlation between the outputs of gastric acid and PGE secreted in response to incremental doses of pentagastrin and histamine acid phosphate. 2. PGE secreted in response to pentagastrin and histamine was not dose dependent. 3. Flurbiprofen significantly inhibited the gastric output of PGE but did not influence acid or pepsin secretion. Inhibition of PGE secretion was accompanied by evidence of gastric mucosal haemorrhage. 4. It is concluded that gastric juice PGE is unlikely to be involved in the physiological control of acid secretion.

Endogenous prostaglandins and stimulated gastric secretion in the cat: the effect of various secretory inhibitors.

1. The effects of cimetidine, somatostatin and atropine upon the outputs of acid, pepsin, prostaglandins (PG) E and F in gastric juice secreted in response to i.v. infusions of pentagastrin and histamine (H) have been studied in the conscious gastric fistula cat. 2. At constant rate infusions secretion of PGE occurs and follows a similar pattern to that of gastric acid. However the ratio of H:PGE varies considerably and to an extent inexplicable in terms of assay variation. 3. Inhibition of acid output is matched by inhibition of the output of PGE, but changes in concentration of PGE suggest this is a volume related phenomenon. 4. It is concluded that gastric juice PGE is most unlikely to have a regulatory effect upon acid secretion.

The effect of anaesthesia on pentagastrin stimulated gastric acid secretion in the cat.

1. The effect of Saffan (alphaxalone and alphadolone acetate) and Nembutal (pentobarbitone) anaesthesia on gastric acid secretion stimulated by I.V. bolus injections of pentagastrin was investigated in the gastric fistula cat. The effect of Saffan anaesthesia was also tested on I.V. near-maximal and sub-maximal infusions of pentagastrin. 2. Neither anaesthetic reduced the acid secreted in response to bolus injections of pentagastrin. Increased acid secretion with the anaesthetic was noted at some doses of pentagastrin in both intact and vagotomized animals. 3. Saffan anaesthesia had no effect on near-maximal gastric acid secretion stimulated by pentagastrin 8 microgram kg-1 hr-1 but increased the response to pentagastrin 1 microgram kg-1 hr-1. 4. It is suggested that the differences in the acid secretory responses of the anaesthetized acutely prepared animal compared with the conscious animal are a consequence of the surgical procedures rather than the state of consciousness.

Gastric and pancreatic responses to meals varying in pH.

1. Gastric acid response to a test meal of 10% peptone was measured in chronic gastric and pancreatic fistula cats using the Fordtran and Walsh method, monitoring the rate at which a solution of 0.5 M sodium bicarbonate had to be added to maintain constant pH of gastric content at pre-selected values ranging from 5.0 to 1.0. Simultaneously, pancreatic secretion was determined by the standard collection technique. In this way the pH profile for the inhibition of gastric secretion and stimulation of pancreatic secretion has been established in cats.2. A peptone meal adjusted to pH 5.0 produced gastric acid output similar to the maximal response to histamine or pentagastrin. It provoked a negligible stimulation of pancreatic flow rate and bicarbonate output but a large protein output.3. Graded decrease of the peptone meal pH to below 4.0 resulted in inhibition of gastric acid production and in a concomitant stimulation of pancreatic secretory volume and bicarbonate output. A meal adjusted to pH 1.0 stimulated gastric secretion only about 30% of the response recorded at pH 5.0. Pancreatic secretion with a meal adjusted to pH 3.0 reached the highest level of about 70% of the maximal response to exogenous secretin.4. Since the observed changes in the secretory activity of the stomach and the pancreas induced by test meals adjusted to pH 3.0 can be fully reproduced by exogenous secretin, it is suggested that in the cat this hormone may be responsible for the gastric inhibitory and pancreatic stimulatory mechanisms activated during normal digestion of food.

Cardiovascular effects of burimamide and metiamide.

In anaesthetized gastric fistula cats with a histamine infusion running the effect of the histamine H2-receptor antagonists burimamide and metiamide on blood pressure and cardiac frequency was investigated.

The Effects of Thyrocalcitonin on Gastric Acid Secretion in Intact and Thyroidectomized Thyroxin-Substituted Gastric Fistula Cats

The Effects of Thyrocalcitonin on Gastric Acid Secretion in Intact and Thyroidectomized Thyroxin-Substituted Gastric Fistula Cats

Acid base balance in relation to gastric acid secretion stimulated by histamine and pentagastrin in cats.

1. In anaesthetized gastric fistula cats gastric acid secretion and the following blood gases and acid base parameters were determined in the arterial blood and in the gastric venous drainage: pH, HCO3−concentration, pCO2 and pO2. 2. During pentagastrin-stimulated gastric acid secretion HCO3−concentration and pH rose in the gastric venous effluent and to a small extent in the arterial blood. The venous pO2 dropped. 3. During histamine-stimulated gastric acid secretion, in addition to the changes occurring during pentagastrin-stimulation, an initial drop in arterial pO2, HCO3−concentration and pH was observed. 4. After pretreatment of the animals with phenoxybenzamine or mepyramine the effects of histamine in the arterial blood were abolished suggesting that a histamine-mediated release of catecholamines is responsible for these effects of histamine. 5. Inhibition of carbonic anhydrase by acetazolamide inhibited gastric acid secretion and produced a rise in pCO2 with a concomitant drop in pH.

Effect of Caerulein on Pentagastrin-induced Gastric Acid Secretion and Peptic Ulcers in Cats

Konturek, S. J., Radecki, T., Biernat, J. & Thor, P. 1970. Effect of Caerulein on Pentagastrin-induced Gastric Acid Secretion and Peptic Ulcers in Cats. Scand. I. Gastroent. 5, 613-616.Caerulein alone produced a maximal gastric acid response equal to that provoked by pentagastrin in gastric fistula cats. Caerulein infused against background stimulation with pentagastrin caused a sharp decline in acid output and almost complete prevention of peptic ulcers mainly due to the increase in duodenal neutralization.

Preparation and maintenance of gastric-fustula cats.

The preparation of the gastric-fistula cat, including details of the design of the cannula and restraining slings, is described. Information about the training and selection of suitable animals, and their housing and diet, is presented. The problems of the long-term use and maintenance of a colony of these animals over a 7-year period are discussed and details of colony losses over this time given. The main health problem was the occurrence of a subcutaneous infection, radiating from the base of the cannula, which was due to a benzylpenicillin-resistant Staphylococcus aureus.

Gastrin‐Like Activity in Different Parts of the Gastro‐Intestinal Tract of the Cat

AbstractMucosal specimens from different parts of the gastro‐intestinal tract of cats were extracted for gastrin according to the method of Komarov. Extracts were also prepared from the mucosa of the antrum and proximal duodenum according to a modification of a method of Gregory and Tracy. The extracts were assayed for gastrin activity on nonanesthetized gastric fistula cats. Gastrin‐like activity was found in the mucosa of the antrum and the proximal duodenum using either method of extraction. Gastrin‐like activity was also found in most extracts from the cardiac region of the stomach. The gastrin‐like activity of the extracts from the cardiac region and the proximal duodenum was 5–10 per cent of the antral activity. No gastrin‐like activity was detected in the acid secreting part of the stomach, in the middle and distal parts of the duodenum, in the jejunum, colon or pancreas.

Gastrin-like activity in different parts of the gastro-intestinal tract of the cat.

AbstractMucosal specimens from different parts of the gastro‐intestinal tract of cats were extracted for gastrin according to the method of Komarov. Extracts were also prepared from the mucosa of the antrum and proximal duodenum according to a modification of a method of Gregory and Tracy. The extracts were assayed for gastrin activity on nonanesthetized gastric fistula cats. Gastrin‐like activity was found in the mucosa of the antrum and the proximal duodenum using either method of extraction. Gastrin‐like activity was also found in most extracts from the cardiac region of the stomach. The gastrin‐like activity of the extracts from the cardiac region and the proximal duodenum was 5–10 per cent of the antral activity. No gastrin‐like activity was detected in the acid secreting part of the stomach, in the middle and distal parts of the duodenum, in the jejunum, colon or pancreas.

Failure of "antigastrin" (SC-15 396) to inhibit gastric acid and pepsin secretion in anaesthetized gastric fistula cats.

1. The effect of “antigastrin” (SC-15 396) on gastric acid and pepsin secretion produced by the gastrin-analogue tetrapeptide amide Try. Met. Asp. Phe-NH2 and by electrical stimulation of the vagus was investigated in anaesthetized gastric fistula cats.