Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial.

BACKGROUND/OBJECTIVES: In spite of the much evidence for the beneficial effects of probiotics, their anti-obesity effects have not been well examined. We evaluated the effects of the probiotic Lactobacillus gasseri SBT2055 (LG2055) on abdominal adiposity, body weight and other body measures in adults with obese tendencies. SUBJECTS/METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled intervention trial. Subjects (n=87) with higher body mass index (BMI) (24.2-30.7 kg/m(2)) and abdominal visceral fat area (81.2-178.5 cm(2)) were randomly assigned to receive either fermented milk (FM) containing LG2055 (active FM; n=43) or FM without LG2055 (control FM; n=44), and were asked to consume 200 g/day of FM for 12 weeks. Abdominal fat area was determined by computed tomography. RESULTS: In the active FM group, abdominal visceral and subcutaneous fat areas significantly (P<0.01) decreased from baseline by an average of 4.6% (mean (confidence interval): -5.8 (-10.0, -1.7) cm(2)) and 3.3% (-7.4 (-11.6, -3.1) cm(2)), respectively. Body weight and other measures also decreased significantly (P<0.001) as follows: body weight, 1.4% (-1.1 (-1.5, -0.7) kg); BMI, 1.5% (-0.4 (-0.5, -0.2) kg/m(2)); waist, 1.8% (-1.7 (-2.1, -1.4) cm); hip, 1.5% (-1.5 (-1.8, -1.1) cm). In the control group, by contrast, none of these parameters decreased significantly. High-molecular weight adiponectin in serum increased significantly (P<0.01) in the active and control groups by 12.7% (0.17 (0.07, 0.26) microg/ml) and 13.6% (0.23 (0.07, 0.38) microg/ml), respectively. CONCLUSION: The probiotic LG2055 showed lowering effects on abdominal adiposity, body weight and other measures, suggesting its beneficial influence on metabolic disorders.

How signaling pathways interact with gene transcription.

Activation of inflammatory cells by extracellular stimuli such as cytokines, viruses, allergens or oxidants lead to stimulation of intracellular amplifying signalling pathways. These activation pathways lead to enhanced inflammatory gene expression through activation of transcription factors such as nuclear factor kappa B (NF-kappa B). Upon activation, NF-kappa B translocates to the nucleus where it binds specific sites in the promoter regions of responsive genes in a time-dependent manner. This leads to the alterations in the structure of the surrounding DNA/chromatin complex resulting in local unwinding of DNA. Changes in chromatin structure occur as a result of recruitment of large, essentially pre-formed, complexes that contain chromatin remodelling factors and histone acetyltransferases (HATs) such as CREB binding protein (CBP). Acetylations of histones are regulated by HATs whose activity is controlled by a number of factors including phosphorylation. Phosphorylation of HATs by signalling pathways, differentiate themselves from those controlling specific transcription factor activation and result in enhanced transcriptional activity as a result of cross-talk between signalling pathways at the level of chromatin modifications.

Glucocorticoid suppression of nuclear factor-kappa B: a role for histone modifications.

Corticosteroids are by far the most effective treatment for chronic inflammatory diseases such as asthma. Inflammation in asthma is characterized by the increased expression of multiple inflammatory genes, including those that encode cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. Increased expression of inflammatory genes is regulated by pro-inflammatory transcription factors, such as nuclear factor kappa B (NF-kappa B). These bind to, and activate, co-activator molecules that then acetylate core histones resulting in elevated gene transcription. Corticosteroids reverse histone acetylation at the site of inflammatory gene transcription, either by direct binding of the activated glucocorticoid receptor to NF-kappa B-associated co-activators or by recruitment of histone deacetylases to the activated transcription complex. Understanding how corticosteroids work in asthma may help in designing novel corticosteroids with fewer systemic effects, as well as novel anti-inflammatory approaches.

Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation.

Glucocorticoids are highly effective in controlling chronic inflammatory diseases by inhibiting the expression of cytokines and chemokines. Glucocorticoids act through binding of their receptor resulting to inhibition of transcription factors such as nuclear factor kappa B (NF-kappa B). This may occur via the transcription integrator protein, CREB binding protein (CBP), which has intrinsic histone acetylase (HAT) activity. Interleukin (IL)-1 beta caused a significant increase in NF-kappa B-mediated granulocyte/macrophage colony stimulating factor (GM-CSF) release, which was inhibited by the glucocorticoid mometasone furoate (MF) (EC(50)=2 x 10(-11) M). This effect was inhibited by CBP over-expression. The role of histone acetylation and DNA methylation in the transcription of GM-CSF was indicated by trichostatin A (TSA), an inhibitor of histone deacetylases, and 5-azacytidine (5-aza), a DNA methylase inhibitor, to increase GM-CSF expression partially blocking glucocorticoid inhibition of IL-1 beta-stimulated GM-CSF release. These data suggest that the mechanism of glucocorticoid action in suppressing interleukin-1 beta-stimulated GM-CSF release in A549 cells may involve modulation of CBP-mediated histone-acetylase activity and DNA methylation.

Diverse gene expression and function of semaphorins in developing lung: positive and negative regulatory roles of semaphorins in lung branching morphogenesis.

BACKGROUND: Previously, we reported that Sema3A, one of the secreted repulsive axon guidance molecules, CRMP (collapsin response mediator protein)-2, a putative intracellular signalling molecule for Sema3A and Sema3A receptor neuropilin-1 are expressed in the developing lung. Sema3A inhibits branching morphogenesis of embryonic lung in organ culture. RESULTS: We examined the gene expression of Sema3A, Sema3C, Sema3F and their receptors, NP-1, NP-2 and plexin-A1 by in situ hybridization. Transcripts of all six genes were detected in mouse lung from embryonic day E11.5 to E17.5, and displayed highly specific spatiotemporal distributions. The distribution of the receptor genes was detected in patterns which were consistent with known receptor usage of the semaphorins. In contrast to Sema3A, we found that the other class 3 semaphorins, Sema3C and Sema3F, stimulated branching morphogenesis. This stimulatory effect of Sema3C or Sema3F was accompanied by a moderate increase in the incorporation of bromodeoxyuridine (BrdU) into DNA in the terminal epithelial cells. CONCLUSION: The coordinated expression patterns of different semaphorins and their receptors, together with the specific activities affecting branching morphogenesis, suggest that the semaphorins act as both positive and negative regulators of branching morphogenesis in the developing lung.

Emotional stress-induced 'ampulla cardiomyopathy': discrepancy between the metabolic and sympathetic innervation imaging performed during the recovery course.

Four patients had the clinical features of 'ampulla cardiomyopathy', consisting of acute-onset transient left ventricular apical akinesis with basal normokinesis, normal coronary angiogram, ST-segment elevation and subsequent giant T wave inversion, which mimicked acute coronary syndrome, the onset of which occurred shortly after extreme mental stress. Myocardial necrosis was minimal, although 2 patients showed elevated serum catecholamine levels in the acute phase. Each patient underwent serial cardiac radionuclide single-photon emission computed tomography of myocardial functional sympathetic innervation, fatty acid metabolism and perfusion using I-123-metaiodobenzyl-guanidine (MIBG), I-123-beta-metyl-iodophenyl pentadecanoic acid (BMIPP) and thallium-201 (201Tl), respectively. In the acute phase, MIBG and BMIPP imaging showed an uptake defect in the apical region, whereas 201Tl uptake was mildly decreased. When assessed semi-quantitatively, the MIBG images had higher defect scores from the acute phase throughout the year of observation compared with BMIPP, and 201Tl. These observations suggest that the primary cause of ampulla cardiomyopathy is related to a disturbance of the cardiac sympathetic innervation.

[Acute myocardial infarction in elderly patients: feasibility of transradial intervention and rapid mobilization].

OBJECTIVES: Rapid mobilization and discharge following rapid acute phase reperfusion are recommended for elderly patients with acute myocardial infarction to achieve a better outcome and performance. The safety and efficacy of new and old treatment protocols were retrospectively compared for patients with acute myocardial infarction. METHODS: The new protocol used transradial intervention, encouraged stent implantation, beta-blocker administration, and rapid mobilization for rapid discharge (10-14 day hospital stay). The previous protocol used transfemoral intervention, bed rest and late mobilization, and discouraged stent implantation and beta-blocker supplementation. High risk patients with cardiogenic shock, left main disease, malignant arrhythmia and impending myocardial rupture were excluded from the study. RESULTS: Thirty-two patients were treated by the new protocol, and 57 patients by the old protocol. The former included more elderly patients (p < 0.05). The prevalence of beta-blocker use (63.3% vs 18.8%, p < 0.001) and stent implantation (43.8% vs 3.5%, p < 0.05) were higher in the new protocol group. Hospital stay (23.6 +/- 9.5 vs 13.3 +/- 5.9 days, p < 0.001) and intensive care unit stay (4.4 +/- 3.0 vs 2.4 +/- 1.2 days, p < 0.001) were shorter in the new protocol than in the old protocol group. Rates of in-hospital death, cardiac events, systemic complications and left ventricular function (left ventricular ejection fraction and left ventricular end-diastolic volume index at admission and discharge) were not significantly different between the 2 groups. The prevalence of systemic complications (including delirium) among patients older than 70 years was lower in the new protocol group (4.7% vs 11.7%, p < 0.05). CONCLUSIONS: The new protocol can shorten hospital stay with no increase in in-hospital death or cardiac events, or decline of left ventricular function. Moreover, the new protocol is potentially effective for reducing systemic complications among elderly patients. Therefore, this protocol can be recommended for elderly patients with acute myocardial infarction.

Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung.

Semaphorin III/collapsin-1 (Sema3A) guides a specific subset of neuronal growth cones as a repulsive molecule. In this study, we have investigated a possible role of non-neuronal Sema3A in lung morphogenesis. Expression of mRNAs of Sema3A and neuropilin-1 (NP-1), a Sema3A receptor, was detected in fetal and adult lungs. Sema3A-immunoreactive cells were found in airway and alveolar epithelial cells of the fetal and adult lungs. Immunoreactivity for NP-1 was seen in fetal and adult alveolar epithelial cells as well as endothelial cells. Immunoreactivity of collapsin response mediator protein CRMP (CRMP-2), an intracellular protein mediating Sema3A signaling, was localized in alveolar epithelial cells, nerve tissue and airway neuroendocrine cells. The expression of CRMP-2 increased during the fetal, neonate and adult periods, and this pattern paralleled that of NP-1. In a two-day culture of lung explants from fetal mouse lung (E11.5), with exogenous Sema3A at a dose comparable to that which induces growth cone collapse of dorsal root ganglia neurons, the number of terminal buds was reduced in a dose-dependent manner when compared with control or untreated lung explants. This decrease was not accompanied with any alteration of the bromodeoxyuridine-positive DNA-synthesizing fraction. A soluble NP-1 lacking the transmembrane and intracellular region, neutralized the inhibitory effect of Sema3A. The fetal lung explants from neuropilin-1 homozygous null mice grew normally in vitro regardless of Sema3A treatment. These results provide evidence that Sema3A inhibits branching morphogenesis in lung bud organ cultures via NP-1 as a receptor or a component of a possible multimeric Sema3A receptor complex.

Reaction of various lectins to mucin derived from the different layers of rat gastric mucosa: comparison of enzyme-linked lectin binding assay with lectin histochemistry.

The purpose of this study was to demonstrate that the histochemical staining reactivities of lectins in rat stomach actually represent the gastric mucins, and to estimate the utility of the lectins for mucin histochemistry. In this paper, the lectin histochemistry was compared with an enzyme-linked lectin binding assay (ELLA) of the mucins derived from distinct regions and layers of the Sprague-Dawley rat stomach and it was examined to determine the definite binding and problematic binding of the conventional lectin. Among the 10 different biotinylated lectins, Canavalia ensiformis (ConA), Griffonia simplicifolia II (GS-II), Triticuin vulgaris (WGA), Ricinus communis I (RCA-I), Arachis hypogaea (PNA), Glycine max (SBA), Dolichos biflorus (DBA), Ulex europaeus I (UEA-I), Sambucus nigra (SNA) and Maackia amurensis II (MAL-II), examined in this study, GS-II, SBA, DBA, UEA-I, SNA and MAL-II bound clearly to the mucin of distinct regions and layers of the Sprague-Dawley rat stomach in agreement with the results of ELLA. Namely GS-II lectins preferentially bound to the mucin in the mucous neck cells of the corpus area. SBA and DBA clearly recognized the mucin in the covering epithelial mucous cells in the corpus and antral area. UEA-I was widely bound to all the mucin present in both the corpus and antrum. On the other hand, SNA and MAL-II could not react with the mucin obtained from the gastric mucosa but was specifically bound to the mucin purified from the mucous gel layer. These results suggested that the lectins described above are useful histochemical tools to recognize the mucus present in the different regions and layers of Sprague-Dawley rat gastric mucosa.

Effects of anion exchange resin as phosphate binder on serum phosphate and iPTH levels in normal rats.

In order to investigate the characteristics of anion exchange resins that may safely and effectively bind dietary phosphate in digestive tract, phosphate binding experiments were carried out in vitro and in vivo with normal rats by comparing anion exchange resins, PAA-B (which has the same chemical structure as Sevelamer HCl) and Dowe 1x8, with CaCO3. In in vitro phosphate binding experiments, PAA-B bound 32.3% less phosphate than CaCO3 at pH 7. In the rat dietary phosphorus excretion experiments, PAA-B, Dowex 1x8, and CaCO3 increased fecal phosphorus excretion by 62.7, 32.3, and 84.0%, respectively. Famotidine significantly reduced the phosphate binding of CaCO3. When phosphate solution was orally administered, PAA-B depressed serum phosphorus augmentations immediately after administration and thereafter effectively depressed serum iPTH. This suggests that anion exchange resins with most primary and secondary amino type anion exchange groups, have bright prospects in the treatment of hyperphosphatemia.

Removal of 125I from radioactive experimental waste with an anion exchange paper membrane.

The behavior of radioactive iodide and chloride ions through an anion exchange paper membrane to remove 125I from radioactive experimental waste has been studied with nonequilibrium thermodynamic analyses. Anion exchange paper membrane was found to be electroconductively more permeable to iodide ion than to chloride ion. The iodide ion bound more strongly to the anion exchange site within a membrane phase than the chloride ion by more than twice. The results suggested that an anion exchange paper membrane was appropriate for the filtration removal system.

[Acute myocardial infarction in elderly patients: medical and social problems].

The number of elderly patients with acute myocardial infarction has been increasing. However, the choice of treatment remains controversial. Medical records of 310 consecutive patients with acute myocardial infarction were reviewed. Two retrospective analyses were performed. 1) Patients were divided into the elderly group(70 years or more) and the younger group(under 70 years). In-hospital course and outcome were compared. 2) Pre-hospital performance status and living status were reviewed in the elderly group. Acute phase reperfusion therapy was performed in fewer patients in the elderly group(60.8% vs 71.9%, p < 0.01). The difference was most pronounced in cases of direct coronary angioplasty(28.6% vs 54.7%, p < 0.05). As a result, the rate of reperfusion success(74.8% vs 86.8%, p < 0.01) was lower in the elderly group. Moreover, the rates of in-hospital death(23.6% vs 6.8%, p < 0.005), pulmonary edema(20.3% vs 10.8%, p < 0.05), cardiogenic shock(11.9% vs 6.0%, p < 0.005), pneumonia(17.3% vs 3.0%, p < 0.005), and delirium(29.4% vs 12.0%, p < 0.001) were higher in the elderly group. Five patients in the elderly group and 3 patients in the younger group required rehabilitation because of worsened performance status. Six of them were non-reperfused patients. Elderly patients considered likely to become bed-ridden because of pre-existing physical disability at admission accounted for 28.9% of the total. Moreover, many elderly patients had poor support systems (8.4% were living alone, 21.0% were living only with their spouse or a child, 30.1% were widows or widowers). These results show that a lower acute phase reperfusion rate(especially angioplasty) resulted in a poor prognosis and worse performance status in elderly patients. Also 30% of patients were not good candidates for conventional treatment because of delirium, and that self-help in daily life is a fundamental goal for most elderly patients. Rapid and simple acute phase reperfusion, subsequent immediate mobilization, and early discharge are recommended for elderly patients with acute myocardial infarction.

Rat gastric mucous gel layer contains sialomucin not produced by the stomach.

The sialylated mucus components of the normal gastric mucosa and mucous gel layer of rats were studied by using various histochemical staining methods including Maackia amurensis II (MAL-II) and Sambucus nigra (SNA) lectins, alcian blue (AB) pH 2.5 -- periodic acid Schiff (PAS) and high iron diamine (HID) -- AB pH 2.5. The acidic and neutral mucins characterized by the AB-PAS staining were abundantly present in the mucous gel layer as well as in the gastric mucosa. The sialomucin characterized by HID-AB was barely found in either the mucous gel layer or the mucosa. The sialomucin positive to MAL-II and SNA, which react with the N-acetyl neuraminic acid residue linked to galactose via an alpha-linkage, was moderately detected only in the mucous gel layer, but not in the entire mucosal layer. Furthermore, in animals given surgery to form an esophageal fistula through which saliva was excluded or in animals subjected to salivectomy, the mucous gel layer stained with MAL-II and SNA lectins was markedly decreased. These results indicate that a part of the sialomucin containing-mucous gel layer covering normal rat gastric mucosa originates from the saliva and that MAL-II and SNA lectins are useful for detecting this specific sialomucin.

Effects of Y-24180, a receptor antagonist to platelet-activating factor, on allergic cutaneous eosinophilia in mice.

We examined the effects of Y-24180, a potent and long-acting antagonist to platelet-activating factor (PAF), on allergic cutaneous eosinophilia and cytokine production in the skin of mice. Mice sensitized actively with ovalbumin (OA) were challenged by an intradermal injection of OA solution. The number of inflammatory cells, including eosinophils and eosinophil peroxidase (EPO) activity reflecting eosinophil infiltration into the tissue increased in OA-challenged skin 12 hr after the challenge. The levels of interleukin-4 (IL-4) and IL-5 also increased significantly in the challenged skin 12 hr and 3-24 hr, respectively, but that of interferon-gamma (IFN-gamma) did not change. Then, we evaluated the effects of Y-24180, ketotifen, suplatast and prednisolone on the increase in EPO activity, IL-4 and IL-5. These drugs were orally administered once a day for 5 days beginning 4 days before the challenge. Y-24180 (10 mg/kg) and prednisolone (5 mg/kg) significantly suppressed these parameters. Suplatast did not affect EPO activity, but significantly decreased the levels of IL-4 and IL-5. Ketotifen had no effect on them. These results indicate that the inhibition of IL-4, IL-5 and PAF are required to suppress the cutaneous eosinophilia and Y-24180 contributes to the treatment of allergic cutaneous eosinophilia.

Biphasic elevation of plasma histamine induced by water immersion stress, and their sources in rats.

The effect of water immersion stress on the plasma concentration of histamine, in Wistar and mast cell-deficient (Ws/Ws) rats, was investigated. The histamine content of the plasma, skin and gastric mucosa, as well as the level of activity of histidine decarboxylase in the gastric mucosa, were determined by high performance liquid chromatography (HPLC)-fluorometry. In Wistar rats exposed to water immersion stress for a total of 6 h, an initial, acute, four-fold, transient increase in the plasma histamine level, followed by a sustained, though lower, elevation of the plasma histamine level, was observed. The initial acute increase in plasma histamine level was also seen in gastrectomized Wistar rats exposed to water immersion stress, but not in Ws/Ws rats exposed to stress. The sustained elevation of the plasma histamine level was observed in the Ws/Ws rats. However, in both the gastrectomized Wistar rats and gastrectomized Ws/Ws rats, the sustained elevation in plasma histamine level was not observed. The histamine content of the skin of Wistar rats after 15 min or more exposure to water immersion stress, was 20% lower than that of control rats. The mucosal histamine content of both Wistar rats and Ws/Ws rats, was 20% lower, whereas histidine decarboxylase activity in the gastric mucosa was enhanced by two-fold, during exposure to stress for 4 h. These findings indicate that water immersion stress causes a biphasic increase in plasma histamine concentration in Wistar rats; the initial acute increase in plasma histamine level originates from mast cells, and the second, sustained increase is attributed to enterochromaffin-like cells.

Effect of Y-24180, an antagonist at platelet-activating factor (PAF) receptors, on IgE-mediated cutaneous reactions in mice.

OBJECTIVE AND DESIGN: We examined the effect of Y-24180, a potent platelet-activating factor (PAF) antagonist, on IgE-mediated cutaneous reactions in mice. MATERIALS: Female BALB/c mice were used. TREATMENT: Drugs were orally administered 1 h before a dinitrofluorobenzene (DNFB) challenge or 1 h before and 12 h after the challenge. METHODS: Biphasic increase in ear thickness, with peak responses at 1 h (immediate phase reaction, IPR) and 24 h (late phase reaction, LPR) after the DNFB challenge, were induced in mice which had been passively sensitized with monoclonal anti-dinitrophenyl IgE antibody 24 h before the DNFB challenge. Ear thickness was measured with a dial thickness gauge. RESULTS: Y-24180, WEB2086, ketotifen, and suplatast suppressed the IPR. Y-24180 also suppressed the LPR when administered once at 10 mg/kg or twice at 1 to 10 mg/kg. WEB2086 suppressed the LPR only when administered twice. However, ketotifen and suplatast did not suppress the LPR even when administered twice. Single administration of prednisolone significantly suppressed both the IPR and LPR. CONCLUSIONS: These results indicate that PAF may be involved in the induction of biphasic cutaneous reactions mediated by IgE, and Y-24180 is more effective compared with WEB2086 in this model. It is possible that the difference in the effectiveness between Y-24180 and WEB2086 depends on the persistence of those activities.

Suppressive effects of Y-24180, a long-acting antagonist for platelet-activating factor, on allergic pulmonary eosinophilia in mice.

We studied the effects of (+/-)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethy l-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180), a long-acting antagonist for platelet-activating factor (PAF), on antigen-induced eosinophil infiltration and interleukin-5 (IL-5) release in the bronchoalveolar lavage fluid (BALF) of mice. Mice actively sensitized with ovalbumin (OA) were challenged by injecting intratracheally OA 3 times every fourth day. Both the number of eosinophils and level of IL-5 were significantly increased in the BALF 24 hr after the last OA challenge. Either Y-24180 or prednisolone was orally administered once a day for 10 days beginning one day before the first OA challenge. WEB2086, another PAF antagonist, was orally administered once or twice a day for 10 days. Y-24180 (0.3 - 3 mg/kg) suppressed the eosinophil infiltration in a dose-dependent manner and suppressed the IL-5 release at the highest dosage. Prednisolone (10 mg/kg) significantly suppressed both the eosinophil infiltration and IL-5 release. In contrast, WEB2086 affected neither the eosinophil infiltration nor IL-5 release when administered once a day (10 - 100 mg/kg/day). This drug never affected the IL-5 release but significantly suppressed eosinophil infiltration even when administered twice a day (30 - 200 mg/kg/day). These results indicate that the suppressive effect of Y-24180 on allergic pulmonary eosinophilia is due to not only to its long-lasting PAF-antagonism but also due to its suppressive effect on IL-5 release.

Anti-inflammatory and ulcerogenic effects of 3-(N,N-diethylamino) propylindometacin HCl.

AIM: To study anti-inflammatory effects of a novel indometacin ester, 3-(N,N-diethylamino) propyl-indometacin HCl (prodrug) and its ulcerogenicity in fats. METHODS: Carrageenin (Car)-induced paw edema and ulcer index were examined. RESULTS: Car-induced paw edema was inhibited by 36.6% (P < 0.01) at 3 h and 34.6% (P < 0.01) at 5 h after a single i.p. injection of the prodrug 7.09 mg.kg-1. On the same molar basis, indometacin (Ind) 5 mg.kg-1 i.p. inhibited edema by 45.6% at 3 h and 39.2% at 5 h, however, there was no statistical significant difference (P > 0.05) between the edema-inhibitory effect of the prodrug and that of Ind. The dose 10 micrograms/paw exhibited 64% inhibition of the swelling, the prodrug > 10 micrograms/paw showed no additional inhibition of swelling; the acute gastric lesion properties of the prodrug were much lower than those of Ind 6 h after p.o. CONCLUSION: The prodrug is a potent anti-inflammatory agent with lower ulcerogenicity in the stomach.

Effects of several denervation procedures on distribution of calcitonin gene-related peptide and substance P immunoreactive in rat stomach.

The effect of chemical deafferentation, vagotomy (VGX), and gangliosympathectomy (GSX) on the density of fibers containing calcitonin gene-related peptide (CGRP) and substance P (Sub.P) in the rat gastric wall was studied. Chemical deafferentation by capsaicin abolished the density of CGRP-immunoreactive (IR) fibers, not Sub.P-IR fibers. Ten days after VGX, the density of CGRP-IR or Sub.P-IR fibers in the mucosa was largely reduced, while no reduction of CGRP-IR and Sub.P-IR fibers was seen in submucosal and muscular layers. GSX significantly reduced the density of CGRP-IR fibers in the mucosa and caused a moderate decrease in the fibers in submucosal and muscular layers. Pretreatment with 6-hydroxydopamine, a neurotoxin for noradrenergic nerves, did not affect the density of CGRP-IR fibers in the gastric wall. The density of Sub.P-IR fibers in the gastric wall was not affected by GSX. These studies indicate that the CGRP-IR and Sub.P-IR fibers in the mucosa are susceptible to extrinsic nerve denervation compared with those in the submucosa and muscle layers, that a major portion of the CGRP-IR fibers in the mucosa is of both vagal and spinal origin, and that a major portion of the Sub.P-IR fibers in the mucosa is of vagal origin. Furthermore, the present results support that CGRP-IR fibers, not Sub.P-IR fibers, in the rat stomach are capsaicin-sensitive.