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PubMed1995

A comparative study of functional 5-HT4 receptors in human colon, rat oesophagus and rat ileum.

1. The pharmacological properties of 5-hydroxytryptamine (5-HT), the 5-HT4 receptor agonists, DAU 6236 and SC 53116 and the 5-HT4 receptor antagonist, GR 1130808, were studied in the rat oesophagus, rat ileum and human colon. 2. 5-HT relaxed the longitudinal muscle of the rat oesophagus and rat ileum and the circular muscle of the human colon. Absolute values of relaxation were measured and showed the order of the maximum responses, rat oesophagus >> human colon > rat ileum with EC50 values of 189 +/- 15 nM, 157 +/- 4 nM, 306 +/- 72 nM, respectively. 5-HT also inhibited the spontaneous contractions of the human colon with an EC50 value of 119 +/- 1 nM. The effect of 5-HT on the human colon was not affected by methysergide (10 microM) or ondansetron (1 microM). 3. The use of the uptake and metabolism inhibitors, cocaine (30 microM) and pargyline (100 microM), did not increase the potency of 5-HT in the rat oesophagus or human colon. In the rat oesophagus, cocaine (30 microM) produced a reduction in carbachol-induced tone of 22.2 +/- 0.6% and reduced the 5-HT maximum effect by 52.0 +/- 0.4%. 4. The compounds, DAU 6236 and SC 53116, showed a different pattern of potencies and efficacies in the rat oesophagus, rat ileum and human colon compared to 5-HT. DAU 6236 relaxed the human colonic circular muscle with an EC50 value of 129 +/- 16 nM but its efficacy was less than that of 5-HT. DAU 6236 (1 microM) also antagonized the 5-HT-induced relaxation of the human colon with a dose-ratio of 9.9. In the rat oesophagus and rat ileum, DAU 6236 was inactive in the majority of tissues. In the minority of oesophagus tissues that did respond the EC50 value was 1.2 +/- 0.7 microM. DAU 6236 also antagonized the effect of 5-HT in the rat oesophagus in a non-surmountable fashion. SC 53116 relaxed the rat oesophagus with an EC50 value of 91 +/- 4 nM, with an efficacy less than that observed to 5-HT; however, at 200 nM it did not antagonize the 5-HT-induced relaxation of the rat oesophagus. SC 53116 showed no agonist activity in the rat ileum and human colon, but at 1 microM it did antagonize the effect of 5-HT in the human colon with a dose-ratio of 11.3 +/- 0.3. 5. GR 113808 competitively antagonized the 5-HT4 receptor-mediated relaxation of the rat oesophagus with a pA2 value of 8.59 (8.18-9.00) against 5-HT and 9.05 (8.79-9.31) against SC 53116. GR 113808(0.01 microM) also antagonized the 5-HT-induced relaxation of human colonic circular muscle with an apparent pA2 value of 9.02 +/- 0.12. However at 1 microM the apparent pA2 value was significantly lower than that measured at 0.01 and 0.1 microM. GR 113808 (0.01 microM) antagonized the 5-HT4 receptor-mediated relaxation of the rat ileum with an apparent pA2 value of 9.30 +/- 0.21.6. In conclusion, these studies have shown that the human colon, rat oesophagus and rat ileum contain functional 5-HT4 receptors. However, the 5-HT4 receptor agonists displayed differences in these tissues making it necessary to be cautious when extrapolating from animal to human tissue. This emphasizes the importance of the use of human tissue in the development of therapeutic drugs.

Animals↗
PubMed1993

Structure of the vitreoretinal border region in spontaneously hypertensive rats (SHR rats).

The morphology of the vitreoretinal border region, also termed the inner limiting membrane, was studied in spontaneously hypertensive rats (SHR rats), in Wistar Kyoto rats (WKY rats), and in Buffalo rats (BUF rats). The region was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) in order to visualize a possible increase in thickness with raised arterial pressure. The median thickness of the lamina densa in TEM in the three groups varied from 34 to 68 nm. In hypertensive SHR rats the lamina densa showed thickening up to the 10th month and was unchanged thereafter. The same pattern was shown in WKY rats, although the thickness increased also after the tenth month in these controls. In BUF rats, however, the lamina densa decreased in thickness with age. The median thickness of the whole vitreoretinal border region varied between: SHR rats: 42 and 84 nm (SEM) and 51 and 127 nm (TEM); WKY rats: 84 nm (SEM) and 51 and 68 nm (TEM); BUF rats: 42 nm (SEM) and 34 and 68 nm (TEM). SHR rats showed in SEM an increase in thickness with age. In TEM, however, only one very old hypertensive rat had a thickened vitreoretinal border region. In WKY rats both SEM and TEM showed an increase in thickness with age, whereas BUF rats showed a decrease. Fundus photographs disclosed narrow, straight and irregular retinal arterioles in hypertensive SHR rats. Light microscopy of older SHR rats demonstrated retinal degeneration from the outer photoreceptor layer to the inner nuclear layer. This was also found in some of the older WKY rats.

Animals↗
PubMed2005

Remodelling of mesenteric arteries in genetically hypertensive rats cross-fostered from birth to normotensive Wistar rats.

1. The effects of cross-fostering genetically hypertensive (GH) with normotensive (N) Wistar rats on the structure of mesenteric resistance arteries (MRA) in young (6 week old) and adult (18 week old) rats were investigated to see whether the abnormal remodelling known to exist in GH rats could be prevented by changing the maternal environment. 2. Genetically hypertensive and normotensive rat pups were reared either by their natural mothers or a foster mother of the opposite strain (NX and GHX) with fostering done within 24 h of birth. 3. Blood pressure (BP) was measured from age 6-18 weeks; at 6 and 18 weeks MRA structure was assessed. 4. At the time of death, intra-arterial mean BP was measured (via the femoral artery), after which MRA were fixed by perfusion (at the systolic BP of the rat) via the abdominal aorta, first with 75% Tyrode's solution containing heparin and papaverine, followed by 2% glutaraldehyde in 75% Tyrode's solution. Arteries were dissected out, processed and embedded in Technovit (Heraeus Kulzer, Werheim, Germany) and serial sections were cut and stained with Giemsa. 5. Stereological techniques were used to determine media width, lumen diameter and medial cross-sectional area (CSA); in addition, the ratio of media width to lumen diameter was calculated. Smooth muscle cell density was also calculated. 6. In MRA from 6-week-old rats, GH rats compared with N rats had increased media width and CSA and an increased ratio of media width to lumen diameter. 7. There were no significant changes in structure in the GHX group compared with GH rats. The NX group compared with N rats had increased media width and CSA and lumen diameter, but no change in the ratio of media width to lumen diameter. Smooth muscle cell density, reduced in GH compared with N rats, was increased (P < 0.001) in the NX group, but not changed in the GHX group compared with GH rats. 8. In 18-week-old GH rats compared with N rats, the MRA had a decreased media width and medial CSA and smaller lumen diameter, but there was no change in the ratio of media width to lumen diameter. 9. In the GHX group compared with GH rats, media width and CSA were reduced; in the NX group compared with N rats, media width was increased, lumen decreased and the ratio of media width to lumen diameter increased. Smooth muscle cell density was increased (P < 0.001) in the GHX group, but not in the NX group. 10. Changing the maternal environment significantly affected BP in GHX and NX groups up to 9-10 weeks of age but, in adult rats, the BP differences were no longer present. Thus, structural changes were seen at 6 weeks of age in MRA from NX rats and also at 18 weeks in GHX and NX rats (even though the BP differences were no longer significant); structural remodelling occurred independently of BP.

Animal Husbandry↗
PubMed1983

A quantitative immunocytochemical study of the luteinizing hormone and follicle-stimulating hormone cells in the adenohypophysis of adult male rats and adult female rats throughout the estrous cycle.

We investigated whether 1) the absolute or the relative numbers of LH and FSH cells change during the rat estrous cycle, 2) the percentages of gonadotrophs that contain LH and/or FSH change during the estrous cycle, and 3) gonadotrophs change in size during the rat estrous cycle. Groups of four female rats were decapitated at one of five different times during the estrous cycle. Four male rats were also decapitated. Serum concentrations of LH and FSH were determined by RIA. Paired horizontal flip-flopped or nonflipped paraffin sections were mounted from the dorsal, middle, and ventral portions of each pituitary gland. In each pair of sections, one was stained with a-rat LH-S4 and the other with a-rat FSH-S7 by the unlabeled antibody peroxidase-antiperoxidase method. All immunoreactive cells were counted. Photographs were taken from randomly chosen corresponding areas, and the cells were individually matched to determine the percentage that contained one or both hormones. Correction factors had to be used because in paired flip-flopped or nonflipped sections stained with the same antibody (a-rat LH-S4), not all of the stained cells found in one section were found in the other section. The absolute numbers of LH and FSH cells did not change throughout the estrous cycle. The ratio of LH cells to FSH cells in the pars distalis of female rats was also constant throughout the estrous cycle. In female rats, 75.2% of LH cells also contained FSH, while 99.4% of FSH cells also contained LH. In the male rats, 88.6% of LH cells also contained FSH, while 98.6% of FSH cells also contained LH. Similar results were obtained in paired flip-flopped sections stained with a-rat LH beta and a-rat FSH beta. Sequential staining of additional individual tissue sections with a-rat LH-S4 and then a-rat FHS-S7 or vice versa revealed the following. Staining of LH-stained tissue for FSH revealed less than 1% new cells, but staining of FSH-stained tissue for LH revealed a 8.7% increase in gonadotrophs in males and a 25.4% increase in females. The gonadotrophs in female rats did not change in size during the estrous cycle and were significantly smaller than the gonadotrophs in male rats. The results suggest that in normal adult rats: 1) virtually all FSH-containing cells contain LH, 2) about 25% of the gonadotrophs in females and about 11% of the gonadotrophs in males contain LH but not FSH, 3) the number of cells containing LH or those containing LH and FSH does not change during the estrous cycle, 4) gonadotrophs in female rats do not change in size during the estrous cycle and are smaller than the gonadotrophs in male rats, and 5) FSH release during the early morning of estrus, when the serum FSH concentration is elevated and the serum LH concentration is low, occurs from cells that contain both LH and FSH.

Animals↗
PubMed1998

One Lewis rat with homozygous defect of the serine proteinase inhibitor 2 (Spi-2) gene and two Lewis rats with heterozygous Spi-2 gene defect.

One LEW/Sea (Lewis) strain rat, Rat P-1, had a homozygous defect of the serine proteinase inhibitor 2 (Spi-2) gene coding for serpin contrapsin. A sibling, Rat P-2, and a rat of the same strain, Rat P-3, had a heterozygous Spi-2 gene defect. The homozygous Spi-2 gene defect of Rat P-1 was diagnosed by the polymerase chain reaction (PCR). The presence of an alpha 1-proteinase inhibitor (PI) gene was confirmed by PCR in all 3 rats. Rat P-1 and the sibling Rat P-2 were sacrificed at 7 days of age because of the severe weakness of Rat P-1, although Rat P-2 appeared healthy. Rat P-3 was sacrificed at 40 days of age because of the severe weakness. Rat P-1's hepatocytes with the homozygous Spi-2 gene defect showed massive accumulation of polymerized alpha 1-antitrypsin (AT) in the rough endoplasmic reticulum (RER). Large, defined accumulations of alpha 1-AT were not found in the heterozygous rats with the Spi-2 gene defects. Nephrogenesis was retarded in all 3 rats, especially in Rat P-1. Extramedullary hematopoiesis was absent in the liver of Rat P-1 and suppressed in the spleen of Rat P-3, where activated alpha 1-AT synthesis was found. Atelectasis mixed with hyperinflated lung regions and thymic apoptosis were observed in the 2 weak rats. As Spi-2 gene defect had some similar clinical points to platelet-derived growth factor (PDGF) deficiency, it was suggested that increased vasoconstrictor peptide hormones competed with PDGF for binding to the PDGF-receptors.

Animals↗
PubMed2003

The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats.

BACKGROUND: Elevated plant sterol accumulation has been reported in the spontaneously hypertensive rat (SHR), the stroke-prone spontaneously hypertensive rat (SHRSP) and the Wistar-Kyoto (WKY) rat. Additionally, a blood pressure quantitative trait locus (QTL) has been mapped to rat chromosome 6 in a New Zealand genetically hypertensive rat strain (GH rat). ABCG5 and ABCG8 (encoding sterolin-1 and sterolin-2 respectively) have been shown to be responsible for causing sitosterolemia in humans. These genes are organized in a head-to-head configuration at the STSL locus on human chromosome 2p21. METHODS: To investigate whether mutations in Abcg5 or Abcg8 exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of Abcg5 and Abcg8 genes in these strains. We isolated the rat cDNAs for these genes and characterized the genomic structure and tissue expression patterns, using standard molecular biology techniques and FISH for chromosomal assignments. RESULTS: Both rat Abcg5 and Abcg8 genes map to chromosome band 6q12. These genes span ~40 kb and contain 13 exons and 12 introns each, in a pattern identical to that of the STSL loci in mouse and man. Both Abcg5 and Abcg8 were expressed only in liver and intestine. Analyses of DNA from SHR, SHRSP, GH, WKY, Wistar, Wistar King A (WKA) and Brown Norway (BN) rat strains revealed a homozygous G to T substitution at nucleotide 1754, resulting in the coding change Gly583Cys in sterolin-1 only in rats that are both sitosterolemic and hypertensive (SHR, SHRSP and WKY). CONCLUSIONS: The rat STSL locus maps to chromosome 6q12. A non-synonymous mutation in Abcg5, Gly583Cys, results in sitosterolemia in rat strains that are also hypertensive (WKY, SHR and SHRSP). Those rat strains that are hypertensive, but not sitosterolemic (e.g. GH rat) do not have mutations in Abcg5 or Abcg8. This mutation allows for expression and apparent apical targeting of Abcg5 protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.

Animals↗
PubMed1998

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats.

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.

Administration, Oral↗
PubMed1984

Prolactin receptors in the hypoprolactinemic male rat (IPL nude rat): measurement in testis and induction in liver.

In order to evaluate the importance of PRL in the regulation of its own receptors, characteristics of specific binding for PRL were studied in membrane preparations from liver and testis of a new hypoprolactinemic male rat, the IPL nude male rat, and this was compared to those found for normal male rats. Under basal conditions, hepatic specific binding of PRL in IPL nude rats, as in normal rats was not detectable. Following castration, it became detectable in both groups, and was 6.99 +/- 0.78% and 6.34 +/- 0.87% for IPL nude and normal rats respectively. Under such conditions, the apparent affinity constant (Ka) and the binding capacity (Nmax) obtained were also similar for both groups (Ka) = 1.36 +/- 0.14.10(9) M-1, Nmax = 102 +/- 14 fmol/mg protein in IPL and Ka = 1.34 +/- 0.28.10(9) M-1, Nmax = 97 +/- 11 fmol/mg protein in normal rats) although a decrease in serum levels of PRL was observed in both groups. This decrease was greater for IPL nude rats. As already reported, estradiol injection following castration was able to further increase the percentage of PRL hepatic specific binding (4 times). Furthermore, our results demonstrated that the affinity constant was significantly increased by estradiol injection in both groups. On the other hand, for testicular PRL binding characteristics, a statistically significant difference was found between IPL nude and normal rats. The PRL specific binding percentage was 7.01 +/- 0.85% for the IPL nude rat and 10.07 +/- 0.64% for the normal rat. By Scatchard analysis, the Ka of testicular membranes for labelled oPRL was similar in both groups, while the capacity differed (Nmax = 9.82 +/- 1.25 fmol/mg protein for IPL nude rat and Nmax = 26.06 +/- 4.39 fmol/mg protein for normal rats). These data established the fact that IPL nude male rats presented characteristics of hepatic PRL receptors similar to those of normal rats, while their testicular oPRL binding significantly differed. These findings therefore suggest that in genetic hypoprolactinemic rats (IPL nude rats), PRL might be more involved in the regulation of testicular PRL receptors than in that of hepatic receptors.

Animals↗
PubMed1995

Spatial learning impairment in aged rats: comparing between aged basal forebrain lesioned and normal aged rats.

Normal aged rats (26 months) displayed significant impairments in learning the Morris water maze task as compared with young adult rats (3 months). The learning deficits of aged basal forebrain (BF)-lesioned rats (26 months; ethylcholine aziridinium ion was injected into the bilateral basal forebrain at 3 months age) were more severe than those of normal aged rats. Choline acetyltransferase (ChAT) in the frontal cortex of aged BF-lesioned rats activity was significantly reduced, but not in normal aged rats which level was almost the same as that in young adult rats. Histological examination showed that cholinergic fibers (acetylcholinesterase staining) in the frontal cortex reduced in aged BF-lesioned rats, but not in normal aged rats. The number of binding sites (Bmax) for [3H]vesamicol, a ligand for the vesicular acetylcholine transporter, in the frontal cortex of normal aged rats was significantly less than that in young adult rats, while the Bmax of aged BF-lesioned rats was higher than that of normal aged rats. The levels of monoamines and their metabolites in the frontal cortex and striatum but not hippocampus of aged BF-lesioned rats were markedly reduced as compared with those of normal aged and young adult rats. These results taken together indicate that normal aged and aged BF-lesioned rats exhibit learning deficits and that the differences of the severity of spatial learning deficits between normal aged and aged BF-lesioned rats may be due to, at least in part, the different properties of cathecolaminergic, serotonergic and cholinergic dysfunctions in the discrete brain sites.

Acetylcholinesterase↗
PubMed2004

Corticotropin-releasing factor gene expression is down-regulated in the central nucleus of the amygdala of alcohol-preferring rats which exhibit high anxiety: a comparison between rat lines selectively bred for high and low alcohol preference.

The role of amygdaloid corticotropin-releasing factor (CRF) in alcoholism is not clear. Alcohol-preferring (P) rats and high alcohol-drinking (HAD) rats are selectively bred for high alcohol preference, and have been considered suitable animal models for studying alcoholism. The CRF neurons in the central nucleus of the amygdala (CeA) of P rats and HAD rats were studied in comparison with those of their respective counterparts, namely, alcohol-nonpreferring (NP) rats and low alcohol-drinking (LAD) rats. Specifically, CRF-immunoreactivity (ir) in the CeA and paraventricular hypothalamic nucleus (PVN) was assessed using radioimmunohistochemical (RIH) assay in alcohol-naive P/NP rats, and HAD/LAD rats. Furthermore, CRF mRNA was examined using in situ hybridization in the CeA of P/NP rats. Anxiety levels were also evaluated using an elevated plus maze. Results of the present study showed that CRF-ir was significantly lower in the CeA of P rats than NP rats. Moreover, CRF mRNA in the CeA was also much lower in P rats than NP rats. Such differences were not seen in the PVN. Interestingly, those P rats exhibited higher anxiety than NP rats. In contrary, there were no innate differences of CRF-ir in both the CeA and PVN between HAD and LAD rats whose anxiety levels were similar. This study is consistent with the literature showing CRF knockout (KO) induces alcohol drinking, and central administrations of CRF reduce alcohol intake. Collectively, the present study suggests that reduced CRF gene expression in the CeA of P rats is associated with their alcohol preference and anxiety.

Alcohol Drinking↗
PubMed1998

Inhibition of early-phase exogenous and endogenous liver carcinogenesis in transgenic rats harboring a rat glutathione S-transferase placental form gene.

Hepatocarcinogenesis initiated with N-nitrosodiethylamine (DEN) and that initiated by feeding of a choline-deficient, L-amino acid-defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S-transferase placental form (GST-P) gene (GST-P-Tg rats) and non-transgenic (N-Tg) rats. Eight-week-old GST-P-Tg and N-Tg rats were administered DEN intraperitoneally at 100 mg/kg body weight, subjected to a selection procedure with 2-acetylaminofluorene and CCl4, and killed at the end of weeks 5 and 12. Other groups were fed the CDAA diet for 12 weeks and killed. Five weeks after the DEN treatment, numbers and sizes of gamma-glutamyltransferase (GGT)- or GST-P-positive lesions and 8-hydroxyguanine (8-OHG) levels in the livers were significantly less in GST-P-Tg rats than in N-Tg rats. The lesion numbers were unchanged between the ends of weeks 5 and 12 in GST-P-Tg rats, but decreased in N-Tg rats. The lesion sizes were increased in GST-P-Tg rats, but unchanged in N-Tg rats. While the proliferating cell nuclear antigen labeling indices (PCNA L.I.) in and surrounding the lesions were decreased, more prominently in GST-P-Tg rats than in N-Tg rats, the 8-OHG levels were also decreased but similarly in both cases. After 12 weeks on the CDAA diet, the lesion incidences, numbers and sizes, 8-OHG levels, PCNA L.I. in and surrounding the lesions, and liver injury were significantly less in GST-P-Tg rats than in N-Tg rats. These results indicate that insertion of a rat GST-P transgene alters the early phase of exogenous and endogenous rat hepatocarcinogenesis, presumably due to enhanced detoxification by GST-P expressed both transiently during the initiation and chronically in the altered hepatocyte populations.

Animals↗
PubMed1999

Reduced T cell response in carcinogen-sensitive Donryu rats compared with carcinogen-resistant DRH rats.

Carcinogen-resistant DRH rats were developed from carcinogen-sensitive Donryu rats, which showed a high incidence of hepatic tumors when they were exposed to 3'-methyl-4-dimethyl-amino-azobenzene (3'-MeDAB4) or other aminoazo hepatocarcinogens. In order to study the mechanism of the difference of carcinogenesis, we studied the immunological competence of Donryu rats compared with that of DRH rats. Anti-keyhole limpet hemocyanin (KLH) antibody and KLH-specific delayed hypersensitivity (DTH) responses after immunization with KLH were reduced in Donryu rats compared with DRH rats. Proliferative responses of spleen cells to KLH and nonspecific mitogens such as conconavalin A (Con A) and phytohemagglutinin (PHA) were significantly lower in Donryu rats than in DRH rats. Upon the cross-linking of T cell receptor (TCR) complex using anti-CD3 monoclonal antibody (Mab), spleen cells from Donryu rats proliferated poorly. Two other strains of rats, SD and Wistar, exhibited high responsiveness, comparable to that of DRH rats, indicating that the responsiveness of Donryu rats was impaired. The production of interleukin-2 (IL-2) upon stimulation with Con A and the responsiveness of Con A blasts to exogenous IL-2 were also attenuated in Donryu rats. In contrast to T cell responsiveness, natural killer (NK) cell activity of spleen was increased in Donryu rats. Flow cytometric analysis revealed that the expression of CD4 and CD8 on T cells was decreased in Donryu rats, though the expression of other T cell markers such as CD2, CD3 and CD5 was not different. These results indicate that Donryu rats, which have been used in many years for cancer research in Japan, have impaired immunological surveillance mechanisms. This is likely to be one of the factors accounting for the high sensitivity to chemical carcinogens and the high susceptibility to transplanted tumor cells of Donryu rats.

Animals↗
PubMed2004

Expression of regucalcin in rat bone marrow cells: involvement of osteoclastic bone resorption in regucalcin transgenic rats.

The expression of regucalcin in rat bone marrow cells was investigated. The expression of regucalcin mRNA in the bone marrow cells of normal (wild-type) rat was shown by using reverse transcription-polymerase chain reaction (RT-PCR) with a specific primer of regucalcin cDNA. Regucalcin protein was detected in the marrow cells of normal (wild-type) rats using Western blot analysis. Regucalcin levels were significantly increased in the marrow cells of regucalcin transgenic (TG) male and female rats with increasing age (5-36 weeks old). When the marrow cells obtained from normal or regucalcin TG rats (36-week-old) were cultured for 7 days, the number of tartrate-resistant acid phosphatase (TRACP), a marker enzyme of osteoclasts, positive multinucleated cells (MNCs) were significantly increased in the marrow culture of regucalcin TG rats. This increase was remarkable in female TG rats as compared with male TG rats. The effect of parathyroid hormone [human PTH (1-34); 10(-7) M] or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; 10(-7) M] in stimulating TRACP-positive MNCs formation was significantly enhanced in female regucalcin TG rats. Calcium content in the femoral-diaphyseal and -meta-physeal tissues was significantly decreased in regucalcin TG rats (10- or 36-week-old). This decrease was greater in female than in male. Femoral-metaphyseal deoxyribonucleic acid (DNA) content was significantly reduced in regucalcin TG male and female rats (36-week-old). Moreover, serum inorganic phosphorus, triglyceride, HDL-cholesterol, and albumin concentrations were significantly increased in regucalcin TG female rats (36-week-old), while serum calcium, zinc, and glucose concentrations were not significantly altered in TG male and female rats. In TG male rats, serum triglyceride and HDL-cholesterol concentrations were significantly raised. This study demonstrates that regucalcin is expressed in rat bone marrow cells, and that osteoclastic bone resorption is stimulated in regucalcin TG rats with increasing age. Also, regucalcin TG aged rats was found to induce serum metabolic disorder.

Animals↗
PubMed1994

Use of glycated hemoglobin to assess Glycemic control in Wistar diabetic fatty rats and Zucker fatty rats.

The Wistar Diabetic Fatty rat (WDF fafa) is a congenic strain of the Wistar Kyoto rat. Studies using blood glucose reveal that only fatty male (not female) WDF rats spontaneously develop hyperglycemia when fed a stock diet. Blood glucose values have not provided consistent results for evaluation of glycemic status in fatty male WDF rats. Zucker fatty (fafa) rats, while sharing the fa gene and the development of hyperinsulinemia and hyperlipemia, do not spontaneously become hyperglycemic. In order to examine strain differences and the effects of age on long-term average glycemic status in WDF and Zucker rats, glycated hemoglobin (GHb) was analyzed. Glycated hemoglobin was measured in male lean and obese WDF and Zucker rats at 2, 3, 6, and 12 months of age. Nonfasted plasma glucose was measured in male lean and obese WDF rats at 2, 3, 6, and 12 months of age and in lean and obese Zucker rats at 3, 6, and 12 months of age. Plasma insulin was measured in lean and obese WDF and Zucker rats at 3, 6, and 12 months of age. Obese WDF rats had significantly elevated GHb compared to lean controls at 3, 6, and 12 months of age. Glycated hemoglobin was substantially above the normal range (3.8-6.5%) at 3 months of age (14.1%). Glycated hemoglobin significantly declined in the obese WDF rats between 6 and 12 months of age. Nonfasted plasma glucose was significantly elevated in the obese WDF rats at 3 months (14.1 +/- 2.1 mM/L) and 6 months of age (16.2 +/- 2.3 mM/L) compared to lean controls. At 12 months of age there was no difference in plasma glucose between obese and lean WDF rats. Obese and lean Zucker rats had similar levels of GHb and plasma glucose at all ages. In conclusion, GHb provides more integrated data for classifying disease status of WDF rats and evaluation of potential long-term complications associated with hyperglycemia.

Age Factors↗
PubMed1992

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.

Animals↗
PubMed1996

Production of a monoclonal dinitrophenyl-specific rat IgE and establishment of an IgE capture ELISA for estimating the concentration of rat IgE antibodies to dinitrophenyl-Ascaris suum.

A hybridoma producing monoclonal rat IgE antibodies of antidinitrophenyl (anti-DNP) specificity was generated by fusion of Sp2/0-Ag 14 (SP2) mouse myeloma cells and spleen cells from a DNP-Ascaris-sensitized Brown-Norway rat. Subsequently, the supernatant of the hybridoma (FE-3) was applied to an affinity column of DNP-bovine serum albumin-Sepharose 4B. The adsorbed protein fraction was pooled, concentrated, and further purified using Sephadex G-200. The molecular weight of the isolated protein was approximately 200,000 by SDS-PAGE, and the protein reacted with peroxidase (POD) mouse antirat myeloma IgE on Western blotting. Rabbit antibodies against DNP-specific rat IgE were also prepared by immunizing Japanese white rabbits with monoclonal DNP-specific rat IgE. These antibodies against DNP-specific rat IgE were applied to an affinity column of normal rat serum-Sepharose 4B and monoclonal DNP-specific rat IgG2b-Sepharose 4B to remove any other reactive substances apart from IgE contained in the serum proteins of the rat sensitized with DNP-Ascaris. On ELISA, it was found that the specificity of POD rabbit antibodies against DNP-specific rat IgE for monoclonal DNP-specific rat IgE was the same as that for rat myeloma IgE (IR 162). In addition, determinations of the monoclonal DNP-specific rat IgE revealed that the sensitivity of ELISA using POD-rabbit antibodies against DNP-specific rat IgE [POD-RA(DNP)RE] was higher than that using POD goat antibodies against rat myeloma IgE. Furthermore, an IgE capture ELISA employing the above-mentioned RA(DNP)RE was established for estimating the rat IgE antibodies to DNP-Ascaris suum. A good correlation was found between the antigen-specific IgE antibodies in the serum of Wistar rats estimated by this IgE capture ELISA and those estimated by passive cutaneous anaphylaxis.

Animals↗
PubMed1996

Pharmacokinetics of DA-125, a new anthracycline, after intravenous administration to uranyl nitrate-induced acute renal failure rats or protein-calorie malnutrition rats.

The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg-1, to control male Sprague-Dawley rats (n = 9) and uranyl nitrate-induced acute renal failure (U-ARF, n = 12) rats, or male Sprague-Dawley rats fed on a 23% (control, n = 8) or a 5% (protein-calorie malnutrition, PCM, n = 9) protein diet. After i.v. administration of DA-125, almost 'constant' plasma concentrations of M1, M2, and M4 were maintained from 1-2 h to 8-10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1-M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUCt values of M1 (115 against 82.5 micrograms min mL-1), M2 (33.0 against 23.6 micrograms min mL-1), and M4 (26.3 against 15.1 micrograms min mL-1) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0.316%), M2 (under the detection limit against 5.58%), and M4 (0.0174 against 0.719%)--expressed in terms of DA-125--were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0.0532% against under the detection limit), M3 (0.0286% against under the detection limit), and M4 (0.702% against 0.305%)--expressed in terms of DA-125--were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0.0320 micrograms mL-1), M2 (0.0265 micrograms mL-1), M3 (under the detection limit), and M4 (0.032 micrograms mL-1) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.

Acute Kidney Injury↗
PubMed1998

Differences in thermal salivation between the FOK rat (a model of genotypic heat adaptation) and three other rat strains.

Rats secrete saliva in response to heat. In the present study, details of thermal salivation were investigated using the FOK rat in comparison with Sprague-Dawley (SD), Donryu, and ACI rats. The FOK rat is a strain inbred for genotypic heat adaptation and endures heat for long periods. Conscious rats of all four strains were exposed to 42.5 degrees C. The order of heat endurance times at this temperature was FOK >> SD > Donryu = ACI. FOK rats spread their saliva over their entire ventral surface, their faces, and their outside legs. This saliva area was wider than those made by the other three strains. SD rats spread in an area wider than those of the Donryu and ACI rats. Saliva spreading in the FOK rats continued for 4.0-4.5 h, far longer than in the other strains. Under ketamine anesthesia and exposure to 40 degrees C, the FOK rats secreted saliva at 1390+/-235 microL/100 g of body weight during a 60-min observation period. This was the highest rate among the four rat strains (p < 0.0001). The body temperature increase rate in anesthetized FOK and SD rats was lower than in the other two strains, suggesting a minor contribution of unknown factors. Ligation of the submandibular gland ducts abolished the thermal salivation of the FOK rats, whereas ligation of the parotid duct had no effect. The submandibular, sublingual, and lachrymal glands in the FOK rats were 1.3-1.5, 1.25-1.4, and 1.3-1.5 times heavier, respectively, than those in the other three strains, whereas the parotid gland of the FOK rats was not enlarged. These findings indicate that the rats' saliva spreading and ET values are significantly correlated. A potentiated and long-lasting salivation from the submandibular gland was acquired during development of genotypic heat adaptation. This salivation is actuated in response to heat. The pronounced thermal salivation is probably attributable to adaptive changes in the superior salivatory nucleus-chorda tympani-submandibular gland pathway.

Acclimatization↗