Mitsuru Aono

Enhancement of the lipid content and physical properties of gastric mucus by geranylgeranylacetone.

The effects of intragastric administration of geranylgeranylacetone (GGA) on the content, composition and physical properties of the mucus component of the gastric mucosal barrier were investigated. One group of rats received twice daily for 3 consecutive days a dose of 100 mg/kg body weight of GGA, while the control group was subjected to daily doses of the vehicle. Sixteen hours following the last dose, the animals were killed, and their stomach was cut open and subjected to measurements of the adherent mucus gel content, analysis of its lipids and molecular forms of elaborated mucin, and evaluation of the viscosity and H+ retardation capacity. The results revealed that GGA elicited a 62% increase in the adherent mucus gel and caused a marked decrease in the proportion of the lower molecular weight mucin. Furthermore, the mucus of the GGA group exhibited a 67% higher content of covalently bound fatty acids and contained 46% more total lipids which were greatly (143%) enriched in phospholipids. The physical measurements demonstrated that mucus elaborated in the presence of GGA also exhibited 2.3 times higher viscosity and had a 32% greater ability to retard the diffusion of H+ than the mucus of the control group. The results suggest that GGA exerts a profound effect on the lipid content and the properties of gastric mucus associated with the maintenance of the mucosal integrity.

Protection against Alcohol-Induced Gastric Mucosal Injury by Geranylgeranylacetone: Effect of Indomethacin

The mechanism of gastric mucosal protection by an antiulcer agent, geranylgeranylacetone (GGA), against ethanol-induced injury was investigated. The experiments were conducted with groups of rats with and without intraperitoneal indomethacin pretreatment. Animals received intragastrically either a dose of GGA (200 mg/kg) or a vehicle, followed 30 min later by 1 ml of absolute ethanol. The rats were sacrificed after 30 min and the gastric mucosa was subjected to macroscopic and histologic assessment and the measurements of adherent mucus, its dimension and chemical composition. In the absence of GGA, ethanol produced advanced macroscopic necrosis (greater than 38%) and the extensive necrotic lesions were visible upon histologic examination. Pretreatment with GGA significantly reduced (p less than 0.001) the extent and depth of mucosal necrotic lesions caused by ethanol, and this protection was not thwarted by indomethacin. Evaluation of the adherent mucus and its dimension by Alcian blue uptake and inverted microscope technique revealed that GGA was also capable of preventing the untoward effect of indomethacin on the adherent gastric mucus gel and its thickness. Results of chemical analyses established that in the absence of GGA indomethacin caused an increase in mucus protein (15%) and a decrease in its covalently bound fatty acids (67%) and lipids (36%). The decrease in lipids was particularly reflected in the content of phospholipids. Indomethacin, however, had no apparent effect on the composition of gastric mucus elaborated in the presence of GGA. The results suggest that gastric mucosal protective action of GGA is not mediated by endogenous prostaglandins but rather appears to involve the metabolism of mucosal lipids.

Centrally administered neuropeptide Y (NPY) inhibits gastric emptying and intestinal transit in the rat

Neuropeptide Y is distributed abundantly not only in the brain, but also in the gastrointestinal tract and suppresses intestinal muscle contraction in isolated muscle preparations. The purpose of the present study was to determine whether centrally administered neuropeptide Y modulated gastric emptying and intestinal transit in conscious rats. Graded doses of neuropeptide Y were administered intracisternally 1 min before ingestion of test meals through an oral tube. Four hours after ingestion of 60 Amberlite pellets, the rats were sacrificed and residual pellets in the stomach and the small intestine segments were counted to calculate the solid meal transit rate. The liquid meal transit rate was calculated 1 hr after 0.07% phenol red ingestion by determining the residual phenol red in the stomach and the small intestine segments. Neuropeptide Y elicited potent suppression of gastric emptying and intestinal transit of both solid and liquid meals. Pretreatment with propranolol antagonized, whereas phentolamine did not affect, the suppressive effect of central neuropeptide Y. Although carbachol blocked the effects of neuropeptide Y, neither atropine nor hexamethonium altered the actions of neuropeptide Y. In conclusions, centrally administered neuropeptide Y strongly inhibited gastrointestinal transit by stimulating a beta-adrenergic pathway.

Centrally administered NPY stimulated gastric acid and pepsin secretion by a vagally mediated mechanism

We investigated the possible roles of centrally administered neuropeptide Y (NPY) on gastric secretion, serum gastrin levels and gastric mucosal blood flow in anesthetized rats. Centrally administered NPY dose-dependently stimulated gastric acid and pepsin secretion. The stimulatory effect of intracerebroventricular administration of NPY was more potent than that of intracisternal administration. Centrally administered NPY also increased gastric secretion in the central noradrenaline depleted rats. In contrast, intravenously administered NPY had no influence on gastric secretion. These stimulatory effects were abolished by vagotomy or atropine pretreatment. The serum gastrin levels did not change after central NPY injection. Although intravenously administered NPY slightly increased gastric mucosal blood flow, centrally administered NPY slightly diminished gastric mucosal blood flow. These results indicate that centrally administered NPY markedly influences gastric functions in the rat.

Lipid composition of the matrix of human submandibular salivary gland stones

The lyophilized stone matrix, prepared by exhaustive dialysis of pulverized stones against 10 per cent EDTA and water, yielded 9.6 +/- 0.9 mg per cent of lipids. Following fractionation of the lipid extract on silicic acid columns, 57 per cent of lipids were found in the neutral lipid fraction, 40 per cent in the glycolipid fraction and 3 per cent in the phospholipid fraction. Of the total neutral lipids, 77.3 per cent were represented by free fatty acids, 14.7 per cent by cholesterol, 4.1 per cent by triglycerides and 3.2 per cent by cholesterol esters. The glycolipid fraction was comprised of simple glycosphingolipids (11.3 per cent), mainly lactosyl- and glucosylceramides, and of neutral and sulphated glyceroglucolipids (88.7 per cent). The sulphated glyceroglucolipids consisted of tri- and tetraglucosyl glyceroglucolipids, whereas hexa- and octaglucosyl glyceroglucolipids were the predominant constituents of the neutral glyceroglucolipid fraction. The phospholipids exhibited a high content of sphingomyelin (22.3 per cent), phosphatidylcholine (12.1 per cent), phosphatidylethanolamine (11.4 per cent), phosphatidylserine (10.5 per cent) and lysophosphatidylcholine (13.3 per cent). The major fatty acids of the neutral lipid fraction were hexadecanoate, octadecanoate and octadecenoate. The glycolipids contained large quantities of hexadecanoate and tetracosanoate, while the hexadecanoate, octadecanoate and tetracosanoate were the principal fatty acids of the phospholipid fraction.

Central Administration of PACAP Stimulates Gastric Secretion Mediated Through the Vagal Pathway in Anesthetized Rats

Pituitary adenylate cyclase activatingpolypeptide (PACAP) is a neuropeptide that wasoriginally isolated from ovine hypothalamic tissue. Thepeptide has two amidated forms, PACAP38 and PACAP27. Inthis study, we examined the effects of centrallyadministered PACAP38 and PACAP27 on gastric secretion inanesthetized rats. Centrally administered PACAPstimulated gastric acid and pepsin secretion in adose-dependent manner. PACAP38 was 1.5-2 times more potentthan PACAP27 on gastric secretion. By contrast,intravenously administered PACAP38 had no effect onbasal or pentagastrin-stimulated gastric secretion.PACAP6-38, a PACAP antagonist, by itself at high dosesalso stimulated gastric and pepsin secretion, but atlower doses had no effect. Centrally administeredPACAP6-38 at a dose that had no effect on gastricsecretion, atropine pretreatment, or vagotomypretreatment, suppressed the stimulatory effect ofPACAP38. It is concluded that centrally administeredPACAP may have a regulatory effect on gastric secretionthrough PACAP receptors and the vagalpathway.

Cholinergic effects of histamine-H2 receptor antagonists partly through inhibition of acetylcholinesterase

SummaryThe effects of histamine H2-receptor antagonists on acetylcholinesterase and pseudocholinesterase activity were studied. All H2-antagonists tested inhibited both enzyme activities dose-dependently. The potency of inhibitory activity of H2-antagonists on acetylcholinesterase estimated from median inhibitory dose were in the following order of decreasing activity: ranitidine > TZU-0460 > cimetidine > YM-11170, whereas that on pseudocholinesterase were TZU-0460 > ranitidine > cimetidine > YM-11170.As the effects derived from the inhibition of acetylcholinesterase by H2-antagonists may affect intestinal motility, we studied ileal muscle contractions. Ranitidine had the most potent stimulating effect on contraction, the pattern of which was similar to physostigmine and was blocked by atropine and morphine. YM-11170 had a weak action on muscle contraction and cholinesterase activities.

Effect of teprenone on the content of phospholipids in gastric secretion in man

SummaryThe phospholipid content of basal and pentagastrin-stimulated gastric secretion was measured in 9 healthy volunteers. One week oral administration of teprenone did not alter the gastric acid and pepsin secretion. The phospholipid content was increased by teprenone. Changes in subclasses of phospholipids in gastric mucus by teprenone treatment, namely, increased phosphatidylcholine and decreased lysophosphatidylcholine, were observed.

Central effects of pituitary adenylate cyclase activating polypeptide (PACAP) on gastric motility and emptying in rats.

Pituitary adenylate cyclase activatingpolypeptide (PACAP) is a new member of thesecretinglucagon-vasoactive intestinal peptide (VIP)peptide family. PACAP is widely distributed not only inthe mammalian brain but also in the gastrointestinal tract.Here, we investigated the effects of central andperipheral administrations of PACAP on gastric motilityand gastric emptying in rats. We found that theintracerebroventricular or intracisternal injection of PACAP increasedgastric motility in a dose-dependent manner. Theintracisternal injection of PACAP delayed gastricemptying. These central effects of PACAP on gastricmotility and emptying were blocked by bilateralvagotomy. In contrast, intravenous administration ofPACAP decreased gastric motility and delayed gastricemptying. The peripheral inhibitory effect wasunaffected by bilateral vagotomy, adrenalectomy,phentolamine, and propranolol. We investigated theeffect of PACAP38 on blood glucose levels (BGL) at thesame doses as those used in the gastric motility andemptying studies in urethane-anesthetized rats. Theintravenous but not intracerebroventricular injection ofPACAP38 (1-8 nmol/rat) produced a significant increasein the BGL. We conclude that PACAP has opposite central and peripheral effects on gastricmotility, ie, central PACAP activates the vagal pathwayin the central nervous system to increase gastricmotility, whereas peripheral PACAP inhibits gastricmotility via an unknown pathway. The delay in gastricemptying after the central administration of PACAP mightbe due to the lack of coordinated gastropyloroduodenalcontraction, whereas that after the peripheral administration might be due to the inhibitionof gastric contraction, and this effect may be relatedto the hyperglycemic action of PACAP.

The role of gastric mucosal hexosamine in aspirin-induced ulcers

SummaryIn order to elucidate the role of gastric tissue hexosamine, used as an index of mucopolysaccharide content, in the development and healing process of peptic ulcers, the distribution of hexosamine and the changes of gastric hexosamine content in the development and healing of aspirin-induced ulcers in rats were studied. In addition, the effects of proglumide and L-glutamine on gastric hexosamine were also studied.The hexosamine content was found to be the highest in the antrum, followed by the corpus and then the forestomach. The mucosa contained significantly higher hexosamine than the smooth muscle layer in both the antrum and the corpus. Prior treatment with proglumide significantly increased the mucosal hexosamine to the extent of 10.3-18.1 % in the glandular stomach. Administration of aspirin decreased the gastric mucosal hexosamine and induced the onset of ulcer, while administration of proglumide suppressed the gastric lesions in proportion to dosage and correspondingly prevented a decrease of the hexosamine. In contrast, Lglutamine showed an anti-ulcerogenic effect without suppressing a decrease of the hexosamine. In the process of curing gastric lesions, proglumide accelerated the healing of the ulcers and simultaneously returned the total hexosamine content to its original level.These results suggest that the gastric mucosal hexosamine is closely related to the onset and healing of aspirin-induced ulcer in rats, and that proglumide contributes to both the prevention and healing of ulcers by increasing gastric mucosal hexosamine.