Comparison of the effects of structurally different H2-antagonists on acid and pepsin activity stimulated by dimaprit in conscious cats

In the present study the effects of three structurally different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) have been investigated on gastric acid and pepsin secretion of eight cats provided with cannulated gastric fistulas. The maximum pepsin output obtained from a set of complete dose-response curves of dimaprit was not statistically different from basal values. In the presence of the H2-antagonists, while the gastric acid secretion induced by dimaprit was competitively antagonized, the pepsin secretion was differently affected. The data obtained on pepsin activity with cimetidine and ranitidine were quite similar to the control values. By contrast, oxmetidine induced a significant increase. The results suggest a very weak involvement of the H2-receptors in pepsin activity and that oxmetidine performance could not be attributable to an H2-receptor block.     

鼻腔分泌物中胃蛋白酶检测在咽喉反流诊断中的应用

目的探讨鼻腔分泌物中胃蛋白酶检测在咽喉反流（LPR）诊断中的应用。方法对50例慢性鼻一鼻窦炎（CRS）患者及20例健康志愿者行反流症状指数量表（RSI）、反流检查计分量表（RFS）检查,CRS患者行质子泵抑制剂（PPI）诊断性实验,三项评定中满足两项及以上者划入LPR组。用酶联免疫吸附方法（ELISA）检测鼻腔分泌物中的胃蛋白酶。比较上述两种方法对诊断LPR的差异。结果50例CRS患者采用RSI评分其诊断阳性率为66％（33／50）,RFS评分阳性率为70％（35／50）,PPI诊断性治疗阳性率为64％（32／50）,有72％（36／50）划入LPR组。CRS组、LPR组及健康组胃蛋白酶阳性率分别为88％（44／50）、100％（35／35）、30％（6／20）,差异有统计学意义（P〈0．01）。对LPR的诊断,胃蛋白酶检测比三联诊断法灵敏度高（P〈0．01）。结论鼻腔分泌物中胃蛋白酶检测可作为LPR诊断的可靠指标。     

Failure of “antigastrin” (SC-15 396) to inhibit gastric acid and pepsin secretion in anaesthetized gastric fistula cats

Summary 1. The effect of antigastrin (SC-15 396) on gastric acid and pepsin secretion produced by the gastrin-analogue tetrapeptide amide Try. Met. Asp. Phe-NH₂ and by electrical stimulation of the vagus was investigated in anaesthetized gastric fistula cats.2. Antigastrin failed to inhibit both acid and pepsin response stimulated by either the tetrapeptide or vagus excitation.3. It was concluded that the ineffectiveness of antigastrin in cats is due to a species difference between rats and dogs on the one hand and cats on the other, and that antigastrin is not a specific gastrin antagonist.Supported by the Deutsche Forschungsgemeinschaft and by the Alfred Teufel-Stiftung.     

Lipopolysaccharide-induced inhibition of gastric acid and pepsin secretion in rats

We used male Wistar rats to determine the effects of lipopolysaccharide (LPS) on gastric secretion. After pylorus ligation, 24-h fasted rats received i.p. injections of different doses of LPS dissolved in sterile saline. The amounts of gastric acid and pepsin secreted were determined 2, 4 or 8 h after injection. Small doses of LPS (10-1000 ng/rat) significantly inhibited the release of both gastric secretants as compared with control animals, and this inhibitory effect of LPS on gastric secretion was dose-related. The gastric antisecretory effect of LPS was still evident 8 h after injection, indicating that this action of LPS was long-lasting. These results suggest that LPS might be involved in the regulation of gastric secretion under certain pathophysiological conditions such as acute bacterial infections.     

Effect of antacids on pepsin activity in gastric acid

The 9 widely used antacids were studied for antipepsic activity.     

Effect of 5-HT on basal and stimulated secretions of acid and pepsin and on gastric volume outflow in the in vivo gastrically and intestinally perfused cod, Gadus morhua

Gastric acid and pepsin responses to 5-HT was measured, in cod, during gastric and intestinal perfusions. During basal conditions, both acid and pepsin secretions were stimulated by 0.25 mumol/kg X h of 5-HT. A higher dose, 1 mumol/kg X h inhibited acid secretion and stimulated the output of pepsin both during basal conditions and during stimulation with histamine or carbachol. Histamine and carbachol, when given alone, were powerful acid stimulators but in comparison with 5-HT poor pepsigogues. Most probably due to inhibition of gastric volume secretion, gastric outflow volume decreased during treatment with higher doses of 5-HT. However, when the intestinal perfusion was omitted and water support instead given by the intramuscular route, 5-HT induced a large increase in gastric outflow volume. Our results suggest that 5-HT may be a physiological regulator of acid and pepsin secretion in the fish. The dipsogenic effect seen in the absence of intestinal perfusion indicates that 5-HT may be involved also in the regulation of drinking.     

Stimulation of the hypothalamo-pituitary-adrenal axis by compounds formed in inflamed tissue.

1 Rat paws were injected with carrageenin, and their subcutaneous tissue perfused 135 min later. These perfusates were injected intravenously into receptor rats in which they caused an attenuation of inflammatory responses. 2 The effect was not observed in adrenalectomized receptor rats nor in receptors with electrolytic lesions in the median eminence of the hypothalamus but persisted in adrenal-demedullated animals. 3 The active perfusates also induced eosinopenia in normal or adrenal-demedullated animals, but not in adrenalectomized rats, and produced an increase in blood corticosterone with a concomitant decrease in the amounts of adrenal ascorbic acid. 4 The active perfusates did not affect the responses of isolated preparations to histamine, bradykinin, prostaglandins and 5-hydroxytryptamine neither did they elicit changes of the arterial blood pressure in receptor animals. 5 The anti-inflammatory activity present in perfusates from inflamed paws seems to be formed slowly at the site of the developing inflammatory reaction, since perfusates collected 30-65 min after the injection of carrageenin were ineffective, as was plasma taken from donor rats at various time intervals after carrageenin injections. 6 It is suggested that the anti-inflammatory factor present in the active perfusates exerts its action by stimulation of the hypothalamo-pituitary-adrenal axis.     

Stimulation of drug metabolism by ascorbic acid in weanling guinea-pigs

Drug metabolism activities such as O-demethylase and N-demethylase and liver microsomal electron transport components including cytochrome P-450 and NADPH-cytochrome P-450 reductase were determined in weanling guinea-pigs under vitamin C deficiency as well as with normal and high intake of the vitamin. Animals depleted of the vitamin for only 8 days, with no signs of scurvy or weight loss, had decreased drug enzyme activities. Further depletion of the vitamin resulted in marked reduction of the microsomal drug-metabolizing system. Furthermore, administration of high amounts of ascorbic acid (2–200 mg/day) led to significant increases in liver drug oxidation activities and electron transport components. Studies of K_m values in microsomes from vitamin C-deficient, normal and animals given high supplements of vitamin C showed no difference in the apparent affinity or V_max of a typical drug oxidation reaction, N-demethylation. Specificity studies indicate that ascorbyl palmitate or d-isoascorbic acid can replace the vitamin, in part, in maintaining drug metabolism.     

胃蛋白酶合剂中胃蛋白酶效价的测定

目的建立胃蛋白酶合剂中胃蛋白酶效价的测定方法。方法采用紫外分光光度法测定胃蛋白酶的效价,测定波长为275 nm,以酪氨酸为对照品,牛血红蛋白为底物。结果酪氨酸浓度在0.324 6～0.757 4 mg mL-1与吸光度呈良好的线性关系（r=0.999 8）。胃蛋白酶合剂所含的其他成分不干扰胃蛋白酶的效价测定。平均回收率为99.9%,RSD为1.0%。结论该方法简便、准确、可靠,可用于胃蛋白合剂中胃蛋白酶的效价测定。     

Stimulation of human fibroblast collagen synthesis in vitro by gamma-aminobutyric acid

Human buccal mucosa fibroblasts were exposed in culture to gamma-aminobutyric acid (GABA) and the areca alkaloid arecaidine. Both GABA and arecaidine stimulated collagen synthesis and proliferation in a concentration-dependent manner, with arecaidine consistently producing the greater stimulation. Prior exposure to GABA or arecaidine for 5 days caused the cells to become insensitive when challenged with either drug.     

Bioadhesive oesophageal bandages: protection against acid and pepsin injury

The rate of acid and pepsin diffusion through solutions of sodium alginate was measured using in vitro techniques. Previous work has demonstrated that solutions of alginate may adhere to the oesophagus for up to 60 min; this work measured their ability to protect the oesophageal epithelial surface from damage caused by refluxed acid and pepsin. Franz diffusion cells were used to measure the rate of acid and pepsin diffusion through an alginate layer. The effect of the type of alginate, alginate concentration and depth of alginate applied were investigated. The rate of both acid and pepsin diffusion was significantly reduced (ANOVA analysis; P<0.05) in the presence of an alginate solution compared to the control. A 2% (w/v) alginate solution with a high guluronic acid component, in a layer of 0.44 mm depth, demonstrated the greatest reduction in acid diffusion with a permeation coefficient 14% than that of a control value. All three alginates demonstrated significant reductions in acid diffusion with both increasing depth and increasing concentration, as expected. Pepsin diffusion was also significantly reduced as the depth and concentration of applied alginate increased. This study demonstrates that an adhesive layer of alginate present within the oesophagus will limit the contact of refluxed acid and pepsin with the epithelial surface.     

Stimulation of fatty acid utilization by sodium clofibrate in rat and monkey hepatocytes

The acute effects of sodium clofibrate (NaCPIB) on the metabolism of [1-14C]palmitate, [1-14C]octanoate, [1-14C]butyrate, and [2-3H]glycerol by freshly isolated hepatocytes were tested to explore its mechanism of action. Labeled long-, medium-, and short-chain fatty acids were incorporated into all the major lipid classes and were oxidized to 14CO2 by the liver cells. The partitioning of labeled fatty acids from lipogenic towards oxidative pathways was inversely related to fatty acid chain length. [1-14C]Palmitate was incorporated mainly into cellular triglycerides and phospholipids; [1-14C]octanoate, mainly into triglycerides and free cholesterol; and [1-14C]butyrate, mainly into free cholesterol and phospholipids of the cells. NaCPIB (1-3 mM) rapidly stimulated the esterification of labeled palmitate or glycerol to triglycerides, but drug levels greater than 5 mM were inhibitory to esterification. NaCPIB (1 mM) increased the oxidation of [1-14C]palmitate to 14CO2 by either rat or monkey hepatocytes and enhanced the release of labeled lipids from [2-3H]glycerol-prelabeled cells into the extracellular medium. Accelerated [1-14C]octanoate incorporation into glycerolipids and sterols and increased [1-14C]octanoate conversion to 14CO2 were observed in rat liver cells incubated with 1 mM NaCPIB. In contrast, the same drug level stimulated the oxidation of [1-14C]butyrate to 14CO2 but greatly diminished its incorporation into hepatocellular sterols or glycerolipids. These results indicate that (a) NaCPIB acutely alters hepatic ultilization of fatty acids by actions at diverse loci; (b) these metabolic alterations vary with fatty acid chain length; and (c) these effects are probably due to rapid changes in biochemical regulatory mechanism and/or in substrate channelling within the cells. These data further suggest that the early hypolipidemic effect of the drug in rats and primates may be related to an enhanced hepatic oxidation of long-chain fatty acids, but cannot be attributed simply to a reduction in their esterification to complex lipids.     

Stimulation of vascular prostacyclin by SKF 525-A (proadifen) and related compounds

SKF 525-A (proadifen), a well-known inhibitor of drug metabolism and cytochrome P-450 activity, stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The threshold concentration producing a detectable effect was 20 microM; the time course of SKF 525-A action exhibited particular features--progressive onset, long duration and slow reversibility--distinct from those of other stimuli (ADP, ionophore A23187 f.i.). The PGI2-stimulating activity of SKF 525-A was characterized by specific structural requirements: activity was abolished by the deletion of the terminal propyl group and increased by its elongation into an isobutyl group; chlorination of the phenyl groups increased the potency. SKF 525-A increased the production of PGI2 by cultured endothelial cells from bovine aorta and human umbilical vein, but had no effect on cultured smooth muscle from the bovine aortic media. Stimulation of PGI2 release could be explained by an increased availability of free arachidonic acid, which was probably independent from cytochrome P-450 inhibition. In human platelets, SKF 525-A inhibited prostaglandin and thromboxane production induced by A23187, thrombin and ADP. Simultaneous stimulation of endothelial PGI2 and inhibition of platelet TxA2 represents an original pharmacological profile: SKF 525-A might thus constitute the prototype of a new class of antiplatelet drugs.     

Stimulation of arachidonic acid metabolism by human slow-reacting substances.

Human slow-reacting substance of anaphylaxis (SRS-A) and calcium ionophore-induced human SRS released prostaglandin-like substances and rabbit aorta contracting substance (RCS) from guinea-pig lungs. This effect was abolished by incubation of SRS-A and SRS with arylsulphatase or pretreatment of the lungs with indomethacin. Human SRS-A and SRS therefore resembled guinea-pig SRS-A in stimulating arachidonic acid metabolism. These results provide further evidence for a similar (or identical) nature of human SRS-A and SRS and suggest a possible role for slow-reacting substances in the release of prostaglandins during anaphylaxis.     

Stimulation of cysteinyl leukotriene production in mast cells by heat shock and acetylsalicylic acid

Immunoglobulin (Ig) E-dependent activation of mast cells is central to the allergic response. The engagement of IgE-occupied receptors initiates a series of molecular events that causes the release of preformed, and de novo synthesis of, allergic mediators. Cysteinyl leukotrienes are able to contract airway smooth muscle and increase mucus secretion and vascular permeability and recruit eosinophils. Mast cells have also recently been recognized as active participants in innate immune responses. Heat stress can modulate innate immunity by inducing stress proteins such as heat-shock proteins (HSPs). We previously demonstrated that treatment of mast cells with heat shock or acetylsalicylic acid results in an increase of TNF-alpha and IL-6 release. This effect was paralleled by expression of HSP70. In the current study, we further investigated the effects of heat shock and acetylsalicylic acid on the activation of mast cells and the release of cysteinyl leukotrienes. In mouse mast cells, derived from a culture of bone marrow cells, responsiveness to heat shock, acetylsalicylic acid and exogenous or endogenous HSP70 was monitored by measuring leukotriene C4 release. We show that after heat shock treatment and exposure to acetylsalicylic acid leukotriene production was increased. Moreover, exogenous rHSP70 also induced leukotriene production. Because it has been reported that leukotriene production in mast cells may be mediated by Toll like receptor (TLR) activation, and HSP70 also activates TLRs signaling, we further explored these issues by using mast cells that are not able to produce HSP70, i.e. heat shock factor-1 (HSF-1) knockout cells. We found that in HSF-1 knockout bone marrow derived mast cells, heat shock and acetylsalicylic acid failed to induce release of leukotrienes. Moreover, in wild type cells the surface expression of TLR4 was attenuated, whereas the intracellular expression was up-regulated. We conclude that heat shock and acetylsalicylic acid induce the production and release of heat shock proteins from mast cells, which in turn stimulate leukotriene synthesis through activation of TLR4.