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PubMed2005

Effect of operation-synchronizing transfusion of apoptotic spleen cells from donor rats on acute rejection of recipient rats after liver transplantation.

AIM: To study effect of operation-synchronizing transfusion of apoptotic spleen cells from donor rats on acute rejection of recipient rats after liver transplantation. METHODS: Two of Wistar rats were chosen randomly for normal liver pathology control and ten of SD rats chosen randomly for liver function control as blank group (no operation). The rest of Wistar and SD rats were divided into four groups: control group (only liver transplantation), Dex group (donors receiving intraperitoneal injection of dexamethasone), SpC group (recipients receiving infusion of spleen cells of donors), Dex-SpC group (recipients receiving infusion of apoptotic spleen cells of donors), with each group except blank group, containing 10 SD rats and 10 Wistar rats, respectively. Wistar rats received liver transplantation from SD rats, in the meantime they received infusion of spleen cells of donors, which were induced by an intraperitoneal injection of dexamethasone (3 mg/(d.kg).b.w) for three days before liver transplantation. The serum alanine transaminase (ALT), total bilirubin (T bili), liver pathological changes and survival time were analysed. Statistical analysis was carried out using SPSS 10.0 for Windows. Differences of the parametric data of ALT in means were examined by one-way ANOVA. Differences of ALT between two groups were examined by LSD. Differences of the nonparametric data of T bili in means and scores of pathology classification for acute rejection were examined by Kruskal-Willis H test. The correlations between ALT and T bili were analysed by Bivariate. Kaplan-Meier curves were used to demonstrate survival distribution. The log-rank test was used to compare the survival data. RESULTS: There were significant differences in ALT of the five groups (F = 23.164 P = 0.000), and ALT in Dex-SpC group was significantly higher than that in blank control, control, Dex, and SpC groups (P = 0.000), and ALT in SpC group was significantly higher than that in blank control (P = 0.000), control (P = 0.004), and Dex groups (P = 0.02). Results of nonparametric analysis of T bili showed that there were differences in T bili of the five groups (chi(2) = 33.265 P = 0.000). T bili in Dex-SpC group was significantly higher than that in blank control, control, Dex, and SpC groups. T bili in SpC group was higher than that in blank control, control, and Dex groups. There were significant differences in scores of pathology classification for acute rejection in each of the groups (chi(2) = 25.933,P = 0.000). The pathologically more serious acute rejection was found in Dex-SPC group than in other groups. No sign of acute rejection was observed in the blank control group. Slight acute rejection was observed in the control group. Slight-moderate acute rejection was observed in the Dex group. Moderate-acute rejection was observed in the SpC group. Severe-acute rejection was observed in the Dex-SpC group. The survival time in Dex-SpC group was shorter than in other groups (statistic = 11.13, P = 0.011). ALT and T bili were positively correlated (r = 0.747, P = 0.000, two-tailed). CONCLUSION: In order to reduce quantity of blood loss from rats after liver transplantation, only one of ALT or T bili is needed for liver function measurement of rats. Simultaneous injection of apoptotic spleen cells from donors induced by dexamethasone to liver transplantation rats aggravates acute rejection. One important mechanism of aggravation of acute rejection may be that apoptotic cells are not removed in time and that dead cells including apoptotic cells release inflammatory factors.

Acute Disease↗

PubMed1989

The 3-methylcholanthrene-inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation.

The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin. The Gunn rat is also deficient in a 3-methylcholanthrene (MC)-inducible UDPGT isoenzyme that has high activity toward phenolic substrates. We have isolated and sequenced a cDNA, designated 4-NP UDPGT, which encodes an MC-inducible UDPGT from normal Wistar rat livers (Iyanagi, T., Haniu, M., Sogawa, F., Fujii-Kuriyama, Y., Watanabe, S., Shively, J.E., and Anan, K.F. (1986) J. Biol. Chem. 261, 15607-15614). In the present study, we found that this cDNA detected MC-inducible UDPGT mRNA in the MC-treated homozygous Gunn rat liver. The level of this mRNA, however, was significantly lower than that of normal Wistar livers. The size of mRNA in Gunn rats was identical to that of the functionally mature UDPGT mRNA in Wistar rats, but the MC-inducible UDPGT protein was absent from homozygous Gunn rat microsomes. We therefore made a cDNA library from MC-treated Gunn rat liver mRNA and isolated cDNA clones, using the 4-NP UDPGT cDNA as a probe. Sequencing analysis of these cDNA clones revealed a single base deletion in the coding region. Northern blot analysis of mRNAs from normal Wistar and heterozygous and homozygous Gunn rats livers was performed using specific oligonucleotide probes, and the results confirmed the presence of mRNA containing the single base deletion in heterozygous and homozygous Gunn rats. These data suggested that the defect of the MC-inducible isoenzyme in Gunn rats arises from a -1 frameshift mutation that removes 115 amino acids from the COOH terminus.

Animals↗

PubMed1997

Genetic characterization of novel strains of rats derived from crosses between Wistar-Kyoto and spontaneously hypertensive rats, and comparisons with their parental strains.

Two novel strains of rats have recently been generated from hybrid crosses of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The breeding pairs chosen to create these strains were initially selected on the basis of two mutually exclusive phenotypic traits, so that the rats called WKHT are hypertensive but not hyperactive, whereas the rats called WKHA are hyperactive but not hypertensive. These strains have been refined by inbreeding on a strict brother-sister basis for more than 25 generations. To increase usefulness of these strains, we characterized them by use of genetic methods, including DNA finger-printing and simple sequence length polymorphism (SSLP) analyses. We found that these two novel strains are more closely related genetically to either SHR or WKY rats than the degree to which the latter two strains are related to one another; heterozygosities of SSLP marker alleles were extremely rare in WKHA and WKHT, indicating that these strains can be considered as truly inbred (in contrast to WKY rats from two sources); and it was almost always possible to match the SSLP marker alleles found in WKHA and WKHT rats with similarly sized alleles in the parental SHR and WKY alleles, indicating that the WKHA and WKHT strains constitute true mixes of the genomes of SHR and WKY rats. Furthermore, immunogenetic analyses indicated that WKY and WKHT rats belonged to the RT1 l haplotype, whereas SHR and WKHA rats belonged to the k haplotype. These results extend the usefulness of WKHA and WKHT rats for further genetic and physiologic studies.

Alleles↗

PubMed1989

Experimental autoimmune uveoretinitis (EAU) in rats: isolation of S-antigen, EAU susceptibility of rat strains, genetic control of EAU induction, and effects of cyclophosphamide and irradiation on EAU.

Highly purified S-antigen was isolated from bovine retinas by high performance liquid chromatography (HPLC), and was used to induce experimental autoimmune uveoretinitis (EAU) in various rat strains. Studies were then made of the genetic control of EAU, the effects of cyclophosphamide or irradiation on EAU, and the correlation between the EAU incidence and the serum levels of antibody to S-antigen. Lewis rats were the most susceptible to EAU followed by Wistar rats. F344 rats and BN rats were resistant to EAU. (Lewis X BN)F1 rats and (LBNF1 X Lewis) rats were susceptible to EAU, while (LBNF1 X BN) rats were resistant. These results indicate that susceptibility to EAU was inherited as an autosomal dominant trait. Treatment of rats with cyclophosphamide or irradiation (200 rad/rat) on the day before immunization markedly suppressed EAU development. On the other hand, the same dose of irradiation 7 days after the immunization did not affect the disease induction, yet the antibody levels to S-antigen were very high in the rats. In addition, BN rats resistant to EAU exhibited very high levels of antibody to S-antigen. Therefore, the antibody to S-antigen seems to play a minor role, if any, in the immunopathogenic mechanisms of EAU.

Animals↗

PubMed1989

Preadipocyte stimulating factor in rat serum: evidence for a discrete 63 kDa protein that promotes cell differentiation of rat preadipocytes in primary cultures.

In primary cultures of rat preadipocytes (PA) isolated from epididymal or perirenal depots, rat serum is more effective than other animal sera (fetal calf, newborn calf, human, horse, rabbit, cat, sheep, goat, dog, pig) in promoting adipogenic conversion, biochemical differentiation, and mitogenesis. Only mouse serum is comparable to rat serum. This activity is attributable to a specific growth factor (preadipocyte stimulating factor, PSF). An assay for PSF in rat serum was devised using PA from perirenal fat of 3-month-old Fischer 344 rats grown first to confluence in FCS for 8 days and then for the next 3 days in test serum, followed by measurement of triglyceride (TG) and glycerol-3-phosphate dehydrogenase (GPDH). Rat serum induces dose-dependent rapid cell division, which coincides with accumulation of TG and increase of GPDH; for routine quantitation, TG is assayed. The biochemical characteristics of PSF in serum are as follows: stable at 4 degrees C for up to 1 year; inactivated at 100 degrees C (80% loss, 30 min) but stable at 56 degrees C for 1 hr; stable at pH 2-12; non-dialyzable; completely resistant to pepsin, trypsin, and chymotrypsin but destroyed by pronase and subtilisn; stable to DTT and periodate; and m.w. between 68 kDa (Sephacryl-300) and 58 kDa (Sephacryl-300 in 5 M urea). PSF activity is greater in serum from Wistar than from Fischer 344 rats, while activity of serum from Zucker obese (fa/fa) rats is at least as great as that from Wistar rats and, like serum of rats made obese by feeding a high-fat, high-carbohydrate diet, is not suppressed. PSF activity is not due to insulin, insulin-like growth factor-1 (IGF-1), growth hormone, glucocorticoids, or combinations of these hormones. PSF activity was not seen with a number of growth factors including colony-stimulating factor (CSF-1), GM-CSF, interleukins 1, 2, and 3, neuroleukin, tumor necrosis factor, and others. PSF is distinct from the low molecular weight (4-8 kDa) differentiation factor present in rat serum, FCS, and human serum that promotes the adipogenic conversion and cellular differentiation of 3T3-L1, 3T3-F442A, and Ob17 cells. PSF appears to be a new differentiation factor for rat preadipocytes, has properties suggestive of a highly glycosylated protein, and may be highly species specific.

Adipose Tissue↗

PubMed1994

Selective alterations in macronutrient intake of food-deprived or glucoprivic rats by centrally-administered opioid receptor subtype antagonists in rats.

Two hypotheses have attempted to account for the abilities of opioid agonists and antagonists to respectively stimulate and inhibit food intake in rats. The first suggests that the opioid system selectively modulates fat intake, while the second suggest that the opioid system selectively alters intake of that macronutrient which the animal prefers. The present study evaluated these two hypotheses by examining total intake and individual macronutrient intake in either food-deprived (24 h) rats or rats made glucoprivic with 2-deoxy-D-glucose (2DG, 200 mg/kg, i.p.) following either vehicle treatment, systemic administration of naltrexone or intracerebroventricular administration of either naltrexone, the mu opioid antagonist, beta-funaltrexamine (B-FNA), the mu1 opioid antagonist, naloxonazine, the kappa opioid antagonist, nor-binaltorphamine (Nor-BNI), the delta opioid antagonist, naltrindole or the delta1 opioid antagonist, DALCE. Systemic administration of naltrexone (0.5-5 mg/kg significantly reduced carbohydrate, fat and total intake in deprived rats, and carbohydrate, fat, protein and total intake in glucoprivic rats. Central administration of naltrexone (5-50 micrograms) significantly reduced fat and total intake in both deprived and glucoprivic rats. B-FNA (5-20 micrograms) significantly reduced carbohydrate, fat and total intake in both deprived and glucoprivic rats Naloxonazine (10-100 micrograms) significantly reduced carbohydrate, fat and total intake in deprived rats, but failed to alter 2DC intake. Nor-BNI (5-20 micrograms) significantly reduced fat and total intake in glucoprivic rats, but failed to alter deprivation intake. Neither naltrindole (20 micrograms) nor DALCE (40 micrograms altered intake in deprived or glucoprivic rats. Carbohydrate or fat preference in deprived rats significantly increased the amount of explained variance in the inhibitory actions of central naltrexone, B-FNA and naloxonazine upon deprivation-induced intake. Carbohydrate or fat preference in glucoprivic rats significantly increased the amount of explained variance in the inhibitory action of systemic and central naltrexone, B-FNA, naloxonazine and Nor-BN upon 2-DG hyperphagia. These data are discussed in terms of the contentions that opioids either selectively alter fat intake pe se or selectively alter the preferred macronutrient.

Animals↗

PubMed2001

Defibrinogenating effect of batroxobin (Defibrase) in rats and inhibition of migration of human vascular smooth muscle cells by the plasma of batroxobin-treated rats in vitro.

The defibrinogenating effect of batroxobin (Defibrase) in male Wistar rats and the inhibitory effects of the plasma of batroxobin-treated rats on the migration of human vascular smooth muscle cells (SMCs) were investigated in vitro. At 1 h after a single intravenous injection of 3.0, 10.0 or 30.0 BU/kg batroxobin (ten rats in each group), the fibrinogen levels in the plasma of the rats decreased to 88.3, 66.2 and 16.5%, respectively, of that in the plasma of control saline-treated rats (261.0+/-26.7 mg/dl). When the plasma from the batroxobin-treated rats was added to Dulbecco's modified Eagle's medium at a concentration of 0.2% for a vascular SMC migration assay and incubated in a modified Boyden's chamber system at 37 degrees C for 24 h, significant inhibitory effects on vascular SMC migration were observed in the 10.0 (P<0.05) and 30.0 BU/kg (P<0.01) batroxobin-treated rats. The plasma of batroxobin-treated rats as well as standard rat fibrinogen induced vascular SMC migration in a fibrinogen content-dependent manner except the plasma of the 30.0 BU/kg batroxobin-treated rats. Moreover, the rat serum (0.1 approximately 5.0%) did not show any activity on vascular SMC migration in the present experimental system. These results indicate that the plasma fibrinogen significantly influences vascular SMC migration, and that the inhibitory effect of the plasma of batroxobin-treated rats on vascular SMC migration is related to the defibrinogenating action of batroxobin in vivo.

Animals↗

PubMed1998

Prostaglandin E2 increases bone strength in intact rats and in ovariectomized rats with established osteopenia.

It is well documented that prostaglandin E2 (PGE2) has the ability to stimulate bone formation, improve bone structure, and increase bone mass in intact or osteopenic rat models. However, the effects of PGE2 on the mechanical properties of bone have not been investigated previously. The purpose of our study was to determine the effects of PGE2 on the mechanical strength of bones in rapidly growing, adult, and ovariectomized rat models. In study I, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injections for 30 days to rapidly growing (3-month-old) intact male rats. Compared with controls, PGE2 significantly increased initial maximal load and stiffness of cancellous bone at the distal femoral metaphysis (DFM) as determined by an indentation test. As determined by a compression test, rats treated with PGE2 showed a significant increase in maximal load, and a nonsignificant increase in stiffness in the fifth lumbar vertebral body (L5) when compared with controls. In study II, PGE2 at 3 mg/kg per day, or vehicle, was given by daily subcutaneous injection for 30 days to mature (10-month-old) intact male rats. PGE2 treatment significantly increased initial maximal load and stiffness of the DFM and L5. PGE2 induced a significant increase in maximal load, but not stiffness, in the femoral neck (FN), as determined by a cantilever compression test. There was an increase in maximal load in a three-point bending test at the femoral shaft (FS) although the increase did not achieve statistical significance. No change in stiffness in the FS was found after PGE2 treatment. In study III, 3-month-old female rats were sham-operated or ovariectomized (ovx) for 30 days. Thereafter, PGE, at 1 or 3 mg/kg, or vehicle, were given by daily subcutaneous injection to these rats for 30 days. After 30 and 60 days, ovx induced a significant decrease in initial maximal load and stiffness of cancellous bone at the DFM as compared with sham controls. In ovx rats with established osteopenia, PGE2 at 1 mg/kg per day nonsignificantly increased the initial maximal load and stiffness, whereas, at 3 mg/kg per day, PGE2 completely restored the initial maximal load and stiffness of DFM to sham control levels. Similarly, maximal load and stiffness of L5 decreased significantly in ovx rats compared with sham controls at 30 days postsurgery. PGE2 at 1 mg/kg per day partially restored the maximal load, whereas, at 3 mg/kg per day, it completely restored the maximal load and stiffness of L5 in the established osteopenia, ovx rats. At the FS, PGE2 at 3 mg/kg per day nonsignificantly increased maximal load (+11%) and significantly increased stiffness (+25%) compared with ovx controls. Neither ovx nor PGE2 treatment caused a significant change in the maximal load and stiffness of the FN in this study. These results reveal that PGE2 significantly increased the mechanical strength at various skeletal sites in rapidly growing and mature male rats, although the increase in femoral shafts was not statistically different. Furthermore, PGE2 completely restored mechanical strength to the cancellous bone in ovx rats with established osteopenia.

Animals↗

PubMed1989

Milk-substitutes comparable to rat's milk; their preparation, composition and impact on development and metabolism in the artificially reared rat.

1. Procedures are described to prepare nutritionally adequate rat milk-substitutes by modifying commercially available processed cow's milk, rich in carbohydrate and low in protein and fat compared with rat's milk. 2. Premilk formulas, prepared as intermediates in the preparation of rat milk-substitutes, are rich in protein but low in their concentration of fat, carbohydrate, and minerals when compared with rat's milk. 3. Premilks were supplemented with lactose, vitamins, minerals, fat as oil mixtures, certain amino acids and other constituents to yield rat milk-substitutes which resemble the known composition of rat's milk in their properties and composition. 4. Detailed analyses of the milk-substitutes show them to be comparable to rat's milk in energy content, pH, osmolarity, the concentration of the macronutrients, fat, protein and carbohydrate, and the major minerals. 5. Rat pups were artificially reared from postnatal day 4 or 5 until days 16-18 by fitting them with gastric cannulas through which the milk-substitutes could be infused automatically. 6. The nutritional impact of the milk-substitutes was assessed by a comparison of growth and metabolic characteristics for artificially reared rats with age-matched sucking rats reared by their mother. 7. Indices which were taken to be appropriate included (a) body-weight gain; (b) the concentration in blood of protein, amino acids, ketone bodies, carnitine, glucose, galactose, lactate, insulin, and the electrolytes calcium, sodium, potassium and chloride; (c) the turnover of glucose and 3-hydroxybutyrate; (d) the concentration in brain of protein, cholesterol, cerebroside sulphate and the activities of the enzymes pyruvate dehydrogenase (EC 1.2.4.1), 3-oxo-acid-CoA transferase (EC 2.8.3.5) and acetoacetyl-CoA ligase (EC 6.2.1.16). 8. The studies suggest that milk-substitutes approximating to rat's milk in composition promote acceptable metabolism in the artificially reared rat pup.

Amino Acids↗

PubMed1992

Inhibitory effects of endosulfan on gap junctional intercellular communication in WB-F344 rat liver cells and primary rat hepatocytes.

The chlorinated cyclodiene insecticide endosulfan is a potent inhibitor of gap junctional intercellular communication (GJIC) in vitro, a property shared by many tumour promoters and suggested to indicate an intrinsic tumour-promoting potential. However, endosulfan did not act as a tumour promoter in an altered hepatic foci assay in the rat in vivo, and ambiguous results regarding the carcinogenic potential of endosulfan have emerged from long-term studies in rodents. In the present study the GJIC-inhibitory potentials of the two isomers of endosulfan were investigated in WB-F344 rat liver epithelial cells and primary rat hepatocytes. The results show that both isomers are inhibitors of GJIC. However, beta-endosulfan (ENDO beta) is a more potent inhibitor of GJIC in primary rat hepatocytes than alpha-endosulfan (ENDO alpha), whereas the two isomers were equally potent as inhibitors of GJIC in WB-F344 rat liver cells. In primary rat hepatocytes membrane-permeant dibutyryl cyclic AMP (dB-cAMP) counteracts the inhibitory effect of ENDO beta without affecting the effect of ENDO alpha. However, in WB-F344 rat liver cells dB-cAMP failed to prevent the inhibitory effects of either ENDO alpha or ENDO beta. In addition, studies in WB-F344 rat liver cells show that ENDO alpha beta does not decrease the intracellular cAMP concentration. Thus, it is unlikely that ENDO alpha beta or its isomers and metabolites inhibit GJIC by lowering the intracellular cAMP concentration. Furthermore, comparison of the effective doses and recovery times imply that GJIC in WB-F344 rat liver cells is more sensitive to treatment by ENDO alpha beta, its isomers and metabolites than GJIC in primary rat hepatocytes. Thus, the present results demonstrate significant differences between primary rat hepatocytes and WB-F344 rat liver cells in the response of their GJIC to endosulfan.

1-Methyl-3-isobutylxanthine↗

PubMed2000

Effects of growth hormone on renal renin gene expression in normal rats and rats with myocardial infarction.

BACKGROUND: Published data regarding effects of growth hormone (GH) on the renin system are controversial. The aim of this study therefore was to evaluate the effects of GH on the renin system in normal rats and rats with myocardial infarction (MI). METHODS: Normal rats received 2, 5, or 10 IU GH/kg/day or vehicle subcutaneously for 4 weeks. Furthermore rats with MI were randomized to receive 2 IU GH/kg/day or vehicle for 4 weeks. Subdivision into MI groups (mild, moderate, and large) was by histological determination of infarct size. Renal renin gene expression was assessed by RNAase protection assay and plasma renin activity by radioimmunoassay. In addition, isolated mouse juxtaglomerular cells were exposed to GH for 20 h, and renin secretion rates were assessed. RESULTS: GH treatment in normal rats for 4 weeks increased body weight, and kidney weight to body weight ratio, but did not affect renin secretion and renal renin gene expression. In rats with large MI, renal renin gene expression increased about fourfold, but was unchanged in rats with small and moderate MI as compared to normal rats. In rats with MI, body weight decreased and this decrease was partially reversed by GH treatment. GH treatment did not change renal renin gene expression, and renin secretion in rats with MI. Renin secretion of isolated juxtaglomerular cells was unaffected by GH. CONCLUSIONS: Our study demonstrates that GH treatment has no significant effect on renin secretion and on renal renin gene expression in normal rats and in rats with stimulated renin system due to MI in vivo. In isolated juxtaglomerular cells in vitro, renin secretion was also unaffected by GH.

Animals↗

PubMed1993

An acute model for IgA-mediated glomerular inflammation in rats induced by monoclonal polymeric rat IgA antibodies.

An acute model for IgA-mediated glomerular inflammation in rats was induced by the in situ deposition of IgA directly into the glomerular mesangium. F(ab')2 anti-Thy1 MoAb was used to anchor an antigen, DNP (2,4-dinitrophenol), in the glomeruli of rats. Subsequent infusion of rat polymeric (p-) or monomeric (m-) IgA MoAb with specificity for DNP resulted in mesangial deposition of IgA in both groups of rats. However, acute proteinuria was observed only in p-IgA-treated rats and not in PBS- or m-IgA-treated rats. Immunofluorescence analysis revealed deposition of C3 in an identical pattern to that of IgA in the glomeruli of p-IgA-treated rats. No mesangial deposits of C4 or C1q were seen in these animals. Rats receiving m-IgA or PBS displayed no detectable C3, C4 or C1q deposition. The amount of proteinuria in p-IgA-treated rats was related to the amount of deposited C3. The presence of intraglomerular monocytes was only observed 2 days after p-IgA injection. By light microscopy, aneurysm formation, mesangial hypercellularity and matrix expansion were seen only in p-IgA-treated rats. However, by 37 days post-injection complete resolution of the lesions was observed. No histological renal changes were observed in PBS- or m-IgA-treated rats. In conclusion, an acute form of IgA-mediated nephritis in rats was induced by p-IgA but not by m-IgA. This reproducible model provides a basis for further study into the mechanisms of IgA-mediated glomerular inflammation.

2,4-Dinitrophenol↗

PubMed1982

Transplantation and metastasis of NB rat prostate neoplasia in congenitally athymic (nude) mice, nude mice treated with antilymphocyte sera and congenitally athymic rats.

The androgen-dependent NB rat prostate adenocarcinoma 2PR 129 and the autonomous tumor 102PR were transplanted into groups of both male and female nude mice, nude rats, and NB rats. Significant growth of the 2PR 129 tumor at the site of transplantation was noted in male but not female nude mice, nude rats or NB rats. Indeed, successful transplantation of 2PR 129 was not achieved in female nude mice even with usage of antilymphocyte sera. In contrast, the autonomous tumor 102PR grew at a significant rate at the local site of transplantation in mice and rats of both sexes. Although significant tumor masses were found at the injection site of male nude mice transplanted with 2PR 129 and in both male and female nude mice injected with 102PR, metastasis was not found. Further, antilymphocyte sera increased the rate of growth of both tumors in nude mice but did not change the apparent metastatic potential. Nonetheless, metastasis was readily observed in male nude rats transplanted with 2PR 129 and nude rats of both sexes transplanted with 102PR. Such metastatic lesions of nude rats were found in lung, liver and kidney with a similar frequency and histologic profile as NB rats. These results suggest that the nude rat, at least for this rat tumor system, is a more versatile and biologically relevant system than nude mice and further cautions against use of xenotransplants as models of tumor natural history. Moreover, it suggests the possible relationship between host recognition of species-determined genetic loci and metastatic potential.

Animals↗

PubMed1991

Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats.

There were two related objectives to this study. The first was to determine the influence of relaxin on development of the mammary apparatus (nipples and glands) during the second half of pregnancy. The second was to determine whether the relaxin-dependent development of the mammary apparatus was required for normal postpartum lactational performance. Both objectives were accomplished by neutralizing endogenous relaxin throughout the second half of pregnancy with a monoclonal antibody specific for rat relaxin (MCA1). MCA1 was administered iv to rats daily from days 12-22 of pregnancy. On day 22 the morphology of the mammary apparatus of MCA1-treated rats differed from that of controls; nipples were dramatically smaller, collagen fibers had significantly greater mean density and consistency, and elastin fibers had greater mean density, length, and interdigitation. In addition, the mean number of alveoli surrounding lactiferous ducts was significantly smaller in MCA1-treated rats than in controls. There were no differences between MCA1-treated rats and controls in the mean thickness of connective tissue surrounding ducts, the height or density of luminal cells lining lactiferous ducts, or the sizes of either adipocytes or arteries. To examine lactational performance, MCA1-treated and control rats were cesarean sectioned between 2100-2400 h on day 22 of pregnancy and given foster pups born of untreated intact donors. Although both MCA1-treated rats and control rats exhibited a high incidence of maternal behavior after cesarean delivery, mean pup weight and incidence of live pups declined markedly during days 1-5 of fosterage in MCA1-treated rats compared to controls. Furthermore, unlike controls, there was no observable postpartum nipple development in MCA1-treated rats by day 5 of fosterage. Mammary glands obtained from MCA1-treated rats on day 5 of fosterage had markedly lower mean weight than controls. This study demonstrates that passive immunization of endogenous relaxin throughout the second half of pregnancy disrupts development of the nipples and mammary glands in the rat. Moreover, it establishes that relaxin's effects on the development of the mammary apparatus during pregnancy are essential for growth and survival of the young during lactation.

Animals↗

PubMed1996

The diabetic state increases the activity but not the number of peritoneal macrophages in the GK rat promoting the tube formation of cultured endothelial cells in rat aorta.

The influence of the diabetic state on the number and activity of intraperitoneal macrophages was investigated in the GK rat. This rat is a model of non-insulin-dependent diabetes mellitus and was established from the normal Wistar rat. The cell number of a macrophages preparation in diabetic GK rats (10-15 weeks of age) did not differ from that in normal Wistar rats (9-10 weeks of age). The co-cultured macrophages in diabetic GK rats (9-12 weeks of age) significantly increased the tube formation of aortic endothelial cells (EC) compared with that in age-matched Wistar rats. The conditioned medium obtained from a culture of macrophages from GK rats also increased tube formation more than that from a culture of macrophages from Wistar rats. The effect of macrophages in the GK rat was not influenced by interferon-gamma (160 and 460 pM), but macrophages in normal rats were activated by these concentrations of interferon-gamma. In conclusion, the diabetic state increased the activity but not the number of macrophages in the GK rat, to stimulate tube formation of EC. The tube-forming effect of macrophages in the diabetic state may depend on released factors which differ from that of normal macrophages.

Animals↗

PubMed2000

Thiazolidinediones exert different effects on insulin resistance between dexamethasone-treated rats and wistar fatty rats.

We determined the in vivo effects of thiazolidinediones on insulin resistance induced by dexamethasone (Dx), as well as that observed in Wistar fatty (WF) rats, using glucose clamp technique to measure glucose uptake (Gu) and percent suppression of hepatic glucose output (HGOsup) to evaluate insulin resistance. Male Wistar rats were treated with Dx (0.5 mg/kg/day) for 7 days. Pioglitazone (P) or troglitazone (T) was coadministered orally for the same period at 10 and 200 mg/kg/day, respectively. Two, 5 and 20 mU/kg/min. of insulin infusion rates (IIR) were used. The Gu levels at clamp steady-state at IIR20 in rats treated with Dx (16.4 +/- 4.7 mg/kg/min.) were significantly lower than those in control rats (36.3 +/- 2.4). The Gu levels at the same IIR in rats coadminstered with P (19.6 +/- 3.2) and T (21.3 +/- 6.3) were slightly but significantly higher than that in rat treated with Dx. HGOsup at IIR5 in control rats (97.5 +/- 6.2%) was decreased by Dx treatment (52.1+/- 31.3). This decrease was slightly but significantly ameliorated by addition of T (78.3 +/- 12.2). The Gu levels at IIR20 in WF rats (6.6 +/- 0.9) were decreased significantly from that in lean littermates of WF (WL) rats (25.8 +/- 2.1). This attenuation of Gu increase was completely ameliorated with administration of P (20.9+/-2.8) or T (22.2+/-3.9). The HGOsup at IIR20 in WF rats (17.4 +/- 11.2) was significantly decreased from that in WL rats. Administration of P or T ameliorated this decrease completely. These results indicate that Dx induces insulin resistance by mechanisms different from those in WF rat, hence thiazolidinedione administration can be only partially useful to treat insulin resistance induced by Dx.

Animals↗

PubMed2005

Susceptibility of newborn rats to hepatotoxicity of 1,3-dibromopropane and 1,1,2,2-tetrabromoethane, compared with young rats.

Newborn rat studies were conducted with oral administration of 1,3-dibromopropane (DBP) and 1,1,2,2-tetrabromoethane (TBE) from postnatal Days 4 to 21 to allow comparison of NOAELs and unequivocally toxic levels with those from 28-day young rat studies starting at 5-6 weeks of age. The unequivocally toxic level was estimated by our specified criteria, requiring simultaneous change of organ weights, histopathology, some biochemical parameters and body weights, because in this study only hypertrophy of hepatocytes was observed as a major histopathological change. DBP caused centrilobular hypertrophy of hepatocytes with alteration in biochemical parameters, as well as lowering of body weights, regardless of sex, in both newborn and young rats. NOAELs and unequivocally toxic levels were considered to be 50 and 150 mg/kg/day in newborn rats and 10 and 250 mg/kg/day in young rats, respectively. In the newborn rat study of TBE, some hepatic effects observed at the top dose of 50 mg/kg were not considered adverse because of the lack of histopathological changes. Significant lowering of body weight was noted at 200 mg/kg in the dose-finding study but histopathological data were not available. In the young rat study, there was no definite toxicity at 6 mg/kg and hypertrophic changes in liver and thyroids without body weight change occurred at 200 mg/kg. There were no clear sex differences in both the newborn and young rat studies. NOAELs were considered to be 50 and 6 mg/kg/day in newborn and young rats, respectively, but unequivocally toxic levels for both rats could not be estimated. Abnormalities of external and sexual development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the target organ of DBP and TBE is the liver in both newborn and young rats, and that while the doses at which toxic signs began to appear are higher in newborn rats, those causing clear toxicity may be paradoxically lower in the newborn case.

Age Factors↗

PubMed1983

Glucosylated and normal human of rat albumin do not bind to renal basement membranes of diabetic and control rats.

Hyperglucosylated and normal human and rat albumin were injected intravenously into control and streptozotocin-induced diabetic rats. Binding of injected human albumin to renal basement membranes was not observed by immunofluorescence microscopy in the diabetic or control rats irrespective of the form of injected albumin. However, human albumin was found as tubular droplets in both the control and diabetic rats injected with either form of albumin. Spontaneous binding of endogenous rat albumin was observed in a linear pattern on diabetic rat glomerular basement membranes (GBM), but not in the GBM of control rats. No appreciable differences in the intensity of staining for rat albumin was observed in diabetic rats injected with either glucosylated or normal rat albumin. Similarly, no binding of rat albumin to the GBM was observed in control rats irrespective of the type of albumin injected. These studies demonstrate that binding of albumin to renal basement membranes is not dependent on glucosylation.

Animals↗