Bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by protein kinase C, and is enhanced by disruption of rho/cytoskeletal pathways.

Isolated canine G cells in primary culture have been used to study calcium, protein kinase C (PKC), and rho/cytoskeletal-dependent intracellular pathways involved in bombesin- stimulated gastrin release. A method to obtain highly purified G cells by culture (64% G cells) after flow cytometry on elutriated fractions of cells from digested canine gastric antral mucosa has been developed. Pretreatment of G cells with thapsigargin (10(-8)-10(-6) M) and release experiments in Ca2+-containing or -depleted media showed that influx of Ca2+ into the cells and not acute release from intracellular stores plays an important role in bombesin-stimulated gastrin release. Inhibition of PKC by the specific inhibitor GF 109 203X did not affect bombesin-stimulated release. Rho, a small GTP-binding protein that regulates the actin cytoskeleton, is specifically antagonized by Clostridium botulinum C3 exoenzyme. C3 (10 microg/ml) enhanced basal and bombesin-stimulated gastrin release by 315 and 266%, respectively. The importance of the cytoskeleton for regulation of gastrin release was emphasized by a more pronounced release of gastrin when the organization of the actin cytoskeleton was disrupted by cytochalasin D (5 x 10(-)7 and 10(-)6 M). Wortmannin, a potent inhibitor of phosphoinositide-3-kinase, did not alter bombesin-stimulated gastrin release. Thus, it is concluded that bombesin-induced gastrin release from canine G cells is stimulated by Ca2+ but not by PKC, and is enhanced by disruption of rho/cytoskeletal pathways.     

Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade

Abstract. The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 μg kg^-1 h^-1) with and without a background of atropine (5 μg kg^-1 h^-1) or loxiglumide (10 mg kg^-1 h^-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion ( P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened ( P < 0.05). Only high doses of bethanechol enhanced gastrin ( P < 0.05), cholecystokinin ( P < 0.05), and pancreatic polypeptide ( P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% ( P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively ( P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.     

幽门螺杆菌感染与十二指肠胃上皮化生及胃泌素之间关系的研究

目的　通过对幽门螺杆菌 (Hp)感染与十二指肠胃上皮化生 (DGM )及胃泌素 (GAS)关系的研究 ,探讨Hp导致十二指肠溃疡 (DU)的发病机制。 方法　检测了 12 1例患者内镜、病理、Hp感染及DGM情况。同时测定了其中 6 6例患者的血清GAS浓度。结果　球部有溃疡者 ,胃及球部Hp检出率均显著高于球部无溃疡者 (P <0 .0 0 1) ;但球部Hp检出率在DU与CU、GU与CG之间无差别 (P >0 .0 5 ) ;球部有溃疡者DGM的检出率显著高于球部无溃疡者 (P <0 .0 0 1) ,且前者的DGM程度更重 (P <0 .0 0 1) ,但在DU与CU、GU与CG之间无差别 (P >0 .0 5 ) ;胃部Hp阳性者DGM的发生率 (73.0 % )显著高于胃部Hp阴性者 (37.5 % ,P <0 .0 0 1) ,DGM( )及以上者在Hp阳性组发生率 (47.2 % )也高于Hp阴性组 (2 1.9% ,P <0 .0 5 ) ;Hp阳性者血清GAS浓度显著高于Hp阴性者 (P <0 .0 1) ,但血清GAS浓度在Hp阳性的DU、CU、GU与CG之间无差别(P >0 .0 5 ) ;有DGM者血清GAS浓度也显著高于无DGM者 (P <0 .0 1) ,且随着DGM程度的加重 ,血清GAS浓度早递增趋势 ,两者呈正相关 (rs=0 .4 2 ,P <0 .0 1)。结论　Hp感染特别是十二指肠Hp定植及DGM是影响DU发生、发展的两大危险因素。Hp可影响DGM的发生与发展 ,其中部分可能通过增加血清GAS分泌的作用。     

Molecular forms of gastrin in peptic ulcer: comparison of serum and tissue concentrations of G17 and G34 in gastric and duodenal ulcer subjects

We have studied the relationships between the main molecular forms of gastrin (G17 and G34) in the serum, antral and duodenal mucosa of duodenal (DU) and gastric (GU) ulcer patients. Fasting serum G17 was similar in both DU and GU (about 6 pmol/l) and in both groups increased about three-fold with feeding. In contrast, basal serum G34 was significantly higher in GU (29 pmol/l) than in DU (12 pmol/l) and the peak post prandial increase over basal of G34 was also higher in GU (57 pmol/l) compared with DU (10 pmol/l). In sharp contrast, in the same groups of DU and GU patients mean total antral gastrin concentrations were similar (about 12 nmol/g), and in both groups 95% of antral gastrin was G17, most of the remainder being G34. In both groups total duodenal gastrin concentrations were about 20% those in antral mucosa and about 70% of duodenal gastrin was attributable to G34. The higher serum G34 in GU could therefore be explained by increased secretion of duodenal gastrin, but further work is needed to examine whether there might also be preferential secretion of antral G34 in GU, or a difference in the metabolism (or volume of distribution) of gastrin variants in GU and DU.     

Molecular forms of gastrin in peptic ulcer: comparison of serum and tissue concentrations of G17 and G34 in gastric and duodenal ulcer subjects

Abstract We have studied the relationships between the main molecular forms of gastrin (G17 and G34) in the serum, antral and duodenal mucosa of duodenal (DU) and gastric (GU) ulcer patients. Fasting serum G17 was similar in both DU and GU (about 6 pmol/1) and in both groups increased about three-fold with feeding. In contrast, basal serum G34 was significantly higher in GU (29 pmol/1) than in DU (12 pmol/1) and the peak post prandial increase over basal of G34 was also higher in GU (57 pmol/1) compared with DU (10 pmol/1). In sharp contrast, in the same groups of DU and GU patients mean total antral gastrin concentrations were similar (about 12 nmol/g), and in both groups 95% of antral gastrin was G17, most of the remainder being G34. In both groups total duodenal gastrin concentrations were about 20% those in antral mucosa and about 70% of duodenal gastrin was attributable to G34. The higher serum G34 in GU could therefore be explained by increased secretion of duodenal gastrin, but further work is needed to examine whether there might also be preferential secretion of antral G34 in GU, or a difference in the metabolism (or volume of distribution) of gastrin variants in GU and DU.     

Elevated cell-associated levels of interleukin 1β and interleukin 6 in inflamed mucosa of inflammatory bowel disease

The aim of this study was to investigate the involvement of the monocyte-derived cytokines interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) in idiopathic inflammatory bowel disease. Endoscopic biopsies of normal and inflamed intestinal mucosa were obtained from patients with ulcerative colitis ( n  = 11) and with Crohn's disease ( n  = 10). Intestinal mucosal cells were isolated by collagenase digestion. Cell viability, morphology and CD14 expression were determined. To measure cell-associated cytokine levels, cells were lysed and analysed for IL-1β and TNF-α in specific radioimmunoassays and for IL-6 using a biological assay. Compared with mucosal cells from control patients without inflammatory bowel disease the inflamed intestine in ulcerative colitis and Crohn's disease displayed markedly enhanced levels of IL-1β (median 245 pg 10⁻⁶ cells, range 30–1275) and IL-6 (median 22 U 10⁻⁶ cells, range 1–298). Non-inflamed mucosa in patients with ulcerative colitis and Crohn's disease did not shown elevated levels of IL-1β (median 50 pg 10⁻⁶ cells, range 33–90) or IL-6 (mean below detection limit of assay, i.e. 1 U 10⁻⁶ cells). In contrast, no clear cut difference between inflamed and non-inflamed mucosa could be detected for TNF-α. High tissue levels of IL-6 were associated with a high endoscopic grade of local inflammation. These results suggest that the monocyte-derived cytokines IL-1β and IL-6 are mediators of inflammation in inflammatory bowel disease.     

Effects of high-altitude chronic hypoxia on platelet α2-receptors in man

During chronic high-altitude (HA) exposure, basal and exercise-induced noradrenaline (NA) increases do not parallel blood pressure (BP) changes observed; unlike β-adrenergic receptors, to our knowledge no data are available on α-receptors. We studied platelet α₂- and leucocyte β-receptors and basal catecholamine levels in 11 trained climbers before and after they had spent a 15-day period at a height of over 4400 m. In six of the climbers we also evaluated catecholamines after maximal bicycle ergometer exercise. After chronic high-altitude exposure, a significant decrease was found in platelet α₂-receptor density and affinity [ B _max from 92.6 ± 6.7 to 54.6 ± 4.2 fmol mg⁻¹ protein ( P  < 0.001) and K _D from 1.271 ± 0.034 to 1.724 ± 0.077 nmol L⁻¹ ( P  < 0.05)], although no changes to β-receptors were observed. No changes were found in basal pre- and post-expedition NA and adrenaline (A), and there was only a slight decrease in post-expedition NA after maximal exercise. Our results suggest that prolonged exposure to hypoxia induces a down-regulation of α₂-receptors, which may be a contributory factor in the regulation of the physiological vascular response to acclimatization.     

Role of serum fasting gastrin in screening for hypergastrinemic syndromes in duodenal ulcer disease.

Basal serum gastrin levels were measured in 237 patients with endoscopically confirmed duodenal ulcer and were higher than normal in 16 cases. Protein meal gastrin stimulation was performed on this group of 16 patients and on a control group of 48 patients with normal basal gastrin concentrations but high rates of either ulcer recurrence or of complications (e.g., bleeding or perforation); 21 patients from the two groups were also tested for serum gastrin inhibition with secretin. Four cases (25%) of antral G-cell hyperfunction were found in the first group, plus 1 case compatible with Zollinger-Ellison syndrome (6.2%). Only 1 case (2%) of antral G-cell hyperfunction was found among the 48 controls. These results suggest the clinical utility of routine basal gastrin measurement in screening for hypergastrinemic patients with duodenal ulcer disease.     

Inhibition of gastrin release by secretin is mediated by somatostatin in cultured rat antral mucosa.

Somatostatin-containing cells have been shown to be in close anatomic proximity to gastrin-producing cells in rat antral mucosa. The present studies were directed to examine the effect of secretin on carbachol-stimulated gastrin release and to assess the potential role of somatostatin in mediating this effect. Rat antral mucosa was cultured at 37 degrees C in Krebs-Henseleit buffer, pH 7.4, gassed with 95% O2-5% CO2. After 1 h the culture medium was decanted and mucosal gastrin and somatostatin were extracted. Carbachol (2.5 X 10(-6) M) in the culture medium increased gastrin level in the medium from 14.1 +/- 2.5 to 26.9 +/- 3.0 ng/mg tissue protein (P less than 0.02), and decreased somatostatin-like immunoreactivity in the medium from 1.91 +/- 0.28 to 0.62 +/- 0.12 ng/mg (P less than 0.01) and extracted mucosal somatostatin-like immunoreactivity from 2.60 +/- 0.30 to 1.52 +/- 0.16 ng/mg (P less than 0.001). Rat antral mucosa was then cultured in the presence of secretin to determine its effect on carbachol-stimulated gastrin release. Inclusion of secretin (10(-9)-10(-7) M) inhibited significantly carbachol-stimulated gastrin release into the medium, decreasing gastrin from 26.9 +/- 3.0 to 13.6 +/- 3.2 ng/mg (10(-9) M secretin) (P less than 0.05), to 11.9 +/- 1.7 ng/mg (10(-8) secretin) (P less than 0.02), and to 10.8 +/- 4.0 ng/mg (10(-7) M secretin) (P less than 0.02). Secretin (10(-7) and 10(-8) M) also increased concomitantly culture medium somatostatin concentration. To determine whether secretion inhibition of carbachol-stimulated gastrin release was mediated by somatostatin, antral mucosa was cultured with carbachol, secretin (10(-9)-10(-7) M), and antibodies to somatostatin. Inclusion of somatostatin antibodies in the culture medium abolished the capacity of secretin (10(-7) and 10(-8) M) to inhibit carbachol-stimulated gastrin release. Results of these studies indicate (a) that secretin inhibits carbachol-stimulated gastrin release and (b) that under the conditions of these experiments secretin inhibition of gastrin release is mediated, at least in part, locally through release of antral somatostatin.     

Antithrombin inhibits lipopolysaccharide-induced tumor necrosis factor-α production by monocytes in vitro through inhibition of Egr-1 expression

Background:  Antithrombin (AT) improves the outcome of septic patients with intravascular coagulation. However, the mechanisms underlying the therapeutic benefits of AT are not fully understood. Tumor necrosis factor-α (TNF-α) plays a critical role in the development of organ failure and intravascular coagulation in sepsis. Aim:  This study aimed to elucidate a molecular mechanism by which AT inhibits TNF-α production Methods:  Human peripheral monocyte was stimulated by lipopolysaccharide (LPS) and TNF-α concentration in media was measured. Levels of phosphorylation of extracellular signal-regulated protein kinases (ERK) 1/2 and early growth response factor-1 (Egr-1) were estimated by western blotting or by electrophoretic mobility shift assay. Results:  Antithrombin (3 U mL^–1) inhibited TNF-α production by monocytes stimulated with LPS. Conversely, chemically modified AT that lacks affinity for heparin did not. AT inhibited the phosphorylation of ERK 1/2 and decreased the expression of Egr-1 in LPS-stimulated monocytes. However, it did not affect the activation of either nuclear factor-κB or activator protein-1. Pretreatment with KT5720, a protein kinase A inhibitor, reversed the inhibitory effect of AT on the LPS-induced phosphorylation of ERK1/2. Although 2 U mL^–1 AT slightly inhibited TNF-α production by LPS-stimulated monocytes, it significantly inhibited TNF-α production in the presence of a low concentration of beraprost, a stable derivative of prostacyclin. Conclusions:  These observations suggest that AT might inhibit LPS-induced production of TNF-α by inhibiting the increase in Egr-1 expression in monocytes via interaction with heparin-like substances expressed on the cell surface.     

Cytokine profile in chronic cardiac failure

Elevated tumour necrosis factor α (TNF-α) has been demonstrated in chronic cardiac failure (CCF) and may relate to severity of CCF and development of cachexia. We measured TNF receptor p55 in addition to TNF-α in an attempt to improve the detection rate of TNF-α activation, and simultaneously measured interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein. Thirty-four patients with CCF and 24 control subjects were studied. Only TNF receptor p55 [6.95 (0.77−42.3) vs. 5.52 (1.50−13.36) ngmL⁻¹ (median (range)] and IL-6 [0.335 (0−9.79) vs. 0 (0−14.71) pgmL⁻¹) were significantly elevated in patients compared with control subjects (both P <0.05). All inflammatory markers were more frequently elevated in patients, but none correlated with any of the clinical parameters studied. Reasons for inflammatory marker elevation in CCF are uncertain, but future studies should measure the p55 TNF receptor and IL-6 in addition to TNF-α, to improve detection of cytokine activity.     

Altered release of endothelin-1,2 and thromboxane B2 from trophoblastic cells in pre-eclampsia

The aim of the study was to investigate whether pre-eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro . Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre-eclamptic pregnancies at preterm (weeks 31–36; n  = 12) and term (weeks 37–40; n  = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin-1,2 (ET-1,2), thromboxane B₂ (TXB₂), 6-keto-prostaglandin F_1α (6-keto-PGF1_α) and leukotriene B₄ (LTB₄) were measured daily in culture media for 5 days by radioimmunoassay. In pre-eclampsia, concentrations of ET-1,2 were decreased ( P < 0.01) at both preterm and term, TXB₂ concentrations were increased P < 0.05) only at preterm and the TXB₂–6-keto-PGF_1α ratio was increased at both preterm and term ( P < 0.01) as compared with the controls. Concentrations of AII, 6-keto-PGF_1α and LTB₄ were similar to the controls. The data suggest that pre-eclampsia is associated with a decreased release of ET-1 and an increased release of TXB₂ from trophoblastic cells in vitro     

The effect of increased gastrin release on lower esophageal sphincter pressure

The present study was performed to induce release of endogenous gastrin from the chronic isolated antrum, and to note the effect of endogenous gastrin on lower esophageal sphincter pressure (LESP). Fifteen mongrel dogs weighing 15-20 kg were divided into 3 groups by the type of operation: 5 dogs with antral excision and B-II gastrojejunostomy (Group I); 5 dogs with a denervated antral pouch and B-II (Group II); and 5 dogs with an innervated antral pouch and B-II (Group III). Fasting serum gastrin levels (SGL) and LESP were determined preoperatively (basal) and at 2 and 4 weeks postoperatively. SGL was measured by radioimmunoassay using an antibody to human gastrin I. LESP was determined by pullthrough technique using an assembly of 3 polyvinyl tubes perfused with water at 0.6 ml/min and connected to external transducers. The mean SGL at 2 and 4 weeks after operation in Group I and in Group II were not significantly different from basal SGL. The SGL rose significantly at 2 weeks and 4 weeks in Group III (p less than 0.05). The mean LESP at 2 and 4 weeks did not significantly change from the basal LESP in Group I, Group II and Group III. The present data show that increased endogenous gastrin was produced only in the presence of an innervated antral pouch, and the increased gastrin level, however, did not affect LESP.     

A snake venom metalloproteinase, kistomin, cleaves platelet glycoprotein VI and impairs platelet functions

Summary.  Background and objectives:  Injuries to the vessel wall and subsequent exposure of the matrix of the subendothelial layer resulted in thrombus formation. Platelet glycoprotein (GP) Ib and VI play a crucial role in matrix-induced activation and aggregation of platelets. Methods and results:  In the present study, we reported that the GPIb-cleaving snake venom metalloproteinase (SVMP), kistomin, inhibited collagen-induced platelet aggregation. Moreover, kistomin inhibited platelet aggregation induced by convulxin (CVX, a GPVI agonist) and a GPVI-specific antibody in a concentration and time-dependent manner. Kistomin treatment decreased platelet GPVI but not integrin α2β1 and αIIbβ3, accompanied with the formation of GPVI cleavage fragments, as determined by flow cytometric and Western blot analyses. In addition, intact platelet GPVI and recombinant GPVI were digested by kistomin to release 25- and 35-kDa fragments, suggesting that kistomin cleaved GPVI near the mucin-like region. We designed four synthetic peptides ranging from Leu¹⁸⁰ to Asn²⁴⁹ as the substrates for kistomin and found that kistomin cleaved these synthetic peptides at FSE²⁰⁵/A²⁰⁶TA and NKV²¹⁸/F²¹⁹TT, as analyzed by MALDI-TOF-MS. In addition, GPVI-specific antibody-induced tyrosine kinase phosphorylation in platelets was reduced after kistomin pretreatment, and platelet adhesion to collagen but not to fibrinogen was attenuated by kistomin. Conclusions:  We provided here the first evidence that a P-I snake venom metalloproteinase, kistomin, inhibits the interaction between collagen and platelet GPVI through its proteolytic activity on GPVI, thus providing an alternative strategy for developing new anti-thrombotic agents.     

Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture.

Bombesin, a polypeptide derived from frog skin, has been shown to stimulate gastrin release from the gastric antrum in vivo and in vitro. To elucidate the mechanisms of this effect, we developed a method to culture isolated and enriched G cells from canine stomach. After digestion of antral mucosa with collagenase and EDTA, dispersed cells were fractionated by counterflow elutriation then cultured on a collagen support. Bombesin and three molecular forms of canine gastrin-releasing peptides all stimulated gastrin release from G cells in a dose-dependent manner. The effect of bombesin was suppressed by somatostatin and potentiated by dibutyryl cyclic AMP (10(-3) M) but not by carbachol (10(-6) M). Extracellular calcium depletion attenuated the stimulation of gastrin release by bombesin but not by forskolin. These findings suggest that the bombesin family peptides directly activate G cells through calcium-dependent mechanisms to cause gastrin release.     

The promoting effect of epinephrine on lipopolysaccharide-induced interleukin-8 production in whole blood may be mediated by thromboxane A2

Summary.  Epinephrine is known to enhance lipopolysaccharide (LPS)-induced interleukin (IL)-8 secretion in a platelet dependent manner. To determine whether thromboxane A₂ (TxA₂; a product from activated platelets) is involved in this process, blood samples drawn either before or 2 h after oral administration of 440 mg acetylsalicylic acid (ASA) were stimulated with LPS (5 ng mL⁻¹) and different concentrations of epinephrine were added (0.1–100.0 µmol L⁻¹). ASA ingestion significantly (global P  < 0.05) reduced the enhancing effect of epinephrine on LPS-induced IL-8 release by 15–28%. To further explore whether TxA₂ may be involved in this process, a TxA₂ agonist (U46619) was added to whole blood together with LPS instead of epinephrine. U46619 mimicked the epinephrine effect: 20 ng mL⁻¹ U46619 enhanced LPS-induced IL-8 release by 39% ( P  < 0.05). Furthermore, preincubation of whole blood with 75 µmol L⁻¹ or 150 µmol L⁻¹ SQ29548, a TxA₂ receptor antagonist, completely blocked epinephrine's promoting effect on LPS-induced IL-8 release. Since thrombin-activated platelets have been reported to be important in the production of IL-8 in monocytes through the activation of monocytes by exposed RANTES in a P-selectin-dependent reaction, we suggest that the epinephrine effect is mediated by enhanced TxA₂ production and subsequent rise in the exposure of RANTES and P-selectin on the platelets of whole blood.     

Intestinal phase of human antro-pyloro-duodenal motility: cholinergic and CCK-mediated regulation

In this study the muscarinic receptor antagonist atropine and the cholecystokinin (CCK)-A receptor antagonist loxiglumide were used to investigate the relative importance of cholinergic and CCK-mediated regulation of intestinal phase antro-pyloro-duodenal motility. Plasma levels of gastrointestinal hormones [pancreatic polypeptide (PP), gastrin, CCK] were concomitantly determined to estimate biological potency of the doses of the receptor antagonists. In eight healthy male volunteers, a 30-min basal interdigestive period was followed by duodenal perfusion of a mixed liquid meal for 150 min at 2.6 kcal min^?1 against a background of saline or atropine (5 μg kg^?1 h^?1) or loxiglumide (10 mg kg^?1 h^?1). Antro-pyloro-duodenal motility was continuously monitored with a sleeve straddling the pylorus. Against a background of saline, duodenal nutrients persistently stimulated isolated pyloric pressure waves. After 60 min, the initially low antral and duodenal contraction rates increased. In the fed state, atropine reduced total number of antral contractions and integrated motility index by 73% (P<0.01) and 76% (P<0.005), total number of pyloric contractions and integrated motility index by 43% and 50% (P<0.05) with inhibition increasing over time. It did not alter duodenal contraction frequency but diminished duodenal motility index by 39% (P<0.05) owing to a reduction in amplitude and duration of contractions. Loxiglumide decreased total numbers of antral, pyloric and duodenal contractions by 44% (P<0.05), 74% (P<0.005) and 41% (P<0.005) respectively. It reduced cumulative antral, pyloric and duodenal motility indexes by 60% (P<0.01), 80% (P<0.01) and 61% (P<0.05) respectively. Atropine fully abolished PP release to duodenal nutrients whereas loxiglumide reduced it by 60% (P<0.05). Both atropine and loxiglumide enhanced gastrin release whereas only loxiglumide markedly stimulated CCK release. We conclude that both cholinergic input and endogenous CCK are major stimulatory regulators of antro-pyloroduodenal motility in the intestinal phase. There appears to be a regional heterogeneity of cholinergic and CCK control. Cholinergic input predominates in the antrum. Both systems are equipotent at the pylorus. CCK predominates in the duodenum. We suggest that CCK primarily interacts with receptors on cholinergic neurons in the antropyloric region and primarily affects smooth muscle receptors in the duodenum.     

Therapeutic Effects and Anti-inflammatory Mechanisms of Heparin on Acute Lung Injury in Rabbits

Objectives:  The objectives were to investigate the potential beneficial effects and molecular mechanisms of heparin and low-molecular-weight heparin (LMWH) on acute lung injury (ALI).
Methods:  Forty-eight rabbits were randomized into four groups: normal control group (Group A), lipopolysaccharide (LPS) group (Group B), LPS + heparin group (Group C), and LPS + LMWH group (Group D). The rabbit ALI model was established by intravenous (IV) injection with LPS. Alveolar–arterial O₂ difference (P_A-aO₂), serum tumor necrosis factor α (TNF-α), circulating p38 mitogen-activated protein kinase (p38 MAPK) levels, lung nuclear factor (NF)-κB levels, and lung dry/wet (D/W) ratio were measured, and the lung injury scores were calculated.
Results:  Lipopolysaccharide caused significant increases in P_A-aO₂, serum TNF-α, expression of p38 MAPK in polymorphonuclear neutrophils (PMNs), the lung injury scores, and nuclear factor-κB (NF-κB) activity in the lung tissue and caused a decrease in lung D/W ratio. A positive linear correlation was found between p38 MAPK and TNF-α at 1, 2, 4, and 6 hours ( r  = 0.68, 0.92, 0.93, and 0.93, respectively) and between NF-κB and p38 MAPK and TNF-α at 6 hours (r = 0.94 and 0.83, respectively). IV heparin or LMWH given after LPS treatment attenuated these changes in inflammatory response, oxygenation, p38 MAPK expression, and NF-κB activation.
Conclusions:  The anti-inflammatory mechanisms of heparin in ALI may be inhibiting p38 MAPK and NF-κB activities, and then TNF-α overexpression, thus alleviating the inflammatory reaction.