Tetsuaki Yamaura

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 offibers containing calcitonin gene-related peptide (CGRP)and substance P (Sub.P) in the rat gastric wall was studied. Chemical deafferentation bycapsaicin 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 reductionof CGRP-IR and Sub.P-IR fibers was seen in submucosaland muscular layers. GSX significantly reduced thedensity of CGRP-IR fibers in the mucosa and caused a moderate decrease in the fibers in submucosaland muscular layers. Pretreatment with6-hydroxydopamine, a neurotoxin for noradrenergicnerves, did not affect the density of CGRP-IR fibers inthe gastric wall. The density of Sub.P-IR fibers in thegastric wall was not affected by GSX. These studiesindicate that the CGRP-IR and Sub.P-IR fibers in themucosa are susceptible to extrinsic nerve denervation compared with those in the submucosa and musclelayers, that a major portion of the CGRP-IR fibers inthe mucosa is of both vagal and spinal origin, and thata major portion of the Sub.P-IR fibers in the mucosa is of vagal origin. Furthermore, thepresent results support that CGRP-IR fibers, notSub.P-IR fibers, in the rat stomach arecapsaicin-sensitive.

Immunohistochemical localization of calcitonin gene-related peptide in the human gastric mucosa

Background/Aim: There have been only a few studies on the distribution of calcitonin gene-related peptide (CGRP) in the human stomach, in which it was stated that CGRP fibers are rare in that organ. The aim of the present study was to investigate the immunohistochemical localization of CGRP in the human gastric mucosa obtained by endoscopic biopsy from patients with gastric ulcers. Methods: Immunohistochemistry was carried out according to the indirect immunoperoxidase method using an anti-human CGRP antibody. Biopsies were taken from the ulcer margin in 18 patients (age 37–78, average 57.4 years) and from two endoscopically normal portions (antrum and body) in 7 other patients (age 36–65, average 51.0 years). One biopsy specimen was obtained from each portion. Results: Twelve of the eighteen biopsy specimens from the ulcer margin, 6 of the 7 biopsy specimens from normal portions of the antrum and 3 of the 7 biopsy specimens from normal portions of the body showed CGRP-immunoreactive staining. Intense staining was more marked in the specimens from the ulcer margin compared to those of the normal portions. Conclusions: CGRP immunoreactivity was observed in the human gastric mucosa in considerable abundance, and it is presumed that CGRP might participate in a restoration mechanism of the ulcer.

ヒト腸上皮細胞株Caco-2のacyl-CoA:cholesterol acyltransferase(ACAT)活性とコレステロールエステル分泌に対するACAT阻害薬,F-1394の作用

The present study was conducted to investigate the inhibitory effect of F-1394, a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), on incorporation of 14C-oleic acid into cholesteryl ester in cultured Caco-2 cells, a human intestinal cell line, and compare its effect to those of other ACAT inhibitors and hypolipidemic agents. The cholesterol esterification in Caco-2 cells was strongly inhibited by F-1394 in a concentration-dependent manner with the estimated IC50 value of 71 nM. In contrast, the estimated IC50 values of the other ACAT inhibitors such as YM-17E, CI-976, CL-277,082 and DL-melinamide are 121 nM, 702 nM, 21.5 microM and 20.9 microM, respectively. Simvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, also inhibited the ACAT activity in Caco-2 cells with an IC50 value of 22.5 microM, whereas pravastatin Na, probucol and clofibrate did not affect the activity. Furthermore, F-1394 at a concentration of 100 nM inhibited the basolateral secretion of cholesteryl ester by 90% from differentiated Caco-2 cells that were cultured on a membrane filter. These results demonstrate that F-1394 strongly inhibits human intestinal ACAT activity and basolateral secretion of cholesterol from Caco-2 cells. Therefore, F-1394 may have a therapeutic potential for dietary hyperlipidemic subjects.