The menstrual cycle influences the gastric emptying of alcohol.

We previously reported that ingestion of 60 mL of red wine or vodka prior to the ingestion of a pancake significantly inhibited the gastric emptying of the pancake in male subjects, but not in female subjects, and that the retention times of wine and vodka were significantly longer than those of the congener of red wine and mineral water in male subjects, whereas in female subjects the retention times of these four drinks did not differ significantly from one another. We hypothesized that the menstrual cycle may influence the gastric emptying of alcohol beverages. Here, we determined and compared the retention times of vodka and water in the stomach during the luteal phase and the follicular phase. Ten female healthy volunteers were studied. They recorded their basal body temperatures every day, and participated in the following experiments: each volunteer drank mineral water or vodka containing 14% alcohol (60 mL) during the low-temperature (follicular) phase as well as during the high-temperature (luteal) phase. The retention time of vodka was significantly longer than that of mineral water during the follicular phase, but no significant differences between the retention times of the two drinks were observed during the luteal phase. In conclusion, the menstrual cycle influences the gastric emptying rate of alcohol.

Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice.

Information concerning the cellular localization of cholecystokinin (CCK)-1 receptors has been discrepant and remained scanty at ultrastructural levels. The present immunohistochemical study at light and electron microscopic levels revealed the distinct localization of CCK1 receptors in visceral organs. Immunohistochemistry by use of a purified antibody against mouse CCK1 receptor was applied to fixed tissue sections of the pancreas, gallbladder, stomach, and intestine of mice. A silver-intensified immunogold method revealed the subcellular localization under electron microscope. The immunoreactivity for CCK1 receptors was selectively found in the basolateral membrane of pancreatic acinar cells and gastric chief cells but was absent in pancreatic islets and gastric D cells. Another intense expression in the gut was seen in the myenteric nerve plexus of the antro-duodenal region and some populations of c-Kit-expressing pacemaker cells in the duodenal musculature. The gallbladder contained smooth muscle fibers with an intense immunoreactivity of CCK1 receptors on cell surfaces. The restricted localization of CCK1 receptors on the basolateral membrane of pancreatic acinar cells and gastric chief cells, along with their absence in the islets of Langerhans and gastric D cells, provides definitive information concerning the regulatory mechanism by circulating CCK. Especially, the subcellular localization in the acinar cells completes the investigation for the detection of circulating CCK by the basolateral membrane.

Sex difference in the effects of alcohol on gastric emptying in healthy volunteers: a study using the (13)C breath test.

Several studies on alcohol and gastric emptying using the (13)C breath test showed that alcohol consumption delayed gastric emptying of meals in healthy male subjects. However, they did not employ female subjects, and the retention time of alcoholic beverages in the stomach has not been examined, yet. We examined the retention time (= gastric emptying rate) of alcoholic beverages in the stomach in healthy male and female subjects. We also examined whether the congeners (nonalcoholic components) of red wine have any effect on gastric emptying. The retention time of 60 mL of red wine, vodka, congeners of red wine, or mineral water, was measured using a (13)C labeled acetic acid breath test. In male subjects, the retention time of wine and vodka was significantly longer than that of congeners and mineral water. In female subjects, although the (13)C content in the breath was slightly but significantly decreased by wine and congeners, but not by vodka, and the parameters for gastric emptying did not differ significantly among the 4 drinks. That is, alcohol hardly influenced the retention time in female subjects. In conclusion, there are sex differences in the gastric emptying rate of alcohol.

Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin.

Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-α and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy.

Age-associated reduction of stimulatory effect of ghrelin on food intake in mice.

Aging is associated with a progressive decrease in appetite and food intake. We focused on the age-associated changes of the stimulatory effect of the appetite-regulating peptide, ghrelin. Food intake and the concentrations of acyl ghrelin and desacyl ghrelin in the plasma and in the stomach were measured with and without overnight fasting in young and old mice. Moreover, the food intake in response to the intraperitoneal administration of graded doses of acyl ghrelin was compared between young and old mice. Fasting drives food intake in young mice, but not in old mice. The concentrations of acyl ghrelin and desacyl ghrelin in the plasma and in the stomach were higher in the old mice than in the young mice. Food intake did not increase in old mice when stimulated by the administration of 1-3 nmol of acyl ghrelin, which could produce a significant increase in food intake in young mice. In conclusion, food intake did not increase in old mice after either overnight fasting or the administration of acyl ghrelin. The release and synthesis of ghrelin seem to be rather higher in old mice compared to young mice. These increases might be the results of compensation for the decline of receptor (and/or post-receptor) functions.

Administration of ursodeoxycholate failed to prevent sludge and/or gallstone formation in cholecystokinin-1(A) receptor-deficient mice.

Gallstone disease is one of the most prevalent digestive diseases. The frequency of gallstone disease is about 10% in middle-age persons and 20% in aged persons. Gallbladder dysmotility and stasis of bile flow promote sludge and/or gallstone formation. Gallbladder contraction depends on cholecystokinin (CCK) via CCK-1 receptors (R)s. Previously, we raised CCK-1R deficient (-/-) mice and observed sludge and/or gallstone formation in more than 30% at 12-24 months of age. As ursodeoxycholate (UDCA) is commonly used for patients with gallstone disease, we expected that continuous administration of UDCA could prevent sludge and/or gallstone formation in CCK- 1R(-/-) mice. A diet containing 0.1% UDCA was administered in age-matched CCK-1R(-/-) and wild-type male and female mice for 8 months. Administration of UDCA decreased the frequency of sludge and/or gallstone formation compared with the control (CRF-1) diet (39%→26% in male, 35%→25% in female mice); however, these effects did not attain a level of statistical significance. Although the body weight was significantly higher in UDCA-fed than CRF-1-fed male mice regardless of genotypes, the plasma lipid concentrations did not differ between the two diets. In conclusion, administration of UDCA was less effective than expected at preventing sludge and/or gallstone formation in CCK-1R(-/-) mice.

Pancreatic hypertrophy in Ki-ras-induced actin-interacting protein gene knockout mice.

OBJECTIVES: Pancreatic functions were determined in a Ki-ras-induced actin-interacting protein (KRAP)-deficient (-/-) mouse mutant. METHODS: Pancreatic enzyme, protein, and DNA contents were measured, and histological examinations were conducted. The mixture of bile-pancreatic juice was collected, and amylase and bile acid outputs were determined. Oral glucose tolerance test was determined. Moreover, the gene expression of KRAP was determined in cholecystokinin (CCK)-A(1) receptor (-/-) mice. RESULTS: The body weight was smaller, and the ratio of pancreatic wet weight/body weight was higher in KRAP(-/-) mice compared with wild-type mice. The enzyme contents, but not DNA content, in the pancreas of KRAP(-/-) mice were higher than those of wild-type mice. Histological examination revealed the increase in the number of zymogen granules in the pancreatic acinar cells of KRAP(-/-) mice. Amylase secretions in response to CCK-octapeptide sulfate were significantly higher in KRAP(-/-) than wild-type mice, whereas the basal secretion did not differ between the 2 genotypes. A normal glucose tolerance was observed in KRAP(-/-) mice. The gene expression of KRAP in CCK-A(1) receptor (-/-) mice was significantly lower than in wild-type mice. CONCLUSIONS: The lack and/or decrease in KRAP level in the pancreas may promote the pancreatic growth and hypertrophy.

Association of aldehyde dehydrogenase 2 gene polymorphism with pancreatic cancer but not colon cancer.

AIMS: Most of the acetaldehyde, a recognized animal carcinogen, generated during alcohol metabolism is eliminated by liver mitochondrial aldehyde dehydrogenase 2 (ALDH2). More than 40% of Japanese people have the inactive form of ALDH2, and inactive ALDH2 is a risk factor for multiple cancer of the esophagus, as well as head and neck cancer. Possible associations between pancreatic cancer and ALDH2 gene polymorphism, as well as between colon cancer and ALDH2 gene polymorphism, in conjunction with smoking and/or drinking habits, were examined in a Japanese population. METHODS: Patients with pancreatic cancer (n = 187) and with colon cancer (n = 49) were examined. The drinking (5 g ethanol consumption/day) and/or smoking habits as well as ALDH2 gene polymorphism were examined. The age-matched control subjects were recruited in the NILS Longitudinal Study of Aging (LSA). RESULTS: Aging, smoking and inactive ALDH2, but not alcohol, are independent risk factors for pancreatic cancer. The frequency of smoking habits tended to be higher in patients with colon cancer compared with the patients without cancer. However, age, body mass index or the distribution of ALDH2 genotypes did not differ significantly among the patients with colon cancer, colon polyps and others. CONCLUSIONS: Inactive ALDH2 is an independent risk factor for pancreatic cancer, but inactive ALDH2 might not be a risk for colon cancer.

Age-associated changes of appetite-regulating peptides.

Aging is associated with a progressive decrease in appetite and food intake. The reasons for the decline in food intake are multifactorial, and relate to both peripheral and central mechanisms. Current studies about the regulation of food intake suggest that there are many central mediators that control the appetite. To determine the mechanism of age-associated decrease in appetite and food intake, we focused on the age-associated changes of the suppressing and stimulatory effect of some appetite-regulating peptides. At first, we examined cholecystokinin (CCK), one of the typical appetite-suppressing factors. Although sensitivity to CCK is enhanced in old animals, the mechanism underlying this effect has not been elucidated. Next, we focused on the appetite-stimulating peptides, orexin-A, neuropeptide Y (NPY) and ghrelin, which are known to play a critical role in food intake. To determine the age-associated decrease in appetite and food intake, we compared the stimulatory effect of intracerebroventricular administration of orexin-A, NPY and ghrelin. We report the studies of the age-associated changes of appetite-regulating peptides in this review.

Stimulatory effect of N-methyltyramine, a congener of beer, on pancreatic secretion in conscious rats.

BACKGROUND: Alcoholic beverages stimulate gastric acid secretion and increase the appetite. Although ingested ethanol stimulates pancreatic secretion, alcoholic beverages contain several congeners. N-methyltyramine (NMT) was isolated from beer as a factor in stimulating gastric acid secretion. In this study, we examined NMT to determine whether the congener stimulated pancreatic secretion in conscious rats. METHODS: Cannulae were inserted into male Wistar rats to separately drain bile and pancreatic secretions: 2 duodenal cannulae, a gastric cannula, and an external jugular vein cannula. The rats were placed in modified Bollman-type restraint cages. After a 4-day recovery period, experiments were conducted on unanesthetized rats. Different concentrations of NMT (5, 25, and 50 microg/kg) solutions were infused into the stomach. To examine the mechanism, the effects of the proton pump inhibitor, cholecystokinin (CCK-BR) antagonist (YM022), CCK-AR antagonist (CR1505), and atropine were administered prior to the NMT (25 microg/kg) infusion. The effect of intravenous infusion of NMT (7.5 microg/kg) was then determined. Moreover, dispersed acini were prepared, and the effect of different concentrations of NMT on amylase release was determined. RESULTS: Intragastric administration of NMT significantly increased pancreatic exocrine secretion in a dose-dependent manner. Atropine eliminated the stimulatory effect of NMT, but the infusion of the proton pump inhibitor, YM022, and CR1505 did not. Intravenous infusion of NMT did not affect pancreatic secretion, and NMT did not stimulate amylase release in vitro. CONCLUSIONS: N-methyltyramine stimulates pancreatic secretion via the cholinergic gastro-pancreatic reflex. The NMT content in beer was 2 mg/l, so that if a person weighing 60 kg consumes a 750 ml of beer, 25 microg/kg NMT will be ingested. Therefore, the stimulatory effect of beer on pancreatic secretion was produced not only by ethanol but also by the congener, NMT.

Gastric acid secretion in cholecystokinin-1 receptor, -2 receptor, and -1, -2 receptor gene knockout mice.

Gastrin is important for stimulating acid secretion as well as differentiating gastric mucosal cells via cholecystokinin-2 receptors (CCK-2Rs). In turn, CCK acts preferably via CCK-1R to release somatostatin, and somatostatin has been postulated to exhibit a tonic inhibition of gastrin bioactivity. The present study was designed to examine the hypothesis that CCK-1R and 2R may act in opposite directions in gastric acid secretion. Having generated CCK-1R(-/-), 2R(-/-), and 1R(-/-)2R(-/-) mice, we examined the regulation of gastric acid secretion in four genotypes including wild-type mice. Parietal cells possess histamine receptors, muscarinic receptors, and CCK-2Rs. Since histamine increases cAMP and carbachol increases calcium, the responses of gastric acid secretion to graded doses of histamine, carbachol, and a combination of histamine + carbachol were determined. The sensitivity to histamine did not differ among the four genotypes, while the maximal acid secretion was lower in CCK-2R(-/-) mice than in wild-type mice. In addition, sensitivity to carbachol was impaired in mice without CCK-2R. The interaction of histamine and carbachol was conserved in all genotypes. In conclusion, CCK-2R is necessary to respond to carbachol as well as to produce the maximal acid secretion, while the role of CCK-1R in acid secretion is less important.

Combination of gemcitabine and paclitaxel as second-line chemotherapy for advanced urothelial carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicities of the gemcitabine and paclitaxel combination regimen as second-line chemotherapy for patients with advanced or metastatic urothelial carcinoma (UC) who have previously been treated with platinum-based chemotherapy for the metastatic disease. METHODS: Thirty-three patients with advanced or metastatic UC who had received platinum-based chemotherapy were treated with an outpatient gemcitabine and paclitaxel combination regimen. A dose of 180 mg/m(2) paclitaxel was administered by intravenous (IV) infusion on Day 1, and 1000 mg/m(2) gemcitabine was administered by IV on Days 1, 8 and 15.The course was repeated every 28 days. Patients were evaluated after every 2 cycles of therapy using computed tomography. RESULTS: Of the 33 patients enrolled in this study, 30 could be evaluated to determine treatment efficacy; 10 had an objective response [overall response rate: 33.3%, 95% confidence interval (CI), 19.2-51.2%]. The median overall survival was 11.3 months (95% CI, 7.2-13.6 months). The chemotherapy sensitivity differed with disease site. The response rates of lung and bone metastases were 27% and 14%, and the progressive disease (PD) rates of lung and bone metastases were 13% and 14%, respectively. On the other hand, the response rate of liver metastasis was 14%, and its PD rate was 57%. None of the patients (n = 3) with adrenal metastasis responded to this regimen. Toxicities were mild, and no life-threatening complications occurred. CONCLUSIONS: Gemcitabine and paclitaxel combination therapy is a tolerable and active regimen for patients with advanced UC after failure of platinum-based chemotherapy.

Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice.

Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP(-/-)) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP(-/-) mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP(-/-) mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP(-/-) mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP(-/-) mice, which could in part account for the metabolic phenotype in KRAP(-/-) mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases.

Cholecystokinin-A receptors regulate photic input pathways to the circadian clock.

Daily behaviors are strongly dominated by internally generated circadian rhythms, but the underlying mechanisms remain unclear. In mammals, photoentrainment of behaviors to light-dark cycles involves signaling from both intrinsically photosensitive retinal ganglion cells and classic photoreceptor pathways to the suprachiasmatic nucleus (SCN). How classic photoreceptor pathways work with the photosensitive ganglion cells, however, is not fully understood. Although cholecystokinin (CCK) peptide has been shown to be present in a variety of vertebrate retinas, its function at a systems level is also unknown. In the present study we examined a possible role of CCK-A receptors in photoentrainment using CCK-A receptor knockout mice. The lacZ reporter gene within a gene-knockout cassette revealed precise localization of CCK-A receptors in the circadian clock system. We demonstrated that CCK-A receptors were located predominately on glycinergic amacrine cells but were rarely found on SCN neurons. Moreover, Ca(2+) imaging analysis demonstrated that the CCK-A agonist, CCK-8 sulfate (CCK-8s), mobilized intracellular Ca(2+) in amacrine cells but not glutamate-receptive SCN neurons. Furthermore, light pulse-induced mPer1/mPer2 gene expression in SCN, behavioral phase shifts, and the pupillary reflex were significantly reduced in CCK-A receptor knockout mice. These data indicate a novel function of CCK-A receptors in the nonimage-forming photoreception presumably via amacrine cell-mediated signal transduction pathways.

Age-associated gallstone formation in male and female CCK-1(A) receptor-deficient mice.

BACKGROUND: Gallbladder dysmotility accelerates cholelithiasis. In turn, gallbladder dysmotility can occur secondary to inflammation and excess cholesterol accumulation in gallbladder smooth muscle. METHODS: The present study was designed to determine how much gallbladder dysmotility contributes to gallstone formation as a primary cause and whether a sex difference exists in gallstone formation by comparing cholecystokinin-1 receptor gene-deficient [CCK-1R(-/-)] male and female mice. RESULTS: No sludge or gallstone formation was observed in mice at 6 months of age. The frequency of sludge and gallstone formation in mice at 12 and 24 months of age was slightly higher in female CCK-1R(-/-) mice than in males, but the difference was not significant. CONCLUSIONS: Gallbladder dysmotility may have accelerated sludge and gallstone formation, but its contribution was limited. A 12-month period was required to produce gallstones, and after the mice reached 12 months of age, further ageing did not increase the frequency of gallstones. The effect of sex did not reach a significant level.

Susceptibility to obesity and gallbladder stasis produced by a protein- and fat-enriched diet in male mice compared with female mice.

BACKGROUND: The frequency of Japanese subjects over 20 years old with metabolic syndrome is 45.6% in men but just 16.7% in women. The reason why Japanese male subjects are more susceptible to metabolic syndrome than women is unknown. One possibility is the higher frequency of Japanese male subjects (40-70 years old) who had a drinking habit (67%), while that of female subjects was only 25%. In addition, daily fat intake was markedly increased in Japanese subjects (from 9% to 25%), and cholesterol cholelithiasis is one of the most rapidly increasing digestive diseases during the past 50 years. The object of this study is to examine whether a potential sex-related risk factor exists in the manifestation of metabolic syndrome as well as gallstone formation. METHODS: Gallbladder dysmotility accerelates gallstone formation and gallbladder contraction depends on cholecystokinin (CCK) and its receptor (CCK-1R). We developed CCK-1R gene knockout (-/-) mice. The effects of the fat- and protein- enriched diet OA-2 on body weight, hyperlipidemia, and frequencies of sludge and gallstone formation were examined, and compared between wild-type and CCK-1R(-/-) male and female mice. The OA-2 diet contains slightly higher protein and fat (7.9 % fat and 27.6 % protein) compared with a standard diet (CRF-1) (5.6 % fat and 22.6 % protein), but their total energies are similar. After weaning, CRF-1 was provided until 3 months of age in all animals. Administration of an OA-2 diet was started when age-matched CCK-1R(-/-) and wild-type male and female mice reached maturity, at 3 months of age. Administration of CRF-1 was continued in the rest of the animals. Mice were sacrificed by guillotine at 6 and 12 months of age and the blood was collected to measure plasma levels of triglyceride and cholesterol. The gallbladder was removed and classified as normal (clear gallbladder), clouded (sludge formation), and/or containing gallstone formations. RESULTS: As long as CRF-1 was provided, the frequency of sludge and/or gallstone formation in CCK-1R(-/-) male mice was 3 of 8 (35%) and 4 of 9 (45%) in females at 12 months of age, whereas no gallstone formation was observed at 6 months of age. On the other hand, male mice fed OA-2 increased their body weight and plasma lipid concentrations, compared with those fed CRF-1 regardless of genotype. Under the OA-2 diet, sludge and gallstone formation was observed at 6 months of age, not only in CCK-1R(-/-) male mice but also in wild-type male mice. In contrast, parameters in female mice did not differ between the two diets. CONCLUSION: Male mice were more susceptible to protein- and fat-enriched diet-induced obesity than female mice, and hyper-nutritional status accelerated sludge and gallstone formation in male mice.

Cholecystokinin 1A receptor polymorphisms.

Since the isolation and sequencing of cholecystokinin (CCK), considerable advances have been made in understanding the roles played by this peptide as a hormone and as a neuropeptide. CCK-1(A) and 2(B) receptor (R) cDNAs have been cloned; shortly thereafter, the naturally occurring CCK-1R gene-deficient rat (the Otsuka Long-Evans Tokushima Fatty (OLETF) rat) was discovered. This strain develops adult-onset diabetes with obesity, and has a 6847 base-pair deletion of the CCK-1R gene in which the promoter lesion and the first two exons are missing. At the same time, the genomic structures of CCK-1R in rats, mice, and humans were clarified. The CCK-1R gene consists of five exons interrupted by four introns. It has been determined that there is species- and tissue-specific CCK receptor heterogeneity of expression; in particular, there is evidence that the human pancreas does not express CCK-1R, while the pancreas in rodents primarily expresses CCK-1R. Although CCK-1R polymorphisms with amino acid changes such as 21Gly to Arg, 71 Arg to Gly, and 364 Val to Ile were discovered in subjects with obesity and diabetes mellitus, these changes occur sporadically. We identified two sequence changes, a G to T change in nucleotide -128, and an A to G change in nucleotide -81, in the promoter region of the CCK-1R gene. This polymorphism is considered to be a single nucleotide polymorphism (SNP) related to weight control difficulties in obese subjects as well as to psychiatric disorders. The precise molecular mechanisms of this polymorphism remain to be clarified.

Decreased hydrogen-potassium-activated ATPase (H+-K+-ATPase) expression and gastric acid secretory capacity in aged mice.

Gastric acid secretion in response to chemical stimulation and to mechanical stimulation was investigated in adult and old mice. The protein expression of a proton pump (H(+)-K(+)-ATPase), a marker of parietal cell function, was determined by Western blotting. Acid secretion was stimulated by histamine (500 and 1000 microg/kg) or carbachol (10 and 20 microg/kg). To investigate the response to mechanical stimulation, the stomach was distended by an intragastric injection of isotonic saline (0.5, 1.0, 1.5, and 2.0 ml). Administration of two doses of histamine produced a dose-dependent increase in acid secretion in adult mice, whereas a higher dose of histamine failed to produce a further increase in old mice. Gastric acid secretion, whether produced by carbachol or mechanical stimulation, did not differ between the two age groups. The protein expression of H(+)-K(+)-ATPase was significantly lower in old mice than in adult. Insofar as histamine increases acid secretion via the cyclic AMP (cAMP) pathway in parietal cells, while carbachol and gastric distention do so via the calcium signaling pathway, the cAMP signaling pathway may be more susceptible to aging than the calcium signaling pathway. The decrease in the secretory capacity of acid secretion in the old mice may be partly attributable to a decrease in parietal cell function, as shown by decrease in H(+)-K(+)-ATPase protein expression.

Acute inhibition of lymphatic cholesterol transport in rat intestine by SCH 58053.

To clarify the pharmacological mechanism of ezetimibe, SCH 58053, an analog of ezetimibe, was intraduodenally administered to lymph-fistula rats, and its effect on lymphatic lipid transport in the intestine was monitored. SCH 58053, 5.0 mg/kg body weight, was administered one hour before a 5-hour infusion of a lipid emulsion containing 40 micromol/h of triolein and 2.74 micromol/h of cholesterol (Experiment 1) or co-administered at 5.0 mg/kg body weight/h with the lipid emulsion for 4 hours to rats that had been infused with the lipid emulsion alone for 3 hours (Experiment 2). SCH 58053 administration significantly inhibited lymphatic cholesterol transport, but not triglyceride transport, in both groups compared to control rats that did not receive SCH 58053. The ratio of free cholesterol to total cholesterol in the lymph of the treated rats was unchanged compared to the control rats. Thus, the results showed that SCH 58053 is a potent, rapid, and selective inhibitor of lymphatic cholesterol transport in the intestine.