Mikio Ito

Meijo University, Nagoya-shi, Aichi-ken, Japan

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Publications (35)9.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In the present study, we investigated the susceptibility to restraint plus water-immersion stress (RWIS) in rats with daunomycin-induced nephrosis in comparison to that in normal rats. The severity of RWIS-induced gastric lesions was significantly less in nephrotic rats on the 20th and 40th days after a single i.v. injection of daunomycin (12 mg/kg) than in the respective control rats. Acid secretion in pylorus-ligated rats significantly decreased under the 3-h stress. On the 20th day after treatment with daunomycin, acid secretion was significantly less in nephrotic rats than in control rats under both stress and unstressed conditions. Pretreatment of normal rats with methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly prevented the stress-induced gastric lesions and decreased acid secretion. N(omega)-Nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, prevented the stress-induced gastric lesion formation only. These results indicate that nephrotic rats are more resistant to RWIS-induced gastric lesions than normal rats. In addition, these results suggest that the decrease in acid secretion related to the decrease in the release of NO from endothelial cells may contribute, at least in part, to the prevention of the stress-induced gastric lesion formation in nephrotic rats.
    The Japanese Journal of Pharmacology 11/1999; 81(2):230-6. DOI:10.1254/jjp.81.230
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    ABSTRACT: This study was performed to evaluate the effect of nephrosis on gastric lesions in the rats. A single i.v. injection of daunomycin (12 mg/kg) into rats produced severe proteinuria and hypercholesterolemia on the 20th and 40th days after the administration. The severity of HCl-ethanol-induced gastric lesions was significantly greater in nephrotic rats than in control animals on the 20th and 40th days. The gastric mucosal blood flow on the 40th day was significantly lower in nephrotic rats. Pretreatment of normal rats withN -nitro-l-arginine or N-nitro-l-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly aggravated the HCl-ethanol-induced gastric lesions and reduced the blood flow. WhenN -nitro-l-arginine methyl ester was given to nephrotic rats on the 40th day, it further increased the aggravation of the gastric lesions caused by nephrosis. These results suggest that the aggravation of HCl-ethanol-induced gastric lesions observed in nephrotic rats may be, at least in part, related to the decrease in the release of NO from endothelial cells.
    Environmental Toxicology and Pharmacology 04/1996; 1(2). DOI:10.1016/1382-6689(95)00019-4 · 1.86 Impact Factor
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    ABSTRACT: It is known that adhesion molecules play a crucial role in the development of glomerulonephritis. Therefore, we investigated the effects of acteoside on the expression of intercellular adhesion molecule-1 (ICAM-1) in nephritic glomeruli, in vivo, and human umbilical vein endothelial cells (HUVECs) and rat mesangial cells, in vitro. Aceteoside treatment significantly decreased the up-regulation of ICAM-1 expression in nephritic glomeruli. Acteoside prevented the up-regulation of ICAM-1 expression mediated by inflammatory cytokines or phorbol 12-myristate 13-acetate on HUVECs and rat mesangial cells. Adhesion of neutrophils and macrophages to acteoside-treated HUVECs was suppressed to one half of that in untreated HUVECs. These data support the finding that acteoside inhibits the up-regulation of ICAM-1 in the nephritic glomeruli. Additionally, it is suggested that the antinephritic action of acteoside is due to the inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of ICAM-1. This is the first paper demonstrating that the up-regulation of ICAM-1 in nephritic glomeruli is inhibited by a natural product, acteoside.
    The Japanese Journal of Pharmacology 03/1996; 70(2):157-68. DOI:10.1254/jjp.70.157
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    ABSTRACT: The possibility that hyperlipidemia and an increase of mononuclear cells in the glomeruli could participate in the pathogenesis of minimal change glomerulopathy was evaluated in puromycin aminonucleoside (PAN) nephrosis in rats. Significant increases in intraglomerular CD4-, IL-2-receptor (R)- and ED-1-positive cells were found in PAN rats. Urinary protein excretion and mononuclear cells in the glomeruli of 1% cholesterol diet-fed rats significantly increased, compared with standard diet feeding. Moreover, administration of a subnephrogenic dose of PAN in cholesterol diet-fed rats substantially increased urinary protein excretion and mononuclear cells in the glomeruli. Additionally, antihyperlipidemia agents and immunosuppressive agents prevented urinary protein excretion and increases of CD4-, IL-2R- and ED-1-positive cells in the glomeruli of PAN nephrotic rats. Monoclonal antibodies directed against these cells also prevented urinary protein excretion. These results suggest that CD4-, IL-2R- and ED-1-positive cells and hyperlipidemia are involved in the progression, but not the pathogenesis, of PAN.
    The Japanese Journal of Pharmacology 02/1996; 70(1):25-33. DOI:10.1254/jjp.70.25
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    ABSTRACT: The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellular adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.
    The Japanese Journal of Pharmacology 02/1996; 70(1):43-54. DOI:10.1254/jjp.70.43
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    ABSTRACT: The effects of cimetidine, omeprazole and atropine sulfate on the healing of acetic acid-induced gastric ulcers in rats with limited food intake time (9:00-10:00 a.m. and 5:00-6:00 p.m.) were evaluated 15 days after the acid injection. Oral repeated administration of cimetidine (25-100 mg/kg twice daily) or omeprazole (10-50 mg/kg once daily) dose dependently accelerated ulcer healing. Atropine sulfate (10 mg/kg twice daily, p.o.) was ineffective. A single oral administration of omeprazole (50 mg/kg) or cimetidine (100 mg/kg) resulted in potent and long-lasting anti-acid secretory and gastrin-releasing actions. The degree and duration of anti-acid secretion by atropine sulfate were equal to those of cimetidine, but the elevation of gastrin release by atropine sulfate was weak and temporary. These results indicate that the gastric ulcers of rats with a limited food intake time are useful for evaluating the healing effects of cimetidine and omeprazole on gastric ulcers. In addition, the effects of both drugs may be related to the increased gastrin release rather than to the reduced acid secretion.
    European Journal of Pharmacology 11/1994; 263(3):245-51. DOI:10.1016/0014-2999(94)90719-6 · 2.68 Impact Factor
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    ABSTRACT: Daily oral administration of cimetidine or omeprazole markedly accelerated the healing of acetic acid-induced gastric ulcers in rats with a limited food intake time. The increased gastric acid secretion induced by daily treatment with histamine affected neither the spontaneous healing of the ulcers nor the healing-promoting actions of both agents. Pretreatment of rats with ulcers with 6-hydroxydopamine significantly inhibited the increase in the antrum gastrin cells, serum gastrin levels and corpus mucosal thickness elicited by repeated administration of cimetidine or omeprazole. Pretreatment with 6-hydroxydopamine did not affect the inhibitory actions of cimetidine and omeprazole on acid secretion, but completely abolished the ulcer healing-promoting actions of both drugs. Daily intraperitoneal administration of pentagastrin accelerated ulcer healing. These results suggest that cimetidine and omeprazole mainly accelerate the healing of gastric ulcers by the trophic action of gastrin via the increase in gastrin secretion, while the inhibition of acid secretion may play a minor role in ulcer healing.
    European Journal of Pharmacology 11/1994; 263(3):253-9. DOI:10.1016/0014-2999(94)90720-X · 2.68 Impact Factor
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    ABSTRACT: We investigated the effect of acteoside in comparison with that of cyclosporin A on leukocyte accumulation in the glomeruli of rats with crescentic-type anti-glomerular basement membrane (GBM) nephritis. Acteoside given p.o. at a dose of 30 mg/kg once a day for 15 consecutive days after treatment with anti-GBM serum markedly suppressed the urinary protein as well as glomerular histological changes. Acteoside given p.o. for 5 or 15 consecutive days markedly suppressed the accumulation of total leukocytes, ED-1-positive cells (monocytes/macrophages), CD4-positive cells, CD8-positive cells, interleukin-2-receptor-positive cells (activated T cells) and Ia-positive cells in the glomeruli. These effects of cyclosporin A (20 mg/kg/day, p.o.) were also as potent as those of acteoside (30 mg/kg/day, p.o.). Cyclosporin A also strongly suppressed the elevation of plasma antibody level against rabbit gamma-globulin. However, in this dose, acteoside did not significantly suppress the antibody formation. It can be concluded from these results that acetoside may exert its antinephritic action by suppressing the accumulation of leukocytes in the glomeruli.
    The Japanese Journal of Pharmacology 10/1994; 66(1):47-52. DOI:10.1254/jjp.66.47
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    ABSTRACT: The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthetase inhibitor, was compared with that of OKY-046, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Test drugs were given p.o. once daily from the day after the the development of glomerular alteration as well as the elevation of proteinuria and plasma cholesterol. On the other hand, OKY-046 (20 mg/kg per day), a thromboxane A2 synthetase inhibitor, significantly inhibited only deterioration in the glomeruli. DP-1904 and OKY-046 inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in normal and nephritic rats. Both drugs inhibited the increase in platelet aggregability, restored decreased renal tissue blood flow to a near-normal level and decreased the deposition of rat immunoglobulin G on glomerular basement membrane in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis.
    European Journal of Pharmacology 08/1994; 259(3):233-42. DOI:10.1016/0014-2999(94)90649-1 · 2.68 Impact Factor
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    ABSTRACT: To establish the regimen for beneficial prolonged treatment with glucocorticoids on nephritis, we investigated the antinephritic effect of methylprednisolone suleptanate (MPS) and its influence on adrenal function by intermittent administration (IA) in comparison with daily administration (DA) in crescentic-type anti-GBM nephritic rats. In IA, MPS (0.25, 1.0 and 3.0 mg/kg) was injected for 3 successive days followed by a 3-day withdrawal during a 40-day period. MPS inhibited the elevation of urinary protein and serum cholesterol and glomerular alterations by both IA and DA. The effect of MPS on these parameters was more potent by IA than by DA. MPS significantly suppressed the increment of the number of ED-1(+) cells and TH-1(+) cells in nephritic glomeruli. DA, but not IA, caused atrophy of the adrenal glands. IA prevented the remarkable decrease in corticosterone level provoked in nephritic rats. In conclusion, for the treatment of nephritis, IA seems to be a better regimen for the administration of MPS. MPS may exert an antinephritic action by inhibiting mesangial cell proliferation and infiltration of monocytes/macrophages into glomeruli in addition inhibiting antibody production.
    The Japanese Journal of Pharmacology 03/1994; 64(2):79-88. DOI:10.1254/jjp.64.79
  • The Japanese Journal of Pharmacology 01/1994; 65(2):143-151. DOI:10.1254/jjp.65.143
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    ABSTRACT: Effects of phellodendrine (OB-5) on crescentic-type anti-GBM nephritis in rats and the cell number of the various leukocyte subpopulations in the glomeruli of the nephritic rats were investigated. OB-5 at 25, 50 and 100 mg/kg/day, p.o. prevented the urinary protein excretion by the 19th day after i.v.-injection of anti-GBM serum. In the OB-5-treated rats, plasma cholesterol and creatinine contents were lower than those of the control rats throughout the 40-day experimental period. Histopathological observations demonstrated that OB-5 inhibited the incidence of crescent formation, adhesion and fibrinoid necrosis in the glomeruli by the 41st day. OB-5 did not affect the plasma antibody titer against rabbit gamma globulin. The increases in total leukocytes, macrophages, cytotoxic/suppressor T cells, Ia positive cells, and IL-2 receptor positive cells in the glomeruli in OB-5, 100 mg/kg-treated rats as well as those of the animals treated with azathioprine or cyclosporin A were lower than those of the anti-GBM nephritic control. These results indicate that OB-5 was effective in crescentic-type anti-GBM nephritis and the antinephritic mechanisms of this agent may be due to its ability to inhibit the proliferation or the migration of macrophages and cytotoxic T lymphocytes in the glomeruli.
    The Japanese Journal of Pharmacology 12/1992; 60(3):187-95. DOI:10.1254/jjp.60.187
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    ABSTRACT: Z-103 at 1 to 25 mg/kg, p.o. prevented 100% ethanol-induced gastric mucosal lesions in a dose-dependent manner. Z-103 at 3 to 25 mg/kg, p.o. significantly elevated gastric mucosal superoxide dismutase (SOD)-like activity 1 hr after its administration to normal rats. In addition, Z-103 at doses (10 and 25 mg/kg, p.o.) which prevented 100% ethanol-induced gastric lesion further increased gastric mucosal SOD-like and glutathione peroxidase (GSH-px) activities elevated by 60% ethanol. Z-103 (10 and 25 mg/kg) significantly inhibited the increase in thiobarbituric acid-reactive substances in gastric mucosa injured by 60% ethanol. The combination with cycloheximide, a protein synthesis inhibitor, completely abolished the prevention of 60% ethanol-induced gastric mucosal lesions and the elevation of both free radical scavenging enzyme activities in the mucosa by Z-103 (10 mg/kg, p.o.). These results suggest that Z-103 may partly protect rat gastric mucosa against ethanol-induced damage by scavenging oxygen-derived free radicals via increases in the synthesis of SOD-like and GSH-px enzymes in the mucosa.
    The Japanese Journal of Pharmacology 08/1992; 59(3):267-74. DOI:10.1254/jjp.59.267
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    ABSTRACT: The present study was conducted to investigate the antinephritic effects of berberine and coptisine, which are contained in Coptidis rhizoma, on original-type anti-GBM nephritis in rats. Berberine and coptisine at the doses of 0.5, 1.0 and 5.0 mg/kg/day, i.p. were effective in inhibiting urinary protein excretion, elevation of serum cholesterol and creatinine contents as well as glomerular histopathological changes. In addition, berberine at 20 mg/kg/day, p.o. also inhibited urinary protein excretion throughout the experimental periods. Berberine and coptisine inhibited platelet aggregation in both in vitro and in vivo assays, and berberine inhibited the decline of renal blood flow. Although berberine inhibited an increase in thromboxane B2 formation, it increased the formation of 6-keto-prostaglandin F1 alpha in platelets and isolated glomeruli. These results indicate that the antinephritic effects of berberine and coptisine may be partly due to antiplatelet action and improved renal hemodynamics via changing prostanoid synthesis.
    The Japanese Journal of Pharmacology 07/1992; 59(2):159-69. DOI:10.1254/jjp.59.159
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    ABSTRACT: The antinephritic effect of pachyman on original-type anti-GBM nephritis in rats was investigated. Pachyman was given to original-type anti-GBM nephritic rats for 10 days from the day of anti-GBM serum injection. Pachyman prevented urinary protein excretion and the elevation of serum cholesterol content. Histopathological observations of the glomeruli indicated that although the number of nuclei and adhesion to capillary walls of Bowman's capsule in nephritic control rats were significantly increased, pachyman reduced the degree of histopathological changes such as hypercellularity and adhesion as compared to the control group. Although the serum complement CH50 ratio in control group was significantly lower than that in the normal group, the decrease in serum complement CH50 was inhibited by pachyman, and rat C3 deposition in the glomeruli in the pachyman-treated group was significantly reduced. These results suggest that pachyman was effective against original-type anti-GBM nephritis in rats and that the antinephritic mechanisms of pachyman may be partly due to the inhibitory action of this agent on C3 deposition in the glomeruli.
    The Japanese Journal of Pharmacology 06/1992; 59(1):89-96. DOI:10.1254/jjp.59.89
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    ABSTRACT: The suppressive effect of cyclosporin A (CyA) on the development of glomerulonephritis was evaluated in rats with either original- or crescentic-type anti-glomerular basement membrane (GBM) nephritis. CyA (2.5, 10 or 20 mg/kg) was given p.o. daily to original-type anti-GBM nephritic rats for 10 days from the day after the injection of anti-GBM serum. The development of the nephritis was dose-dependently suppressed by CyA before the production of specific antibody against rabbit gamma-globulin (the heterologous phase). In addition, CyA suppressed glomerular infiltration of leukocyte subsets (leukocyte with common antigen, T cell, helper T cell, suppressor/cytotoxic T cell, macrophage/monocyte). CyA was given p.o. daily to crescentic-type anti-GBM nephritic rats for 10 days from the 10th day after the injection of anti-GBM serum. CyA-administration caused a distinct suppression of the deterioration of nephritis during the autologous phase. In addition, CyA markedly suppressed the antibody production. The above data indicate that CyA has a beneficial effect on anti-GBM nephritis, and the antinephritic action of this agent may be due to the inhibition of glomerular infiltration of leukocyte subsets as well as the suppression of the antibody production.
    The Japanese Journal of Pharmacology 02/1992; 58(1):27-36. DOI:10.1254/jjp.58.27
  • Folia Pharmacologica Japonica 01/1992; 99(6):391-399. DOI:10.1254/fpj.99.391
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    ABSTRACT: The effect of TJ-8014, a lyophilized extract of Syo-Saiko-To without Zingiberis rhizoma, annexing Coptidis rhizoma and Hoelen, on puromycin aminonucleoside (PAN) nephrosis in comparison with the effect of dipyridamole was evaluated. PAN nephrosis was induced in rats by intraperitoneal injections of PAN, once daily for 6 days. When TJ-8014 was given from the initial day of PAN treatment (just before PAN injection) at 2.0 g and 4.0 g/kg/day, p.o., it was markedly inhibited urinary protein excretion and elevation of serum cholesterol content-throughout the experimental periods. In addition, the mild adhesion of Bowman's capsule to capillary walls in glomeruli was also improved by TJ-8014 at 2.0 g and 4.0 g/kg/day, p.o. Dipyridamole was also effective in inhibiting the urinary protein excretion as well as histopathological changes. TJ-8014 at 4.0 g/kg/day, p.o. inhibited the decrease in superoxide dismutase (SOD-like), catalase and glutathione peroxidase activities in the renal cortex and SOD-like activity in the glomeruli in PAN-induced nephrosis. Dipyridamole failed to inhibit the decrease in scavenger activities. These results suggest that TJ-8014 is effective against PAN-induced nephrosis, and they suggest that the mechanisms of action of this medicine may be partly due to the enhancing activities of scavengers in the renal cortex and glomeruli.
    The Japanese Journal of Pharmacology 09/1991; 56(4):465-73. DOI:10.1254/jjp.56.465
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    ABSTRACT: To clarify the antinephritic effects of ginsenosides, we investigated the effects of crude ginsenoside and ginsenosides Rg1 and Rb1 on original-type anti-GBM nephritis in rats. Crude ginsenoside at 1.0 mg and 5.0 mg/kg, i.p., and ginsenoside Rg1 at 1.0 mg/kg, i.p., prevented urinary protein excretion and elevation of serum cholesterol content, as well as histopathological changes such as hypercellularity and adhesion. On the other hand, ginsenoside Rb1 only inhibited the histopathological parameters. In order to clarify the antinephritic mechanisms of ginsenosides on this model, we investigated the effect of ginsenosides on platelet aggregation and renal blood flow. Crude ginsenoside markedly enhanced the renal blood flow. Ginsenoside Rg1 inhibited the platelet aggregation in vivo and enhanced the renal blood flow on the 1st day. These results suggest that crude ginsenoside and Rg1 exert their antinephritic action via increased renal blood flow.
    Folia Pharmacologica Japonica 03/1991; 97(2):127-34. DOI:10.1254/fpj.97.2_127
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    ABSTRACT: This study was designed to clarify the anti-nephritic effects of the saikosaponins that are contained in Bupleurum falcatum L. crude saikosaponin at 1.0 mg and 5.0 mg/kg, i.p. prevented urinary protein excretion and elevation of serum cholesterol content on the 10th day after the injection of anti-GBM serum. Moreover, crude saikosaponin at 1.0 mg and 5.0 mg/kg, i.p. significantly inhibited histopathological changes such as hypercellularity and adhesion. On the other hand, saikosaponin a (5.0 mg/kg, i.p.) and d (1.0 mg and 5.0 mg/kg, i.p.) also prevented urinary protein excretion, elevation of serum cholesterol content, and histopathological changes. In the second study, to clarify the anti-nephritic mechanisms of saikosaponins on this model, we investigated the effect of saikosaponins on platelet aggregation, release of corticosterone and reactive oxygen species scavengers activity. Crude saikosaponin and saikosaponin d significantly inhibited the increase in platelet aggregation, and saikosaponin d enhanced the serum and intra-adrenal corticosterone levels. Crude saikosaponin and saikosaponin a inhibited the decrease in activity of scavengers (SOD, catalase, glutathione peroxidase). These results indicate that saikosaponins were effective on this model, and anti-nephritic mechanisms of saikosaponins were party due to anti-platelet, corticosterone releasing and enhancing action on the activity of reactive oxygen species scavengers.
    Folia Pharmacologica Japonica 02/1991; 97(1):13-21. DOI:10.1254/fpj.97.1_13