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PubMed2005

PPARgamma agonists diminish serum VEGF elevation in diet-induced insulin resistant SD rats and ZDF rats.

We investigated the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on serum vascular endothelial growth factor (VEGF) in diet-induced insulin resistant SD rats and ZDF rats. SD rats fed a high fat/sucrose diet showed increases in serum insulin and VEGF (both p < 0.01). Treatment with a PPARgamma agonist GI262570 normalized the diet-elevated insulin and VEGF (both p < 0.01). There was a positive correlation between serum insulin and VEGF (p < 0.05) in SD rats. ZDF rats had higher serum glucose, insulin, and VEGF than Zucker lean rats (all p < 0.01). Treatment of ZDF rats with PPARgamma agonist pioglitazone decreased serum glucose and VEGF (both p <0.01). There was a positive correlation between glucose and VEGF in ZDF rats (p < 0.05). In 3T3-L1 adipocytes, GI262570 did not affect insulin-stimulated VEGF secretion. These studies demonstrated that hyperinsulinemia in SD rats and hyperglycemia in ZDF rats were associated with increased serum VEGF; PPARgamma agonists normalized serum insulin, glucose, and VEGF, but did not affect VEGF secretion in vitro.

3T3-L1 Cells↗

PubMed2005

Defects in differentiation of bone-marrow derived dendritic cells of the BB rat are partly associated with IDDM2 (the lyp gene) and partly associated with other genes in the BB rat background.

BB rats develop various organ-specific autoimmune diseases, e.g. autoimmune diabetes and thyroiditis and have proven important to dissect genetic factors that govern autoimmune disease development. The lymphopenia (lyp) gene (iddm2) is linked to autoimmune disease development and is a major genetic difference between diabetes-resistant (DR) and diabetes-prone (DP) BB rats. To study the effects of the lyp gene and other genes on dendritic cell (DC) differentiation from bone-marrow precursors, such differentiation was studied in BB-DP, BB-DR, Wistar and F344 control rats. DC of BB-DP rats showed a lower MHC class II expression as compared to BB-DR, Wistar and F344 rats. LPS-maturation did not restore this low MHC class II expression. DC of BB-DP rats also showed a poor capability to terminally differentiate into mature T cell stimulatory DC under the influence of LPS and produced significantly lower quantities of IL-10, yet these aberrancies were also found in BB-DR rats but did not occur in control rats. This study thus shows that various aberrancies exist in the differentiation of myeloid DC from bone-marrow precursors in the BB rat model of organ-specific autoimmunity. These aberrancies are multigenically determined and partly associated with iddm2 (lyp gene) and partly associated with other genes in the BB rat.

Animals↗

PubMed1998

Comparison of the alcohol-preferring P rat to the Wistar rat in behavioral tests of impulsivity and anxiety.

To determine whether the selectively bred alcohol preferring P rat displays impulsive and anxiety-related behaviors, as have been noted in Type 2 human alcoholics, P rats were compared with outbred Wistar rats, the strain from which P rats were derived, on a series of behaviors reflecting impulsivity and anxiety. The two groups were also compared on their volitional consumption of ethanol. When compared with the Wistar rats, the P rats preferred a higher concentration of ethanol and imbibed a much greater amount of ethanol when they were offered their preferred concentration. However, the behavioral tasks produced inconsistent results. The P rats completed 100 bar presses for food in less time when tested on a constant reinforcement schedule, which suggests that they are hyperactive compared to Wistar rats. However, the P rats also emitted a higher percentage of reinforced responses on differential reinforcement of low rate responding (DRL)-10s and gnawed less from a cork stopper, which suggests that they are less impulsive and possibly neophobic. The two groups did not differ on emergence into or activity in an open field, their activity in or open-arm duration in the elevated plus maze, or performance on DRL-5s and DRL-15s. Collectively, the behavioral data suggest that P rat does not serve as a model for the anxiety and impulsiveness associated with the Type 2 alcoholic individual.

Alcohol Drinking↗

PubMed1987

Infections of forest rat filaria, Breinlia booliati, in neonate and juvenile laboratory white rats.

The kinetics of Breinlia booliati infection in 3 inbred rat strains (Lewis, Wistar and Sprague Dawley) were investigated. One group of rats was infected as neonates (less than 24 hours of age) with third-stage larvae of B. booliati and the other group was infected as juveniles (4 weeks of age). The results showed that infection in the neonates were significantly different from the infection in the juveniles. The 60 rats infected as neonates, when necropsied between 8 to 10 months postinfection, yielded adult worms. The 2 neonatal infection groups of Lewis and Wistar strains showed highest susceptibility to the infections. The mean prepatent period was 85 days. Ninety to 95% of the infected rats were patent with microfilaraemia and a large percentage (33 to 47%) of them had high microfilaraemia counts exceeding 3000 mff/20 mm3 of blood and larger sizes (mean 157.11 mm for female adult worms and 61.88 mm for male adult worms. The adult worms were distributed equally in both the pleural (57%) and peritoneal cavity (43%). In most aspects, the neonatal infection group of the Sprague-Dawley strain was intermediate in susceptibility between the 2 neonatal infection groups of the Lewis and Wistar strains and the 3 juvenile infection groups. In contrast to neonatal infection groups, the 3 juvenile infection groups exhibited low infection rates (37%, 58% and 47% for the Lewis, Wistar and Sprague Dawley strains respectively), longer prepatent periods (mean 101 days), lower recovery rates (2 to 4%), lower adult worm loads (mean 0.4 to 0.8 female worms, and 0.2 to 0.8 male worms per rat), and smaller sizes (mean 141.24 mm for female adult worms and 53.75 mm for male adult worms). Forty-four to 57% of these infected rats harboured either single male or single female adult worms in the body cavity. Most (92%) of the adult worms recovered from the juvenile infection groups resided in the pleural cavity and the remaining 8% were recovered from the peritoneal cavity. Microfilaraemia could be detected in only 3/20 Lewis rats, 5/20 Wistar rats and 5/20 Sprague Dawley rats. The mean peak microfilaraemia of the 3 pooled juvenile infection groups was 632 mff/20 mm3 of blood, ranging from 7 mff/20 mm3 to 1856 mmf/20 mm3. Our results indicate that the susceptibility to B. booliati infection in white rats is both genetic and age-associated. The responses of the 2 distinct infection groups to B. booliati infections are discussed.

Animals↗

PubMed1993

High copper and iron levels and expression of Mn-superoxide dismutase in mutant rats displaying hereditary hepatitis and hepatoma (LEC rats).

The LEC rat is a mutant strain displaying hereditary hepatitis and hepatoma. We established enzyme-linked immunosorbent assays of Cu,Zn- and Mn-superoxide dismutase (Cu,Zn- and Mn-SOD) and measured the levels of both SODs in various organs of LEC and Wistar rats. Mn-SOD concentrations were higher in LEC rats than in Wistar rats in most tissues. Cu,Zn-SOD levels of liver, kidney and intestine were lower in LEC rats than in Wistar rats. Atomic absorbtion techniques indicated that in addition to high Cu concentrations as previously reported, LEC rat livers contained high Fe concentrations relative to those in Wistar rat livers. These data suggest that increased concentrations of Fe and Cu and decreased levels of Cu,Zn-SOD may facilitate the Fenton reaction to produce hydroxyl radicals in the tissues of the LEC rat. To compensate for the decreased scavenging effects due to low levels of Cu,Zn-SOD, an adaptive increase of Mn-SOD may occur in the process of hepatitis and hepatocarcinogenesis in LEC rats.

Animals↗

PubMed1993

Ganglioside distribution in the liver of inbred strains of rats and the cancerous liver of LEC rats.

The gangliosides in the livers of various inbred strains of rats and hepatoma of LEC rats were purified and analyzed by thin-layer chromatography. The patterns of ganglioside distribution in these rat livers were classified into three phenotypes depending on the strain, that is, a-type (ACI, LEA, LEW, BUF), b-type (WKAH, SHR/SP), and LEC type, which are characterized by dominance of a- or b-series of gangliosides, or a variation of a-type, respectively. A sex difference was also recognized in the molar ratio of GM3 which was much higher in males (60-75%) than in females (33-56%) except in LEC rats. In addition, the content of a-series gangliosides was lower and the content of b-series gangliosides was higher in a-type male rats than in a-type female rats. The opposite was true in b-type rats. LEC rats were an exception, characterized by no sex difference and a quite low content of b-series gangliosides. The LEC rat is a mutant strain that spontaneously develops fulminant hepatitis around 14 to 20 weeks of age and hepatoma at 1 to 1.5 years old. The gangliosides of the hepatoma were characterized by the appearance of the newly synthesized gangliosides, fucosyl-GM1 and alpha-galactosyl alpha-fucosyl GM1 (BGM1). In particular, BGM1 ganglioside accumulated in the hepatoma of female rats.

Animals↗

PubMed1999

Interaction between lifetime captopril treatment and NaCI-sensitive hypertension in spontaneously hypertensive rats and Wistar-Kyoto rats.

DESIGN: Previous studies that were based on daytime arterial pressure recordings indicate that lifetime treatment with captopril exacerbates the hypertensive response to a high NaCl diet in spontaneously hypertensive rats (SHR) but has no such effect in normotensive Wistar-Kyoto (WKY) rats. The present study used 24-h recording methods to examine the hypothesis that during the normal waking hours of rats (night-time) the hypertensive response to a high NaCl diet is exacerbated in SHR and induced in WKY rats treated with lifetime captopril. METHODS: SHR and WKY rats were (1) untreated, (2), lifetime captopril treated or (3) lifetime captopril treated but removed from the treatment 2 weeks prior to exposure to a high (8%) NaCl diet RESULTS: Compared to untreated SHR, in SHR that were continuously treated with captopril, the high NaCl diet caused a more rapid and greater rise in arterial pressure. Discontinuation of the captopril treatment did not significantly diminish this NaCl-sensitivity. In untreated WKY rats, the high NaCl diet did not alter mean arterial pressure, but in the lifetime captopril-treated WKY rats the high NaCl diet induced a rapid rise in arterial pressure. In WKY rats, discontinuation of the lifetime captopril treatment did not diminish this NaCl-induced rise in arterial pressure, even though baseline mean arterial pressure in this group is similar to that in untreated WKY rats. CONCLUSIONS: Lifetime captopril treatment accelerates the hypertensive response to a high NaCl diet in SHR, and it induces a similar response in WKY rats. In both strains, the lifetime captopril treatment causes a change in the response that is not dependent on concurrent administration of the drug. This finding further suggests that lifetime captopril treatment causes a long-term resetting of cardiovascular response mechanisms.

Animals↗

PubMed2005

The hypomagnesic rat model: dermatitis-prone hairless rats with mild magnesium depletion fed a diet low in lipids did not develop pruritic dermatitis.

BACKGROUND/PURPOSE: In the hypomagnesic dermatosis of rats, low-dietary magnesium leads to lowered serum Mg2+, universal dermatitis and scratching. The model is postulated to work better if the diet also has a low content of lipids. Pruritus is seen in patients suffering from anorexia nervosa and resolves on weight restoration. Lipid depletion of the diet and/or lowered body weight may therefore be important in developing pruritus. The purpose of the present study was to investigate whether a diet low in lipids can induce pruritus in dermatitis prone rats because of mild magnesium depletion thereby focusing on the role of lipids in the hypomagnesic dermatosis rat model. METHODS: Fourteen male hairless rats, 3 weeks of age, were fed a diet deficient in lipids and with a lower content of magnesium for a 4-week period and compared with 11 controls fed a normal diet. The skin was inspected daily and transepidermal water loss (TEWL), serum Mg2+ and scratching activity were measured. At the end, skin biopsies were taken from the flank and ears. RESULTS: Serum Mg2+ was significantly lowered in the diet group (P<0.001) but the rats developed no dermatitis or increased TEWL compared with 11 rats in a control group. Biopsies were normal with no sign of inflammation. Rats in the diet group had inferior weight gain, were less active and spent more time asleep than control rats (P<0.01). Furthermore, scratching activity monitored in the last week of the study as the number of scratch-sequences per awake minute was reduced in the diet group (P<0.001). CONCLUSION: The lipid-deficient diet was not able to induce pruritic dermatitis despite the fact that the rats were dermatitis prone because of mild magnesium depletion. It is not confirmed that dietary lipid depletion plays any significant role in the hypomagnesic dermatitis rat model. The dermatitis and the model appear to be strictly dependent on efficient magnesium depletion manufactured with very low magnesium levels.

Animals↗

PubMed2006

A set of highly informative rat simple sequence length polymorphism (SSLP) markers and genetically defined rat strains.

BACKGROUND: The National Bio Resource Project for the Rat in Japan (NBRP-Rat) is focusing on collecting, preserving and distributing various rat strains, including spontaneous mutant, transgenic, congenic, and recombinant inbred (RI) strains. To evaluate their value as models of human diseases, we are characterizing them using 109 phenotypic parameters, such as clinical measurements, internal anatomy, metabolic parameters, and behavioral tests, as part of the Rat Phenome Project. Here, we report on a set of 357 simple sequence length polymorphism (SSLP) markers and 122 rat strains, which were genotyped by the marker set. RESULTS: The SSLP markers were selected according to their distribution patterns throughout the whole rat genome with an average spacing of 7.59 Mb. The average number of informative markers between all possible pairs of strains was 259 (72.5% of 357 markers), showing their high degree of polymorphism. From the genetic profile of these rat inbred strains, we constructed a rat family tree to clarify their genetic background. CONCLUSION: These highly informative SSLP markers as well as genetically and phenotypically defined rat strains are useful for designing experiments for quantitative trait loci (QTL) analysis and to choose strategies for developing new genetic resources. The data and resources are freely available at the NBRP-Rat web site 1.

Animals↗

PubMed1990

Plasma from BB/Wor rats increases insulin secretion by perfused rat pancreas.

Diabetes-prone (DP) BB rats develop spontaneous autoimmune diabetes mellitus in the context of multiple abnormalities of humoral and cellular immunity. Diabetes-resistant (DR) BB rats have phenotypically normal immune systems and rarely become spontaneously hyperglycemic, but can be rendered diabetic by in vivo immune elimination of T cells that express the RT6 surface alloantigen. To determine if humoral factors in these animals influence beta-cell function, we studied the effect of BB rat plasma on glucose-induced insulin secretion from the isolated perfused rat pancreas. We found that plasma dialyzed to remove molecules less than 14 kD from nondiabetic DR and DP BB rats significantly enhanced total insulin secretion [4806 +/- 711 ng (+/- SEM; n = 6) and 4968 +/- 1235 ng (n = 7), respectively] from perfused pancreata when compared with the effects of either plasma from Wistar-Furth rats (2585 +/- 336 ng; n = 9) or medium containing no plasma (1862 +/- 92 ng; n = 38). The presence of chemically induced diabetes was also associated with enhanced insulin secretion [3276 +/- 414 ng (n = 8) using alloxan and 3956 +/- 470 ng (n = 7) using streptozocin], but the greatest degree of enhancement was observed with plasma from spontaneously diabetic BB rats (6521 +/- 751 ng; n = 17). The enhancement of insulin secretion by BB rat plasma, both diabetic and nondiabetic (DR and DP), was characterized by preservation of first and second phase hormone release. Heat inactivation of acutely diabetic BB rat plasma did not affect its ability to stimulate insulin secretion. We conclude that the plasma of BB rats, both before and after the onset of autoimmune diabetes mellitus, contains a factor other than complement of greater than or equal to 14 kD that enhances insulin secretion in vitro from the isolated perfused pancreas.

Animals↗

PubMed1995

Glucocorticoid and/or glucocorticoid antagonist effects in inflammatory disease-susceptible Lewis rats and inflammatory disease-resistant Fischer rats.

Lewis (LEW/N) and Fischer (F344) rats are inbred strains that respond antithetically to administration of several inflammatory stimuli. Thus, in response to streptococcal cell wall-derived peptidoglycan/polysaccharide, 6-week-old female Lewis rats develop acute and chronic polyarthritis, whereas age- and sex-matched Fischer rats are arthritis-resistant. The susceptibility of Lewis rats to development of chronic severe inflammatory disease has been attributed to their inability to appropriately activate their hypothalamic-pituitary-adrenal axis in response to inflammatory stimuli, leading to a functional glucocorticoid deficiency. To investigate whether the acute neurogenic inflammatory response was also different in the two strains, we studied the air-pouch model of carrageenin-induced neurogenic inflammation in adult male Lewis and Fischer rats. Both the volume and the leukocyte concentration of the inflammatory exudate were significantly higher in Lewis than in Fischer rats, suggesting that the known differences in the handling of chronic inflammation between the two strains pertain to the acute neurogenic type of inflammation as well. To confirm that glucocorticoids play a major role in the differential response of the two strains to this inflammatory stimulus, we administered graded doses of the glucocorticoid agonist dexamethasone or antagonist RU 486 to both strains and examined their responses to concomitantly administered carrageenin. RU 486 increased, whereas dexamethasone decreased, the inflammatory response of Fischer and Lewis rats, respectively, to approach the magnitude of each other's natural response, suggesting that glucocorticoids are involved in this phenomenon as well. To rule out any differences in end-organ sensitivity to glucocorticoids between the two strains, we evaluated dose-response relations of whole body, thymus, spleen, and adrenal weights after 1 week daily administration of graded doses of dexamethasone. We found similar ED50 for both Lewis and Fischer rats. We conclude that the differences in the susceptibility to acute, carrageenin-induced, neurogenic inflammation between the LEW/N and F344 rat strains are similar to those of chronic inflammatory responses in these strains and likewise glucocorticoid-dependent. No apparent major differences exist in the sensitivity of target tissues to exogenous glucocorticoids between Lewis and Fischer rats.

Adrenal Glands↗

PubMed1991

[Effects of captopril on acute phase in two-kidney Goldblatt hypertensive rats and spontaneously hypertensive rats].

Effects of continuous oral administration of captopril were investigated on acute phase in two-kidney Goldblatt hypertensive (2 KGH) rats and spontaneously hypertensive rats (SHR). Systolic blood pressure gradually rose throughout the experimental period of 7, 14, 21 and 28 days in both 2 KGH rats and SHR. These gradual increases of systolic blood pressure were reduced by administration of captopril in both rats. Plasma renin activity were markedly increased throughout the experimental period in both rats treated with captopril, and were modestly increased in 2 KGH rats. In contrast, those changes in plasma renin activity were not obvious in SHR. In 2 KGH rats, juxtaglomerular index (JGI) and juxtaglomerular cell count (JGCC) of the clipped kidneys increased whereas JGI of the opposite kidneys decreased. In contrast, those changes in JGI and JGCC were not obvius in SHR. On the other hand, JGI and JGCC of the clipped kidneys increased in 2 KGH rats treated with captopril and those of the both kidneys increased in SHR treated with captopril. These results suggested that juxtaglomerular cells were related to the development of hypertension in 2 KGH rats, but were not clear in SHR. And these results were found that captopril showed antihypertensive effects, in spite of rises in JGI and JGCC of both 2 KGH rats and SHR.

Administration, Oral↗

PubMed2004

Comparison of the disposition behavior of organic anions in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Long-Evans Agouti rats.

Long-Evans Cinnamon (LEC) rats have an abnormality similar to that observed in Wilson's disease in humans and are therefore a good animal model for the study of Wilson's disease. LEC rats develop hereditary hepatitis and severe jaundice. Mutant animals with hyperbilirubinemia have been widely used as animal models for human diseases. Among these mutant animals, Eisai hyperbilirubinemic rats (EHBR) have defective biliary excretion of organic anions. Thus, biliary excretion of sulfobromophthalein (BSP) and urinary excretion of phenolsulfonphthalein (PSP) in LEC rats were compared with those in Long-Evans Agouti (LEA) rats. In LEC rats, the excretion of BSP, a multidrug resistance-associated protein 2 (Mrp2/Abcc2) substrate, was significantly decreased compared to that in LEA rats. It has been reported that the transport function for organic anions on the kidney is maintained in EHBR. However, the urinary excretion of PSP is impaired in LEC rats. It is possible that organic anion transporters responsible for the urinary excretion of PSP in LEA rats and EHBR are impaired in LEC rats. It is important to elucidate the relationship between organic anion secretion and Wilson's disease.

Animals↗

PubMed1991

Intestinal brush border calcium uptake in spontaneously hypertensive rats and their genetically matched WKY rats.

The current studies were designed to characterize calcium transport by intestinal brush border membrane in the spontaneously hypertensive rat (SHR) and normotensive control, the Wistar-Kyoto (WKY) rat. The biochemical and functional purity of the intestinal brush border membranes in SHR and WKY rats was validated by marker enzymes and the ability to transiently transport D-glucose in the presence of Na+ gradient. Calcium transport into duodenal and jejunal vesicles represented a minor binding component and transmembrane movement as evident by initial rate studies, A23187 studies, and lanthanum displacement experiments. Initial rate and time course of calcium uptake was lower in SHR compared with WKY rats. Kinetic analysis of calcium uptake by the jejunum (total uptake minus binding component) showed a Vmax of 6.98 +/- 0.2 and 1.8 +/- 0.2 nmol/mg protein/7 sec in WKY rats and SHR, respectively (P less than 0.001), whereas Km values were 0.76 +/- 0.04 and 0.87 +/- 0.1 mM for WKY rats and SHR, respectively. Similar kinetic analysis of calcium uptake by the duodenal segments showed a Vmax of 10.3 +/- 0.8 and 2.8 +/- 0.2 nmol/mg protein/7 sec in WKY rats and SHR, respectively (P less than 0.01). Km values were 0.7 +/- 0.2 and 0.3 +/- 0.06 mM (P greater than 0.05). Vmax of calcium uptake in the 2-week-old rats (prehypertensive period) was 6.0 +/- 0.3 and 3.53 +/- 0.3 nmol/mg protein/7 sec in WKY rats and SHR, respectively (P less than 0.001), whereas Km values were 0.60 +/- 0.07 and 0.5 +/- 0.01 mM, respectively. These results suggest that calcium binding and uptake by duodenal and jejunal intestinal brush border membranes of SHR is significantly decreased compared with WKY rats. The decrease in transmembrane calcium uptake is secondary to decrease in Vmax and is present before the appearance of hypertension, implying a genetically determined defect in calcium uptake in intestinal brush border membranes of the SHR.

Animals↗

PubMed2002

Impaired spatial performance in rats with retrosplenial lesions: importance of the spatial problem and the rat strain in identifying lesion effects in a swimming pool.

Behavioral, electrophysiological, and anatomical evidence suggests that retrosplenial (RS) cortex (areas RSA and RSG) plays a role in spatial navigation. This conclusion has been questioned in recent work, suggesting that it is damage to the underlying cingulum bundle (CG) (areas CG and IG), and not RS, that disrupts spatial place learning (Aggleton et al., 2000). We revisited this issue by comparing Long-Evans rats, the strain used in studies that report RS deficits, to Dark Agouti rats, the strain in which no RS deficit has been reported. Rat groups with RS, RS + CG, or no lesion were tested on a place task in a swimming pool, a test of nonspatial and spatial learning, and a matching-to-place task, a relatively selective test of spatial learning. Long-Evans rats given RS and RS + CG lesions, either before or after training on the two tasks, were impaired on both tasks, a deficit not attributable to impaired visual acuity. Control Dark Agouti rats and RS Dark Agouti rats, although not different on the place task, were both significantly impaired relative to Long-Evans rats. The RS Dark Agouti group, however, was also impaired on the matching-to-place task. Thus, we show that RS cortex is part of an extended neural circuit involved in spatial behavior in both Long-Evans and Dark Agouti rats, but its role in the place task may be masked by an innate nonspatial deficit in Dark Agouti rats. The results are discussed in relation to the importance of assessing spatial learning with appropriate spatial tests, the problems of interpretation posed by rat strain differences, and the role of retrosplenial cortex in spatial behavior.

Analysis of Variance↗

PubMed2004

Differences in the pharmacokinetics of peroxisome proliferator-activated receptor agonists in genetically obese Zucker and sprague-dawley rats: implications of decreased glucuronidation in obese Zucker rats.

Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [(14)C]MRL-I and [(14)C]MRL-II was comparable in the two strains, approximately 96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CL(int)), calculated from the V(max)/K(m) of glucuronidation of [(14)C]MRL-I and [(14)C]MRL-II in liver microsomes, was approximately 2-fold lower in obese Zucker rats; the K(m) values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies.

Animals↗

PubMed1987

Cytotoxic activity of sera from diabetic BB rats against BB rat islet--a functional study.

[3H] leucine incorporation into islet proteins, insulin secretion, hormone content (insulin, glucagon) and DNA synthesis were measured in cultured BB rat islets in a study to compare the effect of freshly prepared BB rat serum obtained from non-diabetic and newly diagnosed diabetic BB rats on islet functions. After exposure of isolated BB rat islet to a mixture of tissue culture medium and BB rat serum (1:1) for 24 hr, islet lysis was induced by 40% of the diabetic BB rat sera whereas the remaining 60% of diabetic BB rat sera tested did not influence islet functions as evidenced by insulin net production, glucose-induced insulin release and DNA synthesis measured in a subsequent culture period in TCM 199, 10 mmol/l glucose supplemented with 10% neonatal calf serum or short-term incubations. After exposure of islets to sera with anti-islet cytotoxicity the majority of islet cells were destroyed as indicated by a drastically reduced [3H] leucine incorporation into islet proteins and by a diminution of hormone and DNA content of islets. This toxicity against islets was overcome by heat treatment (58 degrees C, 30 min) of sera. The results indicate that heat-labile components in certain diabetic sera of BB rats can lyse the majority of islet cells in BB rat islets within 24 hr. Our assay may help to dissociate humoral and cellular components which cause the injury of beta cells and the onset of diabetes in BB rats.

Animals↗

PubMed1998

Renal AT1 receptor: computerized quantification in spontaneously hypertensive rats and DOCA-salt rats.

To assess the involvement of angiotensin II (Ang II) in the regulation of blood pressure, we investigated the alterations of renal Ang II type 1 (AT1) receptors in two different models of hypertension; i.e., in spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats by using the method for quantification of in vitro macro-autoradiography (ARG). In the SHR model, although the number of cortical AT1 receptors equaled that of Wistar Kyoto (WKY) rats at 4 and 12 weeks of age, the number of medullary AT1 receptors in the 4-week-old SHR animals was significantly lower than that in age-matched WKY rats, and increased by 12 weeks of age. The renal AT1 receptor number in DOCA-salt hypertensive rats was significantly higher than that in control rats. The amount of these receptors also increased with age in both DOCA-salt hypertensive rats and control rats. These findings indicate that the development of medullary AT1 receptors in early stages of hypertension in the SHR model differs from that in WKY rats or DOCA-salt hypertensive rats. This suggests that renal AT1 receptors may contribute to the hypertension seen in the SHR group. The renal AT1 receptors appear to be up-regulated in early stages of DOCA-salt-induced hypertension as well.

Age Factors↗