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This review article describes the effect and mechanism of various antisecretory drugs. Both histamine H2-receptor antagonists and gastric proton pump inhibitors are now world-widely used as the first choice for the treatment of acid-related diseases. Because of their potential effectiveness in inhibiting gastric acid secretion, new H2-antagonists and pump inhibitors are under development with the aim of mitigating of the side effects. The local antisecretory effects of FPL-52694, NC-1300-O-3 and ME 3407, which were demonstrated in Heidenhain pouch dogs, will provide clues for the development of new types of antisecretory drugs. Antigastrin drugs are also promising.

Background/Aim To investigate the duration of antisecretory effect of AZD0865, a potassium-competitive acid blocker (P-CAB), in dogs. Methods Four Heidenhain pouch dogs received single, oral doses of AZD0865 (1 μmol/kg) and a 3.5-h period of histamine stimulation. Acid output was determined 4, 10 or 24h post-dose during stimulation. Secretory responses were also assessed 24h after 5 days' dosing (1 μmol/kg/day). AZD0865 concentration was determined in plasma at each secretory test, and in gastric juice 23–25 h after single dose (reversed-phase liquid chromatography and fluorescence detection). Results Inhibition of acid output (mean±SE), 4, 10 and 24h after single doses, and 24h after 5th dose was 99±1%, 79±2%, 41±5% and 45±3%, respectively. Systemic exposure to AZD0865 was similar after single and repeated doses. Plasma concentrations at 24h were: 4 nmol/L in 1/4 dogs after single dose; 24 h. At 24h, similar levels of inhibition and AZD0865 plasma concentrations occurred after one and several doses. The concentration of AZD0865 in gastric juice was higher than in plasma. This may reflect concentration of AZD0865 in the parietal cell canaliculus. Thus, the duration of effect outlasts the time AZD0865 is detectable in plasma. Clinical Pharmacology & Therapeutics (2005) 77, P15–P15; doi: 10.1016/j.clpt.2004.11.059

The effect of atropine on acid secretion and serum gastrin level after feeding was studied in 8 cats with denervated fundic pouches (Heidenhain pouch, HP). Serum gastrin concentration was measured by radioimmunoassay. In the control experiments, the mean peak acid response occurred 45 min after feeding and the mean peak gastrin concentration 15 min after feeding. After the 1st postprandial hr, acid secretion declined but the gastrin level remained elevated. Atropine, 0.1 mg per kg intravenously 5 min before feeding, depressed both acid secretion and the increase in serum gastrin concentration during the 1st postprandial hr In both the control and atropine experiments, acid secretion and serum gastrin level were correlated significantly during the 1st postprandial hr, but no correlation was found later in the experiments. The reduction by atropine of the acid and serum gastrin responses varied among the cats but were correlated significantly. It is concluded that a cholinergic mechanism is implicated in the release of gastrin by feeding in cats during the 1st postprandial hr. Atropine reduces the HP acid response to feeding at least in part by depressing the release of gastrin.

Truncal vagotomy (TV) is known to increase the feeding stimulated acid output of Heidenhain pouches. A series of experiments were performed in dogs to see if proximal gastric vagotomy (PGV) also had this effect. Dogs were prepared with gastric fistulas (GF) and Heidenhain pouches (HP). Gastric function testing included three categories of tests: (1) serum gastrin determinations and Heidenhain pouch acid secretion after feeding, (2) gastric emptying and simultaneous Heidenhain pouch acid secretion, and (3) gastric and Heidenhain pouch acid secretion and serum gastrin levels after insulin. Compelte testing consisting of two control and two post-PGV tests was accomplished in five dogs in each category. Insulin testing confirmed that an adequate PGV was performed because GF peak acid output in response to 0.5 U/kg insulin IV was reduced 88% by PGV (p less than .01). In response to two separate meals peak acid output (PAO) from the HP's was not increased significantly after PGV: Meal I pre-PGV 450 +/- 112 vs post-PGV 400 +/- 99 muEq/15 min; Meal II pre-PGV 256 +/- 62 vs post-PGV 304 +/- 150 muEq/15 min. This finding may represent an important physiologic difference between PGV and truncal vagotomy.

A Heidenhain pouch usable for several months was constructed in a Landrace secondary SPF piglet. The behaviors of electrolytes and pepsin in the gastric juice induced by tetragastrin (TG) were studied in the piglet, in comparison with the dog. A high positive correlation was observed between H+ concentration and secretory volume. The same results were obtained by stimulation with betazole and carbamylcholine. The concentrations of Na+ and Ca++ decreased, but those of K+ and Cl- increased with an increase in volume. The concentrations of these 4 ions correlated highly with H+ concentration or volume. Mg++ concentration increased temporarily after the TG administration and decreased there after. This curious responste of Mg++ concentration was observed in the dog, as well as in the piglet, after administration with any other stimulant. Pepsin concentration increased temporarily after TG stimulation, then turned to be at a basal level, and increased slightly thereafter. The kinetics of electrolytes on the gastric juice in the pig seemed to resemble that in the dog.

The antisecretory potency and duration of action of the new histamine H2-receptor antagonist AH 22216 have been compared with those of cimetidine, ranitidine and SK & F 93479 against histamine-induced gastric acid secretion in the conscious Heidenhain pouch dog. Ranitidine was 4-6 times more potent than cimetidine, with a similar duration of action. SK & F 93479 was approximately twice as potent as ranitidine and had a slightly longer duration of action. AH 22216 was most potent of the four H2-antagonists, some 20-30 times more active than cimetidine, and had an extremely prolonged duration of action.

Heidenhain pouch (HP) dogs were studied. After gastroduodenostomy (GD) gastric emptying time was unaffected, but cineradiography showed that the strength of the antral contractions diminished consider

The possible role of vasoactive intestinal peptide as an inhibitor of stimulated gastric secretion was investigated. Awake dogs with Heidenhain pouches were stimulated with pentagastrin alone and in combination with intraduodenal instillation of various potential inhibitors of gastrointestinal secretion including isotonic phenylalanine, 3 percent hypertonic saline solution and 0.16 normal hydrochloric acid. Plasma vasoactive intestinal peptide is significantly increased by pentagastrin, and this release is enhanced by intraduodenal hydrochloric acid. Simultaneously, there is significant inhibition of pentagastrin-stimulated Heidenhain pouch secretion. These findings provide evidence for a possible physiologic role of vasoactive intestinal peptide as an inhibitor of gastric secretion, at least in dogs.

The effect of compound 48/80 on the mucosal barrier of the canine Heidenhain pouch and mast cell content of gastric mucosa has been studied. 48/80 was administered in increasing doses (0.5--2.0 mg/kg) over 5 days. 0.5 mg/kg produced signs of systemic histamine release and stimulation of acid secretion by the pouch; these effects being most marked on the 1st day and absent on the 5th. Subsequent exposure of the mucosa to sodium taurocholate produced damage to the barrier similar to that in untreated animals. Histological examination revealed no evidence of mucosal mast cell degranulation by 48/80. The results suggest that the effects of 48/80 on gastric mucosa are mediated by systemic release of histamine and that local mast cells are resistant to its action.

The gastric mucosa of animals and man can be damaged by noxious agents and protected by prostaglandins. We developed a Heidenhain pouch dog model which allows the study of multiple doses of the protec

新しいhistamine H2-受容体拮抗薬, ranitidineのhistamine, pentagastrinおよびcarbachol刺激胃液分泌に対する効果を, Heidenhain pouch犬(雄性ビーグルおよび雑犬,計6匹)を使用して検討し, cimetidineの効果と比較した. 20時間絶食したイヌに, histamine 2HCl (40μg/kg), pentagastrin (2μg/kg) およびcarbachol (2μg/kg) を15分間隔に8回筋注し, 15分間に排出される胃液を採取し,胃液量,酸およびペプシン排出量を測定した. ranitidine (0.1, 0.3, 1および10mg/kg)およびcimetidine (1および10mg/kg)は,各種刺激薬投与60分前にgelatin capsuleに封入して経口投与した. ranitidineは用量依存的にhistamine, pentagastrinおよびcarbachol刺激胃液分泌を抑制し,その効果は投与後約3時間持続した. histamineおよびpentagastrin刺激による胃液分泌に対しては強力な効果を示した. cimetidineも同様に各種刺激薬による胃液分泌を抑制したが, histamine刺激分泌を十分に抑制する用量 (10mg/kg) では, pentagastrinおよびcarbachol刺激分泌に対して効果は弱かった. ranitidineのcimetidineに対する効力比を,各種刺激薬による胃液量,酸およびペプシン排出量に対する50%抑制量で比較し,以下の結果を得た. histamine刺激分泌: 5, 3.3および2.7倍, pentagastrin刺激分泌: 16.7, 10および10倍, carbachol刺摘分泌: 13.3, 2および4倍. ranitidine 10mg/kgを経口投与し, 8時間後よりpentagastrin刺激を行ない効力の持続を検討した結果, ranitidineは投与10時間後でも胃液分泌を著明に抑制することが判明した. cimetidine 10mg/kgでもかなり強い抑制を示したが, ranitidineに比較すると持続効果は弱いことが判明した.以上より, ranitidineはイヌにおいて胃液分泌の強力な抑制薬であり,また,作用の持続時間も長く,消化性潰瘍の治療薬には有用であることが示唆された.

The effects of long term treatment with cortisone on the gastric secretion induced by histamine, pentagastrin, porcine gastrin and a meal have been investigated in four dogs with both gastric fistula and Heidenhain pouch. Cortisone increased the postcibal acid output and the observed maximal acid response from the pouch to all three exogenous stimuli. The ED 50′s remained unchanged. The same effects although less marked were observed in the innervated stomach. These data indicate that the increased acid secretion observed after long term treatment with cortisone is largely due to an increased secretory capacity of the gastric mucosa. This latter could result from an increase in the number of secretory units or to partial removal of a non competitive inhibitor of gastric secretion. Ce travail a ete realise avec l'aide du subside nd' 20.318 du Fonds de la Recherche Scientifique Medicate (Belgique). Les auteurs remercient Mr. L. Asselberghs pour l'aide technique apportee au cours de la realisation de ce travail. © 1976 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The inhibition of pepsin secretion by metiamide and atropine has been studied in the gastric fistula rat and the Heidenhain pouch rat. A comparison of the effectiveness of metiamide and atropine in inhibiting pepsin secretion was made by using doses of the antagonists which produced a similar level of inhibition of acid secretion. In the gastric fistula rat both atropine and metiamide inhibited the basal pepsin output, but atropine was more effective than metiamide in this respect. In the Heidenhain pouch rat a large dose of metiamide which inhibited bethanechol-stimulated acid secretion had no significant effect on the corresponding output of pepsin. In this preparation atropine inhibited both acid and pepsin secretion. Possible reasons for these differences in the two preparations are discussed.

The possibility that cyclic AMP in gastric juice is derived from plasma by simple clearance was evaluated. The effect of exogenous cyclic AMP administration (1 mg/min) on radioimmunoassayable cyclic AMP in plasma and gastric juice was studied in dog stomach during histamine (8--16 micrograms/kg/hr) infusion. Experiments were performed in vagally denervated fundic (Heidenhain) and in innervated gastric pouches. During infusion of cyclic AMP with histamine, plasma cyclic AMP concentration rapidly increased 500-fold. Simultaneously, gastric juice cyclic AMP levels decreased almost 50%. In contrast, dibutyryl cyclic AMP infusion increased gastric juice cAMP concentration 5-fold, suggesting that the gastric mucosa is more permeable to dibutyryl cyclic AMP. In Heidenhain pouch experiments the clearance of dibutyryl cyclic AMP into gastric juice was only 1.5% of the clearance of aminopyrine. It appears that plasma clearance of cyclic AMP fails to account for most of the cyclic AMP present in gastric juice.

Plasma immunoreactive gastrin (IRG) levels and abomasal acid secretion were investigated on cows with Heidenhain pouch. In two suckling calves (1 month), plasma IRG levels attained at a peak value of 120-160 pg/ml within 3-4 hours after suckling and decreased gradually to about 50 pg/ml by the next suckling. The titratable acidity rose to a peak value of 75-115 mM/l between 3 and 4 hours after suckling and then gradually decreased to the pre-suckling levels (about 20-40 mM/l) between 9-11 hours after suckling. These acid secretory patterns paralleled to the plasma IRG levels. The significant correlation was observed between plasma IRG and total acidity (p

Evidence was obtained showing that in making comparative studies on gastric secretion the glands should be secreting no free acid. In the Heidenhain pouch dogs there was an optimum sized meal for an optimum secretory response during the first hour, more secretion having been obtained with a 300 gm. meal than a 900 gm. meal. The time of the occurrence of the peak of the hourly secretory output was related to the size of the meal in the Heidenhain and the transplanted (Ivy) pouch dog. A definite sigmoid dose-response curve was obtained in the dog with a transplanted pouch. In two Heidenhain pouch dogs a complete sigmoid dose-response curve was not obtained because with a large meal of 900 gm. the voluntary volumetric capacity of the main stomach was reached before the secretory capacity of the pouch was approached. A complete sigmoid curve could be obtained only with a small Heidenhain pouch. In the linear portion of the dose-response curve in both types of pouches doubling the size of the meal roughly doubled the secretory response.

Dogs prepared with gastric fistulas and Heidenhain pouches had vagal stimulation in a continuous fashion by 2-DG (25 mg/kg/hr) before and after antrectomy. An 86 per cent fall in gastric fistula acid output was seen after antrum removal. Heidenhain pouch acid output fell by 36 per cent after antrectomy and the mean acid output was not significantly greater than basal levels. Increased doses of 2-DG (50 mg/kg/hr and 100 mg/kg/hr) post antrectomy failed to restore gastric fistula output to preantrectomy levels. Small doses of pentagastrin coupled with 2-DG (25 mg/kg/hr) did significantly increase acid secretion more than did the individual effects of pentagastrin and 2-DG combined, demonstrating true synergism. 2-DG and barely suprathreshold pentagastrin were as effective as quadrupling the 2-DG dose alone. The loss of antral gastrin, however, after antrectomy was not compensated for by the supplementary pentagastrin. Vagal-antral gastrin, although small in magnitude, is believed to be an important contributor to the vagal mechanism of acid secretion by virtue of its potentiating synergism with parasympathetic innervation of the oxyntic glands.

Summary A gastrin-like gastric secretory stimulant was isolated by an alkaline extraction method from pyloric and fundic mucosae of the bovine abomasum. Secretory activity was measured after subcutaneous injection into Gregory and Heidenhain pouch dogs. The injected material was shown not to be histamine. The reaction to bovine gastrin is usually delayed for 60 to 90 min., in contrast with porcine gastrin, which reacts within 30 min., and with histamine, which reacts in even less time. The most active fractions of bovine gastrin were obtained by isoelectric precipitation at pH 3.0–4.0, in contrast with porcine gastrin, which has highest activity in the fraction precipitated at pH 5.0–5.5. The response to bovine gastrin, as is the case with the porcine material, persists for from 2 to 4 hr., contrasting with the speedy decline after response to histamine. In preliminary purification, we found a nondialyzable fraction, perhaps conjugated with or tenaciously held by a larger molecule, and a dialyzable fraction. Partial purification by ion-exchange has been effected. Preliminary chemical analysis shows that crude bovine gastrin is very similar to crude porcine gastrin in IR and UV spectra and phosphorus content.

Diversion of gastric contents away from the duodenum by means of gastrojejunostomy led to increases in Heidenhain pouch secretion in 8 dogs previously subjected to total antrectomy. It is suggested that acid in the duodenum may exert a chronic depressant effect on Heidenhain pouch secretion in the antrectomized dog.

Summary1) Heidenhain pouch secretion in dogs is markedly increased following portacaval transposition. 2) This may be due to increased effect, after shunting of portal blood around the liver, of a humoral secretagogue which originates in the abdominal viscera and is normally inactivated or excreted by the liver. 3) This finding offers a new approach to the cause of the ulcer diathesis exhibited by patients with cirrhosis of the liver.

Previous reports from this laboratory have demonstrated that pepsin secretion increases when hydrogen ions back diffuse through the gastric mucosa of the canine Heidenhain pouch. Pepsin output was measured in the effluent from the pouches of 4 dogs during irrigation with 15% ethanol plus or minus HCl and during irrigation with 20 mN salicylic acid. Ethanol by itself damaged the pouches as evidenced by large net fluxes of Na+ and K+ into the pouch and the appearance of protein in the fluid. Pepsin secretion, however, was not stimulated. The combination of ethanol and 100 MN HCl produced the same effects on Na+, K+, and protein and also increased pepsin secretion 4-fold. Small amounts of HCl (10 MN) in combination with ethanol also increased pepsin secretion 2- or 3-fold. Salicylic acid (20 MN) plus 100 MN HCl caused severe damage and increased pepsin output from 3 mg per 15 min during control periods to 26 mg per 15 min. It is concluded that: (1) damage alone does not stimulate pepsin secretion; acid must be present; (2) pepsin secretion during damage is independent of the appearance of total protein in the irrigation fluid; (3) small amounts of acid are effective stimulators of pepsin secretion in the presence of a damaged barrier; and (4) damage by ethanol and salicylic acid in the presence of H+ results in a significant stimulation of pepsin secretion.

Since the derivatives of histamine metabolism are quite well known, those which have been synthesized were tested for gastric secretory activity in Heidenhain pouch dogs. All were inactive in a single total dose of 20 mg or 1.7 mg/kg. N-acetylhistamine is 1000 times less active than histamine. 1-Methyl-4-(aminoethyl) imidazole, the first derivative produced by the methylation of histamine in the liver, was inactive. Imidazole-4-acetaldehyde, the first derivative of the oxidative deamination of histamine has not been synthesized, but the next derivative, imidazole-4-acetic acid, was inactive. Among the five histamine diamine oxidase inhibitors studied in relation to gastric secretion to date, aminoguanidine is the most ideal. It has the additional advantage of not inhibiting histidine decarboxylase.

SummaryAdrenalectomy had no effect on fasting canine Heidenhain pouch juice components. It reduced the volume, hydrogen ion and electrolyte output per minute of the secretion from pouches stimulated with histamine or food. The depression in stimulated gastric juice was greater when the dog was maintained with DCA than with cortisone. The slight stimulation of Heidenhain pouch secretion of intact dogs seen with aldosterone is probably an artifact related to the injections. Aldosterone had no effect on the resting or stimulated Heidenhain pouch secretion of adrenalectomized dogs whether they were well maintained with hormone or severely deficient. If aldosterone has an effect on electrolytes of gastric juice, it cannot be detected by measuring whole juice components of Heidenhain pouches.

In Pavlov and Heidenhain pouch dogs with excluded antrum and duodenum the effects of HCL instillations into those areas upon histamine-stimulated gastric secretion were studied. It was found that acidification of the duodenum produced slight and irregular inhibition in some dogs, but no inhibition in others. These findings led the author to suggest that histamine-stimulated gastric secretion is resistant to duodenal inhibition. Acidification of the antrum had no inhibitory influence on the secretion. No difference in susceptibility to antro-duodenal inhibition was found between secretions from Pavlov and Heidenhain pouches.

Summary It has been confirmed that a rapid intravenous injection of pentagastrin inhibits Heidenhain pouch acid responses in similar fashion to other gastrin preparations. There is no evidence of diminution in the degree or duration of inhibition on repeating the rapid intravenous pentagastrin injections over a period of several hours. It is possible to achieve sustained inhibition of the pouch responses to either the continuous intravenous infusion of histamine, or to a meat meal, by a series of spaced intravenous injections of pentagastrin. The inhibition is not accompanied by observable side effects.

In dogs prepared with both a vagus denervated Heidenhain pouch and a total pancreatic fistula, the intravenous injection of pancreatic secretin (Lilly) produced a profuse secretion of pancreatic juice and a simultaneous marked inhibition of gastric secretion. In dogs prepared with an isolated antrum pouch and a Heidenhain pouch the gastric secretion induced by the instillation of food in the antrum pouch was completely inhibited by the intravenous injection of pancreatic secretin. On the other hand, the intravenous injection of pancreatic secretin had little or no effect on the secretion of gastric juice produced by insulin hypoglycemia or by the injection of histamine. It is suggested that pancreatic secretin may represent the mechanism by means of which acid food in the duodenum inhibits gastric secretion. It is probable that this inhibition is caused by prevention of gastrin release from the antrum rather than to a depressant effect on the parietal cells.

Four dogs with Thomas gastric pouches and one dog with a Heidenhain pouch were stimulated to secrete gastric juice by feeding 100 gm of lean beef. Feeding whole desiccated thyroid ordinarily caused a significant fall in volume of gastric juice and in the total quantity of HCl secreted. Crystalline thyroxine yielded erratic results and one trial with triiodothyronine produced a significant increase in gastric secretion. Thyroidectomy in one dog resulted in a gradual decline in secretion, but hypothyroidism produced by administration of mercaptoimidazole in another animal lead to a significant increase in secretion.