Prediction of African Swine Fever Virus Inhibitors by Molecular Docking-Driven Machine Learning Models.

African swine fever virus (ASFV) causes a highly contagious and severe hemorrhagic viral disease with high mortality in domestic pigs of all ages. Although the virus is harmless to humans, the ongoing ASFV epidemic could have severe economic consequences for global food security. Recent studies have found a few antiviral agents that can inhibit ASFV infections. However, currently, there are no vaccines or antiviral drugs. Hence, there is an urgent need to identify new drugs to treat ASFV. Based on the structural information data on the targets of ASFV, we used molecular docking and machine learning models to identify novel antiviral agents. We confirmed that compounds with high affinity present in the region of interest belonged to subsets in the chemical space using principal component analysis and k-means clustering in molecular docking studies of FDA-approved drugs. These methods predicted pentagastrin as a potential antiviral drug against ASFVs. Finally, it was also observed that the compound had an inhibitory effect on AsfvPolX activity. Results from the present study suggest that molecular docking and machine learning models can play an important role in identifying potential antiviral drugs against ASFVs.

Tegoprazan, a Novel Potassium-Competitive Acid Blocker to Control Gastric Acid Secretion and Motility.

Tegoprazan [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], a potassium-competitive acid blocker (P-CAB), is a novel potent and highly selective inhibitor of gastric H+/K+-ATPase. Tegoprazan inhibited porcine, canine, and human H+/K+-ATPases in vitro with IC50 values ranging from 0.29 to 0.52 µM, while that for canine kidney Na+/K+-ATPase was more than 100 µM. A kinetic analysis revealed that tegoprazan inhibited H+/K+-ATPase in a potassium-competitive manner and the binding was reversible. Oral single administrations of tegoprazan ranging from 0.3 to 30 mg/kg in dogs were well absorbed into the blood stream and distributed in gastric tissue/fluid higher than in plasma. Tegoprazan potently inhibited histamine-induced gastric acid secretion in dogs, and a complete inhibition was observed at 1.0 mg/kg starting from 1 hour after administration. Moreover, an oral administration of tegoprazan at 1 and 3 mg/kg reversed the pentagastrin-induced acidified gastric pH to the neutral range. Interestingly, 3 mg/kg tegoprazan immediately evoked a gastric phase III contraction of the migrating motor complex in pentagastrin-treated dogs and similar effects was observed with the other P-CAB, vonoprazan. Tegoprazan is the novel P-CAB that may provide a new option for the therapy of gastric acid-related and motility-impaired diseases.

Comparative assessment of calcitonin stimulation test using calcium gluconate and pentagastrin and the usefulness of procalcitonin basic and post-stimulation concentrations in the diagnosis of patients after surgery for medullary.

OBJECTIVES: The aim of the study was to compare the calcitonin (CT) stimulation tests with tests of calcium gluconate (CaG) and pentagastrin (PG), their tolerance and usefulness of PCT in the patients' diagnosis with active Medullary thyroid cancer (MCT) after thyroidectomy. METHODS: CT was marked in serum by the immunosorbent sandwich test. PCT was marked by the immunosorbent sandwich test, with the final reading of fluorenscence. PG was given intravenously at a dose of 0.5 mg/kg body weight for 10 seconds. CaG was also given by intravenous injection at a dose of 2.5 mg of elemental Ca/kg body weight at a rate of 5ml/min, for minimum 3 minutes. Blood was taken at the 0 minute, the 3 and 5 minute after getting the stimulating substances. RESULTS: The post-stimulation CT concentration in the 3 and 5 minute of the CaG test vs PG is significantly higher compared to the baseline. The maximal stimulation of the CT is in the 3 minute, but higher concentrations occurred using the CaG. CONCLUSION: The results of the study suggest a similar diagnostic value of the tests with CaG compared to the PG as stimulants. In the present study we noticed a trend of basic and post-stimulation concentrations of PCT to increase in the tests with PG and CaG which correspond with the elevated concentrations of CT.

Esomeprazole inhibits the pentagastrin-stimulated secretion of gastric acid in healthy Japanese volunteers.

Gastroesophageal reflux disease (GERD) is a common disease, in which the reflux of gastric acid causes mucosal damage of the esophagus and/or troublesome symptoms. Esomeprazole, a proton pump inhibitor, has been used for treatment of GERD in Japan since 2011; namely, only little is known about its effect on gastric acid secretion in Japanese. We, therefore, assessed the relationship between dose and timing of esomeprazole administration and gastric acid inhibition in 11 healthy male Japanese volunteers by directly examining gastric acid secretion capacity. In this randomized, open-label, three-way crossover study, the subjects were dosed with esomeprazole 10 mg or 20 mg once a day (q.d.), or 20 mg twice a day (b.i.d.) for 14 days, and pentagastrin-stimulated gastric acid secretion was measured by endoscopic gastrin test. At steady states, gastric acid inhibition rates were significantly higher in esomeprazole 20 mg b.i.d. (median 100.0%, interquartile range [IQR] 99.4-100%, P = 0.027) or 20 mg q.d. (100.0%, IQR 99.7-100%, P = 0.016), compared with 10 mg q.d. (98.4%, IQR 84.4-100%). At trough states, esomeprazole 20 mg b.i.d. showed significantly higher gastric acid inhibition (99.6%, IQR 99.0-100%) than did 20 mg q.d. (84.2%, IQR 76.4-88.8%, P = 0.002) or 10 mg q.d. (64.9%, IQR 59.1-76.7%, P = 0.001). Thus, esomeprazole 20 mg b.i.d. was sufficient to inhibit > 99% gastric acid secretion in healthy subjects. We propose that esomeprazole 20 mg b.i.d. is effective for treating Japanese patients with refractory GERD who require long-lasting gastric acid inhibition.

Calcium carbonate breath test for non-invasive estimation of gastric acid secretion.

Gastric acid measurement is useful in assessing the effectiveness of antisecretory drugs, however, the conventional tests involve invasive nasogastric intubation. Orally administered ¹³C-labeled calcium carbonate (Ca¹³CO3) reacts with gastric acid to produce ¹³C-labeled carbon dioxide (¹³CO2), which is then excreted in the breath. The objective of this study was to evaluate the suitability of Ca¹³CO3 breath test for estimating gastric acid secretion in human noninvasively. First, the Ca¹³CO3 breath test and the measurement of pooled gastric acid under a fasting condition were performed in 6 healthy volunteers to evaluate the correlation between the two parameters. Next, endoscopic gastric acid collection and the Ca¹³CO3 breath test were performed on different days after pentagastrin injection in 20 subjects to evaluate the correlation between the tests and the reproducibility. Finally, the same studies were repeated in 4 subjects before and after 1-week rabeprazole, a proton pump inhibitor, administration. The maximum CO2 concentration (Cmax) correlated very well with the amount of pooled gastric acid (r = 0.95), suggesting that Ca¹³CO3 breath test values well reflected the fasting intragastric acidity. The ¹³CO2 concentration after pentagastrin injection correlated well with pentagastrin-stimulated maximal acid output (r = 0.79 at 20 min). The reproducibility of the Ca¹³CO3 breath test under pentagastrin-stimulation was good (coefficient of variation = 0.11). Rabeprazole administration markedly reduced the values of the Ca¹³CO3 breath test, suggesting that it can sensitively assess the efficacy of rabeprazole. The Ca¹³CO3 breath test can potentially be a useful method for non-invasive estimation for gastric acid secretion in human.

Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs--reversing the effect of elevated gastric pH with betaine HCl.

Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure.

Netazepide, a gastrin/CCK2 receptor antagonist, causes dose-dependent, persistent inhibition of the responses to pentagastrin in healthy subjects.

AIMS: To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing. METHODS: We did two studies in which we infused pentagastrin (0.6 µg kg(-1) h(-1) intravenously), aspirated gastric secretion and measured the volume, pH and H(+) secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100 mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100 mg) twice daily for 13 doses on the response to pentagastrin. RESULTS: Netazepide was well tolerated. After placebo, pentagastrin increased the volume and H(+) secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100 mg) abolished the response. After 13 doses, the reduction in volume and H(+) secretion rate persisted (P < 0.001), but the pH effect was mostly lost. CONCLUSIONS: Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.

Reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy.

BACKGROUND: Gastric mucus is considered to play an essential role in gastric mucosal defense mechanisms, especially when irritants are present in the stomach. AIM: To investigate the relationship between low-dose aspirin-induced gastropathy and gastric secretory function, especially gastric mucus secretion, in healthy volunteers. METHODS: Thirty male, asymptomatic, Helicobacter pylori pylori-negative healthy volunteers were asked to take 100 mg of enteric-coated aspirin (Bayaspirin) once a day for 10 days. Endoscopic examination was performed before and 3 and 10 days after drug administration. The extent of endoscopically assessed gastric mucosal injury was semi-quantitatively evaluated according to the modified Lanza score. The pentagastrin-stimulated gastric juice was collected for 10 min during the endoscopic examination and subjected to analysis for gastric acid (mEq/10 min) or mucus (mg hexose/10 min) output. RESULTS: Overall, the 10-day aspirin treatment significantly increased gastric mucus secretion from 0.8 (interquartile range 1.7) to 1.6 (1.6) mg hexose/10 min (P < 0.05), with a concomitant and significant decrease in the gastric acid/mucus ratio from 4.3 (5.2) to 2.9 (4.7) (P < 0.01). Subsequent analysis of two subgroups of volunteers categorized according to their endoscopic status ("severe gastropathy" vs. "modest gastropathy") revealed that changes in gastric secretory parameters occurred exclusively in those subjects without severe gastric injury; there was no alteration in these parameters in subjects with severe gastric injury. CONCLUSIONS: The results of this study suggest that the reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy. In some individuals, such a response may be insufficient to prevent the development of severe mucosal injury and even ulcers and their complications.

Vacuolar-type H+-ATPase-mediated proton transport in the rat parietal cell.

The vacuolar-type H-ATPase (V-ATPase) plays an important role in the active acidification of intracellular organelles. In certain specialized cells, such as the renal intercalated cell, apical V-ATPase can also function as a proton secretion pathway. In the parietal cells of the stomach, it has been thought that acid secretion is controlled solely via the H,K-ATPase. However, recent observations suggest that functional V-ATPase is necessary for acid secretion to take place. This study aimed to investigate and characterize the role of V-ATPase in parietal cell proton transport. Individual rat gastric glands were incubated with the pH-sensitive dye (BCECF) to monitor changes in intracellular pH in real time. Parietal cell V-ATPase activity was measured by quantifying the rate of intracellular alkalinization (ΔpH/minute) following an acid load, while excluding the contribution of non-V-ATPase proton transport mechanisms through pharmacological inhibition or ion substitution. Expression of V-ATPase was confirmed by immunohistochemistry. We observed concanamycin A-sensitive V-ATPase activity in rat parietal cells following intracellular acidification and H,K-ATPase inhibition. Furthermore, V-ATPase-mediated proton transport could be abolished by inhibiting trafficking mechanisms with paclitaxel and by stimulating H,K-ATPase with acid secretagogues. Our results propose that parietal cells contain a functional V-ATPase that can be mobilized using a microtubule network. V-ATPase may function as an auxiliary acid secretion or proton-buffering pathway in parietal cells, which is inactive during H,K-ATPase activity. Our findings may have important implications for patients experiencing acid breakthrough under proton pump inhibitor therapy.

Morphological evidence that pentagastrin regulates secretion in the human parotid gland.

Salivary secretion is principally regulated by autonomic nerves. However, recent evidence from in vivo animal experiments suggests that gastrointestinal peptide hormones can also influence saliva production. The aim of the present study was to define the secretagogue activity of the gastrin-analogue pentagastrin in human salivary glands. For this purpose, parotid tissues were exposed to pentagastrin in vitro. Morphological techniques were used to evaluate modifications to serous acinar cells associated with secretion. Using a variant of the osmium maceration method, high resolution scanning electron microscopy allowed assessment of the morphology of the cytoplasmic aspect of the plasmalemma to demonstrate secretory activity. To quantify responses to pentagastrin, we recorded morphometric data on microvilli, microbuds, and protrusions. Dose-dependent morphological changes were observed, whereas protein concentration increased in the incubate. The use of selective receptor antagonists showed pentagastrin to act principally via cholecystokinin-A receptors. The morphological responses observed following exposure to pentagastrin differed from those elicited following exposure to the pan-muscarinic agonist carbachol. This study provides the first demonstration of a direct secretory action of gastrointestinal peptides on salivary glands in humans.

Calcium [¹³C]carbonate breath test for quantitative measurement of total gastric acid in rats.

OBJECTIVE: A traditional measurement of gastric acid, involving nasogastric intubation of stomach and acid suction, has been suggested as a gold standard. However, this causes the patient discomfort and cost increase, and is 'time-consuming'. MATERIAL AND METHODS: A calcium [(13)C]carbonate (Ca(13)CO(3)) breath test was carried out in rats without or with concomitant drugs omeprazole (OMP) and pentagastrin (PG) known as an inhibitor and an inducer of acid, respectively. This test was aimed at evaluating a correlation between the breath response and the total amount of gastric acid. To search for an absorption pathway of (13)CO(2) gas produced by the reaction of Ca(13)CO(3) with hydrochloric acid in the stomach of rats, we compared the breath responses after intra-gastric administration of (13)CO(2) gas and sodium [(13)C]bicarbonate (NaH(13)CO(3)). RESULTS: A linear relationship of the breath parameter (breath-C(max)) with the dose of Ca(13)CO(3) was obtained in the range of 4-200 µmol/kg. However, theses parameters were saturated at >200 µmol/kg. The direct correlation between the breath-C(max) and the total amount of gastric acid in rats with or without OMPs or PG (r = 0.994) demonstrated that the change in breath response is an accurate or sensitive indicator of the total amount of gastric acid. (13)CO(2) gas generated in the rat stomach was likely to diffuse across the stomach wall as (13)CO(2) gas directly into the blood plasma. CONCLUSIONS: The present study showed that Ca(13)CO(3) breath test is a good tool to accurately predict the total amount of gastric acid.

The Effect of Gastric pH on the Pharmacokinetics-pharmacodynamics of Naphthoquine in Rodents, as well as in Human Predicted Using a PBPK Model.

BACKGROUND: Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin- based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in humans. OBJECTIVES: The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated. METHODS: The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii. RESULTS: Neither pentagastrin nor famotidine affected NQ absorption (AUC0-t and Cmax) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in humans did not show an effect of gastric pH. Compared to pure NQ (ED90, 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED90, 1.1 mg/kg). Correspondingly, the elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED90, 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity. CONCLUSIONS: Although the food was found to significantly impact NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with the acid-related disease is not expected to be clinically meaningful.

A meal test improves the specificity of chromogranin A as a marker of neuroendocrine neoplasia.

Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.

Relationship between respiratory, endocrine, and cognitive-emotional factors in response to a pharmacological panicogen.

BACKGROUND: The cholecystokinin agonist pentagastrin has been used to study panic attacks in the laboratory and to investigate hypothalamic-pituitary-adrenal axis activity. Its mechanism of panicogenesis remains unclear. Data from other models suggest that respiratory stimulation itself may induce panic, but pentagastrin's effects on respiration are not well established. Data from another model also suggest links between respiratory and HPA axis reactivity and cognitive modulation of both. To further explore these phenomena, we added respiratory measures to a study of cognitive modulation of HPA and anxiety responses to pentagastrin. METHODS: Healthy subjects received pentagastrin and placebo injections, with measurement of cortisol and subjective responses, on two different laboratory visits. They were randomly assigned to receive standard instructions or one of two versions of previously studied cognitive interventions (to either facilitate coping or increase sense of control), given before each visit. Capnograph measures of heart rate (HR), respiratory rate (RR), and end-tidal pCO(2) were obtained on 24 subjects. RESULTS: Relative to placebo, pentagastrin induced a significant decline in pCO(2) with no change in RR. Cortisol and HR increased, as expected. Cognitive intervention reduced the hyperventilatory response to pentagastrin. CONCLUSIONS: Pentagastrin stimulates respiration, likely via increases in tidal volume. Respiratory stimulation could play a role in its panicogenic potency, though perhaps indirectly. As with HPA axis responses, higher-level brain processes may be capable of modulating pentagastrin-induced hyperventilation. This model may be useful for further study of cortical/cognitive control of interacting emotional, respiratory, and neuroendocrine sensitivities, with potential relevance to panic pathophysiology.

Traffic noise exposure increases gastric acid secretion in rat.

Noise is considered as one of the most severe sources of environmental and work place constraints. Noise effects on immune function, hormonal levels, cardiovascular and respiratory systems are well known. The aim of the study is to evaluate the effects of traffic noise on basal and stimulated gastric acid secretion. 48 healthy rats were divided into five traffic noise exposures (1, 7, 14, 21, 28 days) and a control groups. Pentagastrin was used i.p. for stimulation of gastric acid secretion. The gastric contents were collected by the wash-out technique and then titrated. Histological studies were performed on gastric epithelial layer. In the 1, 7, 14 and 21 days traffic noise exposure, basal and pentagastrin-stimulated gastric acid secretion increased compared to the control group (P<0.001), but a significant decrease was seen in hyperacidity in 28th days, in the both basal and stimulated states (P<0.05). Histological study showed that mucosal layer thickness of stomach increased, while the number of oxyntic glands and cell nuclei decreased. It seems that 1,7,14 and 21 days traffic noise increase gastric acid secretion, while 28 days traffic noise can induce adaptation.

Targeting the SARS-CoV-2 main protease using FDA-approved Isavuconazonium, a P2-P3 α-ketoamide derivative and Pentagastrin: An in-silico drug discovery approach.

The SARS-CoV-2 main protease (Mpro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of Mpro in complex with an α-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with Mpro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ∼33,000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (α-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ΔGbind of Lig13b, Isavuconazonium, α-KI, Pentagastrin was -28.1, -45.7, -44.7, -34.8 kcal/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the Mpro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-Mpro was slightly altered relative to apo-Mpro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), α-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.

Human intrinsic factor secretion: immunocytochemical demonstration of membrane-associated vesicular transport in parietal cells.

The human gastric parietal cell synthesizes and secretes intrinsic factor (IF) and acid. In contrast to the cellular mechanisms of acid secretion, little is known about the mechanisms of IF secretion. To elucidate these mechanisms we obtained gastric secretions and sequential fundic biopsies from three subjects before and after pentagastrin stimulation (6 microgram/Kg s.c.). IF was localized in the biopsies using an ultrastructural immunoperoxidase technique using a well-characterized, monospecific antibody to human IF. IF output was quantified using a specific radioimmunoassay in concurrently obtained gastric secretions. Before stimulation, IF was associated with tubulovesicles scattered throughout the cytoplasm and with some in rough endoplasmic reticulum (RER). The tubulovesicles associated with IF migrated to the periphery of the secretory canaliculi within 8 min of stimulation. IF was present on secretory microvilli between 8 and 30 min when IF output in gastric juice was at its maximum. The cessation of IF secretion coincided with the depletion of IF associated with tubulovesicles. IF appeared in the perinuclear space and RER as the IF associated with tubulovesicles was secreted. These observations indicate that IF secretion depends upon membrane-associated vesicular transport and provides support for a membrane translocation-fusion hypothesis to explain the morphologic changes that occur in the parietal cell during secretion.

Gastrin injected into the lateral hypothalamus stimulates secretion of gastric acid in rats.

Intrahypothalamic injections of 100 picomoles of pentagastrin or natural gastrin promptly increased secretion of gastric acid in conscious rats. The response was blocked by atropine and by vagotomy. The same doses, injected intravenously or into other forebrain sites, did not increase secretion, nor did intrahypothalamic injections of other peptides common to the gut and brain.

Ontogeny of gastric acid secretion in the rat: evidence for multiple response systems.

Gastric acid secretion has been thought to depend on histamine stimulation of the parietal cell. However, in the 2-week-old rat neither exogenous histamine nor the H-2 receptor agonist impromidine stimulates acid secretion, whereas pentagastrin and the cholinergic agent bethanechol are potent stimuli. At this age, the effect of pentagastrin in acid secretion is not blocked by the H-2 receptor antagonist cimetidine, nor is it potentiated by impromidine. These data suggest that, in the rat pup, the acid secretory response to pentagastrin and cholinergic agents occurs before the histamine-mediated system is functional and operates independently of the actions of histamine.

Cholecystokinin octapeptide: continuous picomole injections into the cerebral ventricles of sheep suppress feeding.

Cholecystokinin octapeptide decreased food intake in a dose-related manner when injected continuously into the lateral cerebral ventricles of sheep that had been deprived of food for 2, 4, 8, or 24 hours. In sheep deprived of food for 2 hours, as little as 0.01 picomole per minute suppressed feeding 35 percent 1 hour after beginning injection. Pentagastrin also decreased feeding in the 2-hour group, but only at a much higher dose range. Secretin had no effect. These findings support the hypothesis that cholecystokinin octapeptide acts on central nervous system structures that are involved in control of food intake.