Transforming growth factor alpha (TGF-alpha) is a potent stimulator of normal hepatocyte proliferation, considered to have relationship to the liver regeneration or carcinogenesis. In this study, we investigated immunohistochemically the association between expression of TGF-alpha and cell proliferation activity in mouse hepatoblastomas (HBs) and hepatocellular carcinomas (HCCs) induced in B6C3F1 mice by diethylnitrosamine and sodium phenobarbital. The TGF-alpha-positive rate in HBs (29.2%) was significantly higher than that in HCCs (12.7%). Likewise, the proliferating cell nuclear antigen-positive rate (22.2%) was higher than the HCC value (14.5%). On the individual data for both TGF-alpha and PCNA, most of the HBs showed higher positive rates than HCCs. In HBs, TGF-alpha was localized only in the nuclei, whereas some HCC cells stained positive both in their nuclei and cytoplasm (0.6%). These results suggest expression of TGF-alpha and its localization might be linked to cell proliferation and play a role in malignant progression of mouse HBs.

Administration, Oral↗

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N-phenylimidazolium triflate as a highly effective promoter for the interribonucleotide-bond formation via the phosphoramidite method.

N-Phenylimidazolium triflate has been invented as an extremely effective promoter for the construction of interribonucleotide linkage according to the phosphoramidite strategy.

Imidazoles↗

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Comparative studies on the pharmacological actions of antiarrhythmic drugs in isolated rate papillary muscle.

1. The effects of ajmaline, cocaine, phenytoin, lignocaine, procainamide, propranolol, quinidine and trimetazidine on the contractility and the refractory period of isolated rat papillary muscles were compared. 2. At the higher concentrations used, all drugs suppressed the contractile tension of the rat papillary muscles. 3. The effects of these drugs on the refractory period were compared at concentrations at which the contractile tension was suppressed by 30% of the control. At this point, lignocaine, procainamide, ajmaline and quinidine prolonged the refractory period more than two-fold while the effects of propranolol and phenytoin were slight, cocaine and trimetazidine had little or no effect.

Animals↗

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The contraction induced by calcium ions in isolated guinea-pig vas deferens.

1. When isolated guinea-pig vas deferens was pretreated with 0.01% sodium edetate in an isotonic sucrose medium and then transferred to an edetate-free sucrose medium, the addition of CaCl2 (1.1 to 35.2 mmol/l) induced a contraction. 2. The contraction was greatest when the CaCl2 was added soon after pretreatment with edetate, and decreased with increasing time, almost disappearing after 1 h. 3. When KCl (1.4 to 22.4 mmol/l) was added in place of CaCl2, the contraction was lowest soon after pretreatment with edetate, and increased with time; after 1 h, the effect, was 80.7% of that observed in a preparation that had not been pretreaated with edetate.

Animals↗

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The contraction induced by ethylenediaminetetracetic acid-4 sodium (EDTA-4Na) in guinea-pig isolated vas deferens kept in isotonic sucrose medium.

1. Ethylenediaminetetracetic acid--4 sodium (EDTA--4Na) induced a contraction in guinea-pig isolated vas deferens kept in isotonic sucrose medium containing 0.07% Nahco3 and 0.1% glucose after preincubation in Locke's solution. The maximum contraction was 82.1 +/- 6.7% of that induced by added KCl. 2. EDTA--Ca--2Na (10(-7) to 10(-3) g/ml) induced no contraction in preparations kept in the sucrose medium. 3. The EDTA--4Na-induced contraction was also obtained when sucrose in the sucrose medium was replaced by glucose but not when the preparation was kept in Locke's solution. 4. The EDTA--4Na-induced contraction was decreased by reduction of the CaCl2 of KCl concentration of the Locke's solution in which the preparation had been preincubated before placing in the sucrose medium. 5. The EDTA--4Na-induced contraction was suppressed with increasing concentrations of NaCl used to partially replace sucrose in the sucrose medium. 6. When the preparation was kept in EDTA-free sucrose medium after pretreatment with 10(-4) g/ml of EDTA--4Na in the sucrose medium for 20 min, a contraction was induced by added CaCl2. The maximum contraction induced by CaCl2 was 30.1 +/- 11.8% of that of the EDTA--4Na-induced contraction, when CaCl2 was added at 20 min after the exchange of medium.

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The effects of diazepam on rat isolated heart muscle.

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Animals↗

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Influence of sodium and potassium ions on the contraction induced by calcium ions in guinea-pig isolated vas deferens.

1. When guinea-pig isolated vas deferens was pretreated with 0.01% tetrasodium edetate in an isotonic sucrose medium and then transferred to an edetate-free sucrose medium, the addition of CaCl2 (0.28-8.80 mmol/l) induced a contraction. 2. When the edetate-free sucrose medium was replaced by saline containing NaHCO3 and glucose, the contraction induced by CaCl2 was only slightly smaller than that obtained in the sucrose medium. 3. When the saline medium was replaced by Ca-free Locke's solution, the contraction induced by CaCl2 was almost the same as that obtained in the saline medium. 4. When the Ca-free Locke's solution was replaced by Ca-free K-Locke's solution (in which NaCl and CaCl2 were replaced by KCl), the contraction induced by CaCl2 was almost the same as that obtained in the sucrose medium.

Animals↗

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Influence of manganese ions on the contraction of the guinea-pig isolated vas deferens.

1. The CaCl2-induced contraction of guinea-pig isolated vas deferens, pretreated with tetrasodium edetate and then transferred to edetate-free sucrose medium, was increased in the presence of MnCl2 in extremely low concentrations (0.005-0.01 mmol/l) but was suppressed by the salt in concentrations higher than 1.0 mmol/l. 2. The KCl-induced contraction of the preparation, kept in a sucrose medium without edetate-pretreatment, was suppressed by MnCl2 (0.005-0.5 mmol/l) in a concentration-dependent manner. 3. The noradrenaline-induced contraction of the preparation kept in Locke's solution, was not influenced by MnCl2 in concentrations lower tha 0.1 mmol/l but was inhibited by higher concentrations (0.1-1.0 mmol/l).

Animals↗

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Glomerulonephritis with fibrillary deposition in a transgenic mouse carrying the human prototype c-Ha-ras gene (rasH2 mouse).

Glomerulonephritis was observed in a 34-week-old transgenic CB6F1 mouse carrying the human prototype c-Ha-ras gene (rasH2 mouse) from a medium-term carcinogenicity study of N-methyl-N-nitrosourea (MNU). Lesions were characterized by severe diffuse enlargement and prominent hyalinization of glomeruli. The hyaline material was positive for periodic acid-Schiff but negative for amyloid by the Congo red method. Immunohistochemically, affected glomeruli were positive for polyclonal anti-mouse IgG. Ultrastructurally, there were characteristic subendothelial and mesangial deposits composed of fibrils showing a fingerprint pattern. Lamellae were 7.5-14.3 nm in diameter and formed multilayered structures. In addition to the renal lesions, a lymphoma was observed in the thymus, with metastasis to the spleen and some lymph nodes. However, there was no glomerulonephritis in 32 other mice bearing thymic lymphomas and in more than 40 males and females given MNU in the same study. Thus, the lesions in this mouse may have been spontaneous. Glomerulonephritis was not found in more than 120 other male and female rasH2 mice in our facility. This is the first report of glomerulonephritis in a rasH2 mouse, a promising candidate for medium-term carcinogenicity risk assessment.

Animals↗

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Immunohistochemical localization of transforming growth factor alpha in chemically induced rat hepatocellular carcinomas with reference to differentiation and proliferation.

Hepatocellular carcinomas (HCCs) were induced in male Fischer 344 rats with dietary 3'-methyl-4-(dimethylamino)-azobenzene treatment and were classified into solid, glandular (well- or poorly differentiated), and trabecular types. Investigation of cell proliferation kinetics and immunohistochemical localization of transforming growth factor alpha (TGF-alpha) demonstrated all solid (n = 24) and poorly differentiated glandular type (n = 6) HCCs to have TGF-alpha-positive nuclei. Nuclear staining of TGF-alpha was also observed in 13 of 28 (46%) trabecular-type HCCs, whereas 12 (43%) exhibited cytoplasmic staining, and 3 (11%) were negative. As for well-differentiated glandular HCCs, 7 of 20 (35%) were positively stained in their nucleus, another 7 (35%) demonstrated antibody binding in the cytoplasm, and 6 (30%) were negative. The order for growth rate evaluated by bromodeoxyuridine (BrdU) labeling was solid (38.22%), poorly differentiated glandular (26.82%), trabecular (7.98%), and well-differentiated glandular (2.57%) types. For trabecular HCCs with nuclear, cytoplasmic, or negative TGF reactions, values were 13.39% (n = 13), 3.61% (n = 12), and 2.01% (n = 3), respectively. Likewise, BrdU-labeling indices for the counterpart groups of well-differentiated glandular type HCCs were 4.53, 1.91, and 1.29%, respectively. The results indicate that TGF-alpha expression might be linked to histopathological differentiation and cell proliferation in rat HCCs.

Animals↗

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Alterations in glomerular anionic sites in canine anti-glomerular basement membrane nephritis with onset of severe proteinuria.

Rabbit anti-glomerular basement membrane serum (AGBM) or normal rabbit serum (NRS) were given intravenously (2 ml/kg body weight) to 8 male beagle dogs. Light and transmission electron microscopy and immunofluorescence were performed on the kidneys on day 7 postinjection. Alterations of anionic sites (ASs) of glomerular basement membrane (GBM) in peripheral, proximal, and paramesangial portions were studied quantitatively by electron microscopy using polyethyleneimine (PEI; molecular weight = 1,800) as a cationic probe. Severe or mild proteinuria developed on day 1 and continued until day 6 postinjection. On day 7 after AGBM injection, the number of PEI granules per 1,000 nm length of the lamina rara externa of GBM in all portions was significantly less than that in NRS-treated dogs (10.48 +/- 1.78 versus 14.19 +/- 2.35 granules per 1,000 nm of GBM in peripheral portion, 10.81 +/- 1.91 versus 14.97 +/- 1.35 granules per 1,000 nm of GBM in proximal portion, 8.44 +/- 1.76 vs 13.43 +/- 2.10 granules per 1,000 nm of GBM in paramesangial portion; p < 0.001). These results indicate that a reduction glomerular AS occurs in AGBM-treated dogs in association with severe or mild proteinuria and alterations in glomerular ASs might play an important role in the pathogenesis of proteinuria in the canine anti-GBM nephritis in addition to morphological changes.

Animals↗

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Alterations in glomerular anionic sites in the autologous phase of canine anti-glomerular basement membrane nephritis.

There have been a few studies on canine nephrotoxic glomerulonephritis produced by anti-glomerular basement membrane serum (AGBM), but these reports have not focused on an alteration in the charge properties of glomerular basement membrane (GBM). In this study, rabbit AGBM or normal rabbit serum (NRS) was given intravenously (2 ml/kg body weight) to 16 male beagle dogs. An alteration of anionic sites (ASs) of GBM was studied quantitatively using polyethyleneimine as a cationic probe by electron microscopy at weeks 1, 2, 4, and 8 postinjection. In AGBM-treated dogs, severe or mild proteinuria continued until week 2. At weeks 4 and 8, there was no significant difference in the intensity of proteinuria between AGBM- and NRS-treated groups. Until week 2 postinjection, there were significantly fewer ASs of GBM in AGBM-treated dogs than in NRS-treated dogs. At week 8, however, there was no difference in ASs of GBM between AGBM- and NRS-treated dogs. The fact that a reduction of glomerular AS occurred in AGBM-treated dogs with severe or mild proteinuria and the recovery of AS in the GBM coincided with an improvement of proteinuria suggested that alteration of the glomerular ASs might play an important role in the pathogenesis of proteinuria in canine anti-GBM nephritis.

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