Acid-induced increase in duodenal mucosal alkaline secretion in the rat involves the L-arginine/NO pathway

Duodenal mucosal alkaline secretion increases in response to hydrochloric acid exposure. The tentative role of nitric oxide (NO) in the mediation of this response was investigated. The mucosal alkaline output by a duodenal segment was recorded by in situ titration in chloralose-anaesthetized rats. In some experiments the duodenal blood flow was estimated by laser-Doppler flowmetry. Exposure of the duodenum to acid (0.01 M HCl, 5 min) increased the alkaline secretion by ≈85%. The NO synthase inhibitor N^G-nitro-L -arginine methyl ester (L -NAME, 10 mg kg^?1 intravenously or 0.3 mM intraluminally) blocked the secretory increment after mucosal acid exposure. Mean arterial pressure and basal alkaline secretion were markedly raised, whereas duodenal blood flow was decreased, when L -NAME was given intravenously (i.v.). Intraluminal (i.l.) administration left mean arterial pressure as well as duodenal blood flow unaltered, and the duodenal mucosal alkaline secretion was only slightly elevated. The stereoisomer N^G-nitro-D -arginine methyl ester (D -NAME) had no effect on either basal or acid-induced duodenal alkaline output. In animals receiving L -arginine (10 mg kg^?1 min^?1 i.v., or 3 mM i.l.) and L -NAME, the acid exposure elicited an increase in duodenal mucosal alkaline secretion, similar to that observed in controls. The results suggest that the acid-induced increase in duodenal mucosal alkaline secretion involves NO synthesis, which takes place close to the lumen, probably within the mucosa.     

Noradrenergic terminal excitability: effects of opioids

The local infusion of morphine or D-Ala2, Met5-enkephalinamide into the frontal cortical terminal fields of noradrenergic neurons of the nucleus locus coeruleus resulted in a decrease in the excitability of the axon terminal regions to direct electrical stimulation. These effects were concentration dependent and could be blocked or partially reversed by the local infusion of naloxone. Some evidence was obtained for a differential antagonizing effect of naloxone upon the effects of morphine and D-Ala2, Met5-enkephalinamide. These results are discussed with respect to an effect of opioids on the polarization and/or ionic conductance of the terminal fields of locus coeruleus neurons, and to the possible regulation of neurotransmitter release by presynaptic opiate receptors.     

No colocalization of immunoreactivities for VIP and neuronal NOS, and a differential relation to cGMP-immunoreactivity in bovine penile smooth muscle

The distribution of immunoreactivity (IR) for the neuropeptide vasoactive intestinal polypeptide (VIP) and neuronal nitric oxide synthase (nNOS) in the bovine retractor penis muscle (RP) and penile artery (PA) was studied by using two different methods. The distribution of these immunoreactivities was also compared with that of the immunoreactivity for cyclic guanosine monophosphate (cGMP). In both tissues the nerve fibers and terminals immunoreactive for VIP had a distribution that was completely different from that of the nerve fibers and terminals immunoreactive for nNOS. This contrasts with the previous observations in penile smooth muscle of other species. In the RP, as well as in the PA, many of the VIP-IR fibers were also immunoreactive for neurofilaments (NF), whereas the nNOS-IR fibers were consistently devoid of NF-IR. Stimulation with sodium nitroprusside, a nitric oxide donor, considerably increased cGMP-IR in the smooth muscle cells in both RP and PA, and in several nerve fibers in PA. Many of these cGMP-IR nerve fibers exhibited nNOS-IR, whereas none of them was immunoreactive for VIP. Our results suggest that the degree of coexistence of VIP-IR and nNOS-IR in the nerve fibers and terminals innervating penile smooth muscle show wide species differences. They also suggest that the mechanisms by which VIP could be involved in neurogenic penile erection may vary between species.     

Anti-CD3 induces bi-phasic apoptosis in murine intestinal epithelial cells: possible involvement of the Fas/Fas ligand system in different T cell compartments

Recent studies have suggested that Fas-mediated apoptosis is involved in the pathogenesis of intestinal injury. In this study, we determined the role of Fas/Fas ligand (FasL) interactions in different T cell compartments using a murine model of small intestinal injury. An intraperitoneal injection of 145-2C11 (anti-CD3) antibody into C3H/HeN, BALB/c and MRL mice induced mucosal flattening and rapid, bi-phasic intestinal epithelial cell (IEC) apoptosis, which was detected by conventional light and electron microscopy and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. In the first, early phase, villous apoptosis was observed up to 4 h after injection, and in the second, later phase, apoptotic crypt cells gradually accumulated for up to 24 h. The early and later phases of apoptosis were reduced in lpr/lpr and nude mice compared with those in control strains. In addition, the kinetics of Fas-mediated killer activity induced by the antibody injection were different between intestinal intraepithelial lymphocytes (IEL) and splenocytes (SPL) and seemed to correlate with the bi-phasic occurrence of the apoptosis. Finally, the transfer of intestinal IEL from euthymic to nude mice induced both phases of apoptosis, whereas SPL induced the second phase's crypt apoptosis only by the antibody injection. Together, these results suggest the involvement of Fas-mediated killer activity of thymus-derived T cells in different compartments. Namely, T cell populations in different compartments are differentially involved in the induction of IEC apoptosis and contribute to the complex pathogenesis of immune-mediated intestinal injury in which Fas/FasL interactions may play a critical role.     

Co-localization of neuropeptide Y, vasoactive intestinal polypeptide and dynorphin in non-noradrenergic axons of the guinea pig uterine artery

Two major populations of perivascular axons containing immunoreactivity to neuropeptide Y (NPY) have been revealed in the main uterine artery of the guinea pig by immunohistochemical procedures which allow the simultaneous visualization of two antigens. One population contained immunoreactivity to dopamine-beta-hydroxylase (D beta H) and was presumably noradrenergic. The other main population of axons with NPY-like immunoreactivity (NPY-LI) did not have D beta H-like immunoreactivity (D beta H-LI) and was presumably non-noradrenergic. These non-noradrenergic axons also contained immunoreactivity to vasoactive intestinal polypeptide (VIP) and dynorphin (DYN). Indeed, nearly all axons with VIP-LI also contained NPY-LI and DYN-like immunoreactivity (DYN-LI). NPY constricted the uterine artery perfused in vitro, whilst VIP dilated uterine arteries preconstricted with noradrenaline or NPY. Thus, we have evidence for the coexistence of a vasoconstrictor peptide and a vasodilator peptide in the same non-noradrenergic perivascular axons, which also contain an opioid peptide, dynorphin.     

An unusual bandlike web in an infant with lethal multiple pterygium syndrome

We report on a patient with a lethal multiple pterygium syndrome who also had an unusual, bandlike web across one axilla and partial intestinal atresia. Umbilical cord wrapping with subsequent vascular compromise appears to be the most likely pathogenetic mechanism for the additional anomalies.     

Absence of either gastric or intestinal phenotype in microscopic differentiated gastric carcinomas

Differentiated gastric carcinoma (DGC) corresponds roughly to the intestinal type of gastric carcinoma described by Laurén. It has been suggested that DGCs arise from intestinalized gastric mucosa, but recent findings regarding their mucin expression do not support this hypothesis. To evaluate the histogenetic relationship between DGCs and intestinal metaplasia, lesions that are as small as possible should be examined. Twenty-five DGCs, ranging in their greatest dimension from 0.4 to 2.7 mm, were collected and divided into two groups by size. Group A consisted of 13 lesions less than 1.4 mm across, and group B of 12 lesions 1.4 mm or more. The presence of mucin and a brush border was assessed by immunostaining with antibodies against human gastric mucin, pyloric-gland-type mucin, Muc-2 glycoprotein, and CD10 antigen, and the lesions were classified as having the gastric phenotype (G-type), intestinal phenotype (I-type), mixed gastric and intestinal phenotype (M-type), or null phenotype (N-type). Thirteen (52%) of the 25 lesions were N-type, 5 (20%) lesions were G-type, 5 (20%) were I-type, and 2 (8%) were M-type. Group A had a larger proportion of N-type lesions than B (10/13, or 77%, vs. 3/12, or 25%; p = 0.027, chi-square test for proportions). Group B had a larger proportion of G-type lesions than A (5/12, or 42%, vs. 0/13, or 0%; p = 0.033). The phenotypes of the carcinomas and their surrounding mucosa were unrelated. Therefore, DGCs may arise from gastric mucosa affected by intestinal metaplasia or not, without having either the gastric or intestinal phenotype.     

Inhibition of Intestinal Pyrimidine Nucleoside Phosphorylases

The activity of 5-deoxy-5-fluorouridine (dFUR) depends on its activation to 5-fluorouracil (FU) by pyrimidine nucleoside phosphorylases. These enzymes are found in tumors and normal tissues, with the highest activity in the small intestines. The present study examined the inhibition of dFUR phosphorolysis in intestinal tissues. dFUR metabolism in intestinal homogenates was inhibited by uracil (U), uridine (UR), and thymidine (TdR), which are the normal substrates for the phosphorylases. Conversely dFUR reduced the metabolism of these inhibitors. A good agreement was found between the observed data and the computer-fitted data using the equations for competitive inhibition between dFUR and the inhibitors. In the absence of inhibitors, the V _max of dFUR phosphorolysis was 47.1 ± 4.9 µM/min and the apparent K _m was 910 ± 167 µM. The V _max was unaltered by the inhibitors, while the K _m was increased with increasing inhibitor concentrations. The maximal inhibition of dFUR metabolism by UR and TdR was about 80%. The K _i,'s were 372 µM for U, 87.2 µM for UR, and 112 µM for TdR and are orders of magnitude higher than their reported endogenous serum concentrations. The rate of dFUR phosphorolysis to FU in the intact intestinal epithelial crypt cells, indicated by the ratio of FU to dFUR in the intracellular fluid, was reduced by UR in a concentration-dependent fashion. These data indicate that the naturally occurring pyrimidines inhibit competitively the dFUR metabolism by the intestinal phosphorylases, that this inhibition occurs at concentrations much higher than the circulating endogenous levels, and that phosphorolysis is the major route of dFUR metabolism.     

Apamin distinguishes two types of relaxation mediated by enteric nerves in the guinea-pig gastrointestinal tract

Summary Eight smooth muscle preparations from the stomach, small intestine and large intestine of the guinea-pig were used to compare apamin's actions in reducing the effectiveness of transmission from enteric inhibitory nerves and in reducing responses to inhibitory agonists ,-methylene ATP, VIP and isoprenaline. The effects of apamin on inhibitory reflexes in the ileum and colon were also evaluated. Apamin had little or no effect on responses to VIP and isoprenaline in any region, but consistently and substantially reduced responses to ,-methylene ATP. Responses to stimulation of enteric inhibitory neurons were substantially reduced by apamin in the antrum circular muscle, ileum longitudinal and circular muscle, taenia coli and distal colon longitudinal muscle, but it was ineffective in the fundus circular muscle, proximal colon longitudinal muscle and distal colon circular muscle. It caused a small reduction of the relaxation of the ileal circular muscle caused reflexly by distension, but did not modify the similar descending inhibitory reflex in the circular muscle of the colon. It is concluded that apamin can be used to distinguish two types of non-noradrenergic transmission from enteric inhibitory nerves to gastrointestinal muscle. Furthermore, neither VIP nor ATP can be the sole transmitter chemical released from enteric inhibitory neurons throughout the gastrointestinal tract.     

黄芩汤对溃疡性结肠炎小鼠肠道菌群的影响及肠黏膜屏障的保护作用机制

目的：研究黄芩汤对溃疡性结肠炎(UC)模型小鼠的药效,并探究黄芩汤在UC中是否能调节肠道菌群,发挥屏障保护作用。方法：雄性Balb/c小鼠按体质量随机分为正常组、模型组、黄芩汤高(20 g·kg^-1)、中(10 g·kg^-1)、低(5 g·kg^-1)剂量组、菌群干扰组、菌群干扰模型组、菌群干扰黄芩汤组(黄芩汤,20 g·kg^-1)。灌胃抗生素(杆菌肽200 mg·kg^-1、万古霉素200 mg·kg^-1)8 d构建菌群干扰模型,自由饮用3%葡聚糖硫酸钠(DSS)溶液7 d构建UC模型,黄芩汤给药治疗7 d。实验结束后处死小鼠,取血、结肠及粪便,苏木素-伊红(HE)染色观察结肠病变,酶联免疫吸附测定法(ELISA)检测血清白细胞介素-4(IL-4)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)含量,实时荧光定量聚合酶链式反应(Real-time PCR)及蛋白免疫印迹法(Western blot)检测结肠组织中紧...