Effect of exogenous serotonin on intragastric pH and its influence on serum gastrin levels in rats.

The effect of various doses of serotonin on the serum gastrin levels and intragastric pH in rats, was studied. After serotonin administration of 10 mg/kg i.p., a significant increase in serum gastrin levels was noted, as well as a strong increase in the intragastric pH. It was also observed that a lower dose, 5 mg/kg i.p., significantly increased serum gastrin levels, while intragastric pH was not affected, remaining at baseline values throughout the study. These results suggest that the increase observed in serum gastrin levels after administration of exogenous serotonin is not mediated by increase in intragastric pH.     

Sex-related difference in antral and serum gastrin levels in the rat.

Antral and serum gastrin concentrations were found to be significantly lower in female than in male rats. Following ovariectomy, serum gastrin concentration significantly increased to male levels; tissue gastrin also increased, but not significantly. Daily injections of estradiol benzoate (2 mug/day) abolished the rise in gastrin levels after ovariectomy. Antral and serum gastrin concentrations were significantly higher in lactating rats than in any other group tested. The possible relationships among sex-dependent changes in food intake, gastrin concentration, and gastric secretion are discussed.     

CCKB/gastrin receptor antagonists: recent advances and potential uses in gastric secretory disorders.

Cholecystokinin (CCK) and the structurally related peptide, gastrin, have numerous effects on tissues in the central nervous system and gastrointestinal tract. Recent studies show these effect are mediated by a CCKA and CCKB receptor. Knowledge of the physiological role and role of CCKB receptors in pathologic processes has been particularly limited by the availability of selective, potent receptor antagonists. Recently, new members of five different classes of non-peptide CCKB receptor antagonists are reported and are reviewed briefly. these include compounds isolated from Streptomyces (tetronothiodin, virginiamycin analogues), ureido-acetamide analogues (RP 69758, RP 72540, RP 73870), newer benzodiazepine analogues (L-368,935, L-740,093, YM022), pyrazolidimine analogues (LY 262,691) and glutamic acid analogues (CR2194). Many of these compounds have greater than 1000-fold selectivity for the CCKB over the CCKA receptor and some have greater than 10,000-fold selectivity. The pharmacology and effects of CCKB receptor antagonists on gastric acid secretion is briefly reviewed. Furthermore, the possible clinical usefulness of CCKB receptor antagonists in treating disorders of gastric acid secretion, in inhibiting the trophic effects of gastrin and in other clinical conditions is briefly discussed.     

Clinical significance of serum gastrin levels in patients with colorectal cancer

AIMS: An association between elevated serum gastrin levels and the presence of human colorectal cancer has been reported, and gastrin has been shown to stimulate the growth of experimentally induced colon neoplasia. The aim of this study was to determine the preoperative and postoperative concentrations of serum gastrin in 53 patients with colorectal cancer and to assess the correlation between gastrin levels and tumor characteristics and prognosis. MATERIALS AND METHODS: A prospective study was performed over a six-year period during which 53 patients received potentially curative surgery for colorectal cancer. The prognostic variables used for the analysis included age, sex, tumor site, stage and degree of differentiation, preoperative and postoperative serum values of carcinoembryonic antigen (CEA) and gastrin, cancer-related mortality, and survival. CEA and gastrin serum values were determined using radioimmunological methods. Follow-up was carried out with clinical and radiological tests. RESULTS: The mean preoperative gastrin concentration was 51.2+/-27.4 pg/mL (range 12-146). Significantly increased serum gastrin concentrations, which returned to normal after surgery, were detected only in patients with well-differentiated cancer (74.2+/-28.3 pg/mL; moderately differentiated, 52.1+/-23.8; poorly differentiated, 29.9+/-12.3, p=0.02). The prognosis was unrelated to serum gastrin level; instead, tumor stage, preoperative CEA value, and degree of differentiation affected patient survival. CONCLUSIONS: This study showed that the serum gastrin concentration is not an appropriate clinical oncogenic factor. Although occurring only in well-differentiated tumors, serum gastrin is unrelated to the prognosis of patients with colorectal cancer.     

The influence of prolonged cimetidine administration on serum gastrin levels and gastric acid secretion in rats.

The correlation between serum gastrin levels and gastric acid secretion during 4 weeks of cimetidine administration (once daily) was investigated. Serum gastrin levels and gastric acid secretion were estimated on the 7th, 14th, 21st and 28th day after cimetidine administration (25 mg.kg-1, intragastrically). At the mentioned time intervals gastric acid secretion stimulated by histamine and pentagastrin was also studied. It was found that on the 14th and 21st day after cimetidine administration serum gastrin levels were significantly elevated. Basal gastric acid secretion after cimetidine administration was significantly decreased at all the observed time intervals. Histamine-stimulated gastric acid secretion was increased on the 14th, 21st and 28th day after cimetidine administration. Hypoacidity was not followed at all time intervals by hypergastrinaemia (only on day 14 and 21 after cimetidine).     

Novel C-terminal gastrin antagonists. Synthesis and biological activity

The C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, is a full agonist of gastrin, but des-Phe analogues, including Boc-Trp-Met-Asp-NH2, are antagonists. To ascertain the minimum structural requirement for an antagonist, we used conventional solution phase methodology to synthesize analogues with further modifications including removal of the alpha-amino group of Trp, conversion of the indole to a phenyl ring, and methylation of amide bonds. These analogues were tested for their effect on pentagastrin-stimulated acid release in dogs surgically prepared with a gastric fistula. When infused intravenously at a dose of 20 pmol kg-1 h-1, the peptides significantly inhibited acid secretion. The extent of inhibition ranged from 12% to 60%. Thus, tripeptide analogues based on the C-terminal sequence of gastrin act as potent and specific antagonists of gastrin-stimulated acid secretion.     

Effects of H1 and H2 receptor antagonists on Tetrahymena.

In Tetrahymena pyriformis the phagocytotic rate increases in response to histamine, but neither the H1 antagonist phenindamine nor the H2 antagonist metiamide stimulate phagocytosis. The H1 antagonist counteracts the effect of histamine, whereas the H2 antagonist does not. The histamine receptor of Tetrahymena is of H1-type, since it cannot distinguish between histamine and antagonists which are closely related to it chemically. It does, however, distinguish between histamine and the chemically unrelated H1 antagonist, phenindamine. The H2 antagonist does not interact with the receptor.     

A new class of potent gastrin antagonists

The hexapeptide Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, from the natural sequence of C-terminal cholecystokinin was found to be a competitive antagonist of cholecystokinin receptors, in vitro. In the present study, we report that this peptide inhibits gastrin-induced acid secretion in vivo, (ED50 = 1.5 mumol . kg-1), without agonist activity. Desulfation of the tyrosine residue slightly altered this effect. The tripeptide Boc-Trp-Met-Asp-NH2 showed similar effects, but had lower potency (ED50 = 12 mumol . kg-1). From these preliminary results, it can be concluded that removal of the phenylalanine residue from the C-terminal sequence of CCK or gastrin, leads to an antagonist of the natural hormones and that C-terminal phenylalanine residue is important for agonist activity. As compared with proglumide, a well known gastrin receptor antagonist, these peptides were 20-200 times more potent as inhibitors on the same model.     

Effect of beta-endorphin on gastric acid secretion and serum gastrin concentration in humans

The effect of synthetic human β-endorphin on gastric acid secretion was studied in 9 healthy subjects. Neither 2.5 mg or 15 mg β-endorphin had a significant effect on acid secretion or on serum gastrin concentration despite the fact that this dose of opiate caused a significant increase in serum prolactin concentrations. The role of endogenous opiate-like peptides on gastric secretion is discussed.     

Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX₂R subtype and culminating in the discovery of 23, a highly potent, OX₂R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX₁R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.     

Effect of serum on phenylalanine hydroxylase levels in cultured hepatoma cells.

Continued high levels of phenylalanine hydroxylase in cultured H4-II-E-C3 rat hepatoma cells require either serum or glucocorticoids in the culture medium. Upon withdrawal of serum, cellular phenylalanine hydroxylase levels decay exponentially with a half-life of 22 hours for about 60 hours, after which time a low, constant enzyme content persists for at least 96 hours. This decline of phenylalanine hydroxylase is fully reversible; normal enzyme levels are restored in a time- and dosage-dependent fashion upon addition of serum to basal cultures. The serum factor is nondialyzable and moderately heat-stable. The stimulation by serum of the phenylalanine hydroxylas content of basal cultures is blocked by 3-[2-(3,5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl]glutarimide and requires ongoing cellular protein synthesis. When added to the enzyme-assay mixture in vitro, serum does not alter the phenylalanine hydroxylase activity of extracts from basal cultures. Three lines of evidence suggest that serum contains a nonsteroidal phenylalanine hydroxylase stimulatory components(s): (a) glucocorticoid antagonists inhibit less than one-half of the biological activity of serum; (b) exhaustive extraction of endogenous serum glucocorticoids with charcoal reduces the activity of serum to about one-half of control values; and (c) the stimulatory effects of charcoal reduces the values; and (c) the stimulatory effects of charcoal-extracted serum and hydrocortisone are additive. The phenylalanine hydroxylase stimulatory activities of the charcoal-extracted sera from four mammalian species and from three stages in development in one mammalian species are comparable. A survey of partially purified preparations of a number of known hormones failed to reveal any one capable of elevating the phenylalanine hydroxylas levels of basal cultures in a manner comparable to that of charcoal-extracted serum.     

Effect of endothelin receptor antagonists on ventricular susceptibility in postinfarcted rats

This study investigated whether selective endothelin (ET) type A (ET(A)) or nonselective ET(A)/ET(B) receptor blockade exerted antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats received either vehicle, ABT-627 (selective ET(A) receptor antagonist), bosentan (nonselective ET(A)/ET(B) receptor antagonist), or hydralazine for 4 wk. The measurement of myocardial ET-1 levels at the remote zone revealed a significant increase in vehicle-treated infarcted rats compared with sham-operated rats, consistent with increased activities of ET-1 after infarction. Sympathetic nerve function changes assessed by the norepinephrine content of myocardium and the dialysate and plasma dihydroxyphenylglycol levels were parallel to ET-1 levels. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the change of nerve function. This was accompanied with a significant upregulation of nerve growth factor protein expression and mRNA in the vehicle-treated infarcted rats, which reduced after the administration of either ET(A) or ET(A)/ET(B) blockade to a similar extent. The beneficial effects of ET receptor antagonists on sympathetic nerve function and structures were dissociated from their blood pressure-lowering effect because ET receptor antagonists and hydralazine reduced arterial pressure similarly. Arrhythmic severity during programmed stimulation in ET receptor antagonists-treated rats was significantly lower than that in vehicle-treated infarcted rats. Our data indicate that the ET system, especially via ET(A) receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, a chronic use of either ET(A) or ET(A)/ET(B) antagonists may modify the arrhythmogenic response to programmed electrical stimulation.     

Effect of cholecystokinin receptor antagonists on voluntary food intake in chickens

The effect of two cholecystokinin (CCK) receptor antagonists (L-364718 and L-365260) and of diazepam on voluntary food intake in chicken was studied. L-365260 significantly increased cumulative food intake at 30 and 60 min, whereas L-364718 had no effect. Diazepam also increased food intake at 30 minutes. It was therefore concluded that anxiolytic effects could account for an increase in food intake in the conditions under which the study was carried out. Consequently, the effect of L-365260 could either be due to its anxiolytic properties or to its direct effects on food intake control.     

Effect of glucagon on blood gastrin levels in hepatic cirrhosis: correlation with blood levels of cyclic AMP

The effect of glucagon on fasting gastrin levels was studied in normal subjects and in patients with advanced liver cirrhosis. Intravenous glucagon was given e.v. at a dose of 200 ng/kg/h and produced a significant decrease of serum gastrin levels at 50 min in controls while in cirrhotic patients there was no significant decrease. (p less than 0,01) Gastrin inhibition in normal subjects during glucagon infusion was significantly correlated to a simultaneous increase found in plasma cAMP and glucose levels. These findings suggest that hypergastrinemia in cirrhosis could be consequence of the failure of glucagon metabolic interactions.     

幽门螺杆菌根除治疗对消化性溃疡患者血清胃泌素水平的影响

目的 观察幽门螺杆菌(H.pylori)根除治疗对消化性溃疡患者血清胃泌素水平的影响,为该病治疗提供参考。 方法 选择我院2017年8月至2019年8月收治的120例H.pylori感染的消化性溃疡患者作为观察组,根据H.pylori分型结果进一步分为HPⅠ型组和HPⅡ型组,观察组患者接受根除幽门螺杆菌治疗。选择同期入院的40例非幽门螺杆菌感染消化性溃疡患者作为对照组,对照组患者接受常规治疗。比较两组患者治疗效果、胃镜检查结果、H.pylori清除情况及血清胃泌素、IL10、IL17水平。 结果 HPⅠ型组、HPⅡ型组和对照组患者临床总有效率差异无统计学意义(92.75%、96.08%、97.50%,χ2=1.384,P=0.051)。HPⅠ型组、HPⅡ型组、对照组患者胃镜检查总有效率差异无统计学意义(91.30%,96.08%,97.50%,χ2=1.384,P=0.051)。HPⅡ型组患者幽门螺杆菌根除率高于HPⅠ型组(98.04% vs 85.51%,χ2=4.129,P=0.042)。HPⅠ型组患者治疗后血清胃泌素、IL10、IL17水平均高于对照组(均P结论 不同类型H.pylori感染消化性溃疡患者行幽门螺杆菌根除治疗后临床效果无显著差异。幽门螺杆菌根除治疗可降低消化性溃疡患者血清胃泌素、IL10、IL17水平。     

2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists

High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.