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PubMed1998

Mammalian iron transport: an unexpected link between metal homeostasis and host defense.

Iron deficiency and iron overload disorders are common in clinical practice. Both can result from perturbations in the flux of iron across the absorptive intestinal enterocyte. Until recently iron transport has been poorly understood. In 1997 two independent cloning strategies identified Nramp2 (DCT1) as the first mammalian transmembrane iron transporter. In this review we discuss evidence that Nramp-related proteins play essential roles in metal homeostasis and host defense.

Animals↗
PubMed1988

Disposition of D-fenfluramine in lean and obese rats.

The anorectic drug D-fenfluramine (D-F) was administered as single i.v. doses of 1.25 and 6.25 mg/kg to lean female Sprague-Dawley and lean and obese female Zucker rats. Blood samples were collected serially and analysed by electron capture gas-liquid chromatography for D-F and its main metabolite, D-norfenfluramine (D-NF). At the lowest dose the disappearance of D-F followed an apparent first-order process with mean elimination half-life (T1/2) of approximately 2 h in female Sprague-Dawley and 4 h in lean and obese Zucker rats. Mean absolute steady-state volume of distribution (Vss) was the same in the lean female of both strains but total clearance (Cl) was significantly lower in the Zucker rats. Therefore elimination T1/2 of D-F was longer in female Zucker than Sprague-Dawley animals. Obese rats presented lower relative Cl and Vss but no change in absolute Cl and Vss and elimination T1/2 of the drug. Intra- and inter-strain differences were observed in hepatic microsomal protein and P-450 content. As in the case of D-F the elimination T1/2 of D-NF was also longer in Zucker than Sprague-Dawley rats. No differences were observed between lean and obese rats but in all cases the elimination T1/2 of the metabolite was much longer than that of its parent drug. After larger doses (6.25 mg/kg) the kinetics of the drug were not linear. The apparent Cl declined changing the metabolite-to-parent drug ratios in all types of rats, but more evidently in Zucker than Sprague-Dawley rats and in obese than lean animals. Inter- and intra-strain differences in D-F and D-NF kinetics should be considered in neurochemical studies of the drug and extrapolation of data across animal species requires consideration of dose dependence in the rat.

Animals↗
PubMed2002

Aberrant reduction of an inhibitory protein factor in a rat epileptic model.

Certain forms of seizure involve excessive glutamate transmission. We have recently identified a protein, referred to as the inhibitory protein factor (IPF), which potently inhibits glutamate uptake into isolated synaptic vesicles. In an effort to understand the mechanism underlying excessive glutamate transmission associated with seizure, we have analyzed IPF content in various brain regions of the spontaneously epileptic rat, SER (tm/tm, zi/zi), the absence-seizure tremor rat, TM (tm/tm), and the seizure-free control rats zitter ZI (zi/zi) and Wistar tremor control, each at 13 weeks of age. IPF content was found to be markedly reduced in the hippocampus, but not in the other brain regions, of SER, compared to the control and TM rats. TM rats also exhibited reduced IPF content compared to seizure-free controls. These changes appear developmentally regulated; no such alteration was observed in 8-week-old rats, which rarely show seizure. These observations indicate that an aberrant decrease in IPF is associated with certain forms of seizure; this decrease could lead to an abnormal increase in the amount of exocytotically released glutamate through its excessive accumulation in synaptic vesicles.

Aging↗
PubMed1982

Starvation increases gastrointestinal somatostatin in normal and obese Zucker rats: a possible regulatory mechanism.

Normal, male Sprague-Dawley (S-D) rats and female, lean and obese Zucker rats were studied in the fed state and after 48 hours of food deprivation. Somatostatin-like immunoreactivity (SLI) was measured from acetic acid extracts of oesophagus-cardia, stomach, small and large intestine, pancreas, hypothalamus, pituitary and cerebellum. Within the CNS, the highest levels of SLI were found in the hypothalamus, while in the gut, these levels were highest in the stomach and pancreas. All Zucker rats displayed higher hypothalamic levels of SLI than did S-D rats. Obese Zucker rats in the fed state differed from their lean littermates in that SLI levels were lower in oesophagus-cardia, stomach and hypothalamus, while being higher in pancreas and pituitary. The response to starvation in both obese and lean Zucker rats was qualitatively similar, and included significant increases in stomach and oesophagus-cardia SLI, but with a significant fall hypothalamic SLI. We have concluded that the increase in gastrointestinal SLI with starvation in Zucker as well as in S-D rats may represent a significant regulatory mechanism in nutrient homeostasis. We postulate that gastric SLI may decrease the availability of intestinal insulin secretagogues in the fasting state. This adaptive mechanism appears to be intact in the obese Zucker rat.

Animals↗
PubMed1987

Immunological surveillance against DNA-virus-transformed cells: correlations between natural killer cell cytolytic competence and tumor susceptibility of athymic rodents.

Adenovirus type 2 (Ad2)-transformed hamster and rat cells are susceptible to lysis by natural killer (NK) cells from the host of origin and are nontumorigenic in immunocompetent hamsters and rats, respectively. These NK-cell-susceptible, virus-transformed cells are, however, highly tumorigenic in athymic (nude) mice--animals with intact NK-cell responses. In vitro lysis of these xenogeneic, Ad2-transformed cells by nude-mouse NK cells was found to be defective. In contrast, Ad2-transformed hamster and rat cells were highly susceptible to lysis by nude-rat NK cells. Furthermore, xenogeneic, Ad2-transformed hamster cells were nontumorigenic in nude rats unless the NK-cell responses of the challenged animals were compromised. The results of the nude-rat studies show that thymus-dependent, cytotoxic T-lymphocyte-mediated, host cellular immune responses are not essential for rejection of xenogeneic cells transformed by nononcogenic Ad2. The data suggest instead that immunologically nonspecific host cellular immune responses, such as those mediated by NK cells, are sufficient for rejection of Ad2-transformed cells. These results indicate that biologically important differences exist in the NK-cell-mediated defenses mounted by nude mice and nude rats against transformed cells that may account for the different patterns of tumor induction by various neoplastic cell types in these athymic animals.

Adenoviridae↗
PubMed1989

Uneven blunting of chronotropic baroreflexes in obese Zucker rats.

We compared reflex chronotropic responses to intravenously infused drugs in three groups of age-matched normotensive female rats, namely, Sprague-Dawley, lean Zucker, and obese Zucker. Initial mean pressures did not differ between rat groups, but heart rates tended to be lower in obese Zucker rats. Baroreflex impairment was already evident, because heart rate responses to infused phenylephrine (reflex bradycardia) or sodium nitroprusside (reflex tachycardia) were consistently weaker in obese Zucker than in other rats. Regardless of rat grouping, subsequent cholinergic blockade with atropine elevated, whereas beta-adrenergic blockade with propranolol lowered, basal heart rates without affecting mean pressure. Reflex heart rate responses were all appreciably reduced after either type of autonomic blockade, and although the extent of inhibition varied between rat groups, the residual heart rate responses remaining after blockade were nonetheless always smaller in obese than in lean rats. This difference suggests that efferent sympathetic and parasympathetic mechanisms normally responsible for mediating heart rate reflexes were unevenly blunted in obese Zucker rats.

Animals↗
PubMed1991

Zucker and Wistar diabetic fatty rats show different response to adrenalectomy.

The short-term effects of adrenalectomy on certain aspects of glucose homeostasis and adiposity were examined in Zucker and Wistar diabetic fatty (WDF) rats. Ten-week-old male obese and lean WDF and Zucker rats were adrenalectomized or underwent sham operation. Obese rats of each strain were pair fed the intake of obese adrenalectomized rats. Intragastric glucose tolerance tests showed that sham-operated obese rats of both strains were severely hyperinsulinemic compared with leans; adrenalectomy and pair feeding reduced palsma insulin to lean levels in Zucker but not WDF rats. At the time they were killed, sham-operated obese WDF rats were significantly hyperglycemic and hyperinsulinemic compared with other groups, but adrenalectomy reduced plasma glucose and insulin to lean levels in both strains. Adrenalectomy reduced inguinal and retroperitoneal fat pad weights more in Zucker than WDF obese rats. Although adrenalectomy decreased epididymal and inguinal fat cell size in both obese rat strains, the effect was greater in Zucker compared with WDF rats. These data suggest that the basis for the differential response to adrenalectomy in obese WDF and Zucker rats may reside in their different genetic backgrounds.

Adipose Tissue↗
PubMed1985

[Fructose utilization by hepatocytes isolated from fed obese fa/fa Zucker rats. Metabolic fate of fructose in the absence of the modulator].

The utilization of fructose by isolated hepatocytes was investigated in fed obese Zucker fa/fa rats compared with their lean littermates (Fa/?) and Sprague-Dawley rats. Hepatocytes were incubated during 3 h using U14C fructose (20 mM). Our results show: a significant increase of fructose consumption, glucose, lactate and pyruvate production and faster turnover of glycogen by fa/fa rats. In these animals, synthesis of acylglycerol was also significantly enhanced. Our results suggest that fructose in fa/fa rats was used preferentially as precursor for lipid synthesis not only by the liver but also by the adipose tissue after a prior transformation into glucose by hepatocytes. All these abnormalities result in an accumulation of acylglycerols maintaining an obesity state in fa/fa rats.

Animals↗
PubMedDate not supplied

Response of the aorta of the obese Zucker rat to injury.

The response of the thoracic aorta to balloon-catheter-induced endothelial denudation was studied in two animal models of diabetes: the obese Zucker rat and the streptozotocin-treated Wistar rat. The obese Zucker rat, an animal with a metabolic profile similar to that of noninsulin-dependent human diabetics, was characterized by excessive body weight, hyperinsulinemia, hyperlipidemia, and a mild increase in plasma glucose levels. In Zucker rats sacrificed 3 weeks after endothelial denudation, the cross-sectional areas of the fibrocellular intimal lesions were found to be approximately twice as large as those of the lean control. In all other respects, the morphology of the lesions in the obese rats, as assessed by both light and transmission electron microscopy, was similar to that of the lean control rats. In streptozotocin-treated Wistar rats, neither the cross-sectional areas nor the morphology of the intimal lesions differed from those in control rats. These results indicate that, in the obese Zucker rat, the response to aortic intimal injury is altered.

Animals↗
PubMed1987

Quantitative studies of lymphoid organs, blood and lymph in inbred athymic and euthymic LEW rats under germfree and specified-pathogen-free conditions.

Four groups of inbred male LEW rats were examined: A, germfree athymic; B, specified pathogen free (SPF) athymic; C, germfree euthymic; D, SPF euthymic. All animals were killed at 18 weeks and compared with respect to body weight, histological appearance and cell density of the lymphoid organs, haematological values and differential counts of bone marrow, peripheral blood and lymph. Athymic rats had a lower body weight, less densely populated lymphoid organs, and fewer lymphocytes in the blood and lymph compared with euthymic animals. No difference was seen between athymic rats under germfree and SPF conditions, and in general the differences between athymic and euthymic animals were less pronounced under germfree conditions.

Animals↗
PubMed1998

Development of vascular pole-associated glomerulosclerosis in the Fawn-hooded rat.

Fawn-hooded hypertensive (FHH) rats constitute a spontaneous model of chronic renal failure with early systemic and glomerular hypertension, proteinuria, and development of focal and segmental glomerulosclerosis. The goal of the present study was to elucidate a step-by-step sequence of histopathologic events leading from an initial glomerular injury to segmental sclerosis. Segmental sclerosis in the FHH rat is consistently associated with the glomerular vascular pole. The initial injury involves the expansion of primary branches of the afferent arteriole. Apposition of those capillaries to Bowman's capsule, together with the degeneration and detachment of corresponding podocytes, allows parietal cells to attach to the naked glomerular basement membrane of this capillary, i.e., allows the formation of a tuft adhesion to Bowman's capsule. The adhesion enlarges to a broad synechia by encroaching to neighboring capillaries, apparently based on progressive podocyte degeneration at the flanks of the adhesion. Capillaries inside the adhesion--before undergoing collapse or hyalinization--appear to stay perfused for some time and to maintain some kind of filtration misdirected toward the cortical interstitium. Thereby, a prominent paraglomerular space comes into existence, enlarging in parallel with the adhesion. Toward the cortical interstitium this space is delimited by a layer of sheetlike fibroblast processes, which has obviously been assembled in response to the formation of this space. Toward the urinary space, the paraglomerular space is demarcated by the parietal epithelium and by the interface between the adhesion and the "intact" tuft remnant. Thus, the sclerotic tuft portions all become enclosed within the paraglomerular space.

Animals↗
PubMed2000

Review of colorectal cancer and its metastases in rodent models: comparative aspects with those in humans.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) remains one of the most common cancer forms developing in industrialized countries, and its incidence appears to be rising. Studies of human population groups provide insufficient information about carcinogenesis, pathogenesis, and treatment of CRC. To study these phenomena in detail, a number of animal models of human CRC have been developed. The hypothetical ideal animal model should mimic the human disease in terms of morphology, biochemical alterations, and biological behavior. No existing model replicates the disease as an entity, but available models approximate many of the characteristics of human colonic carcinogenesis and metastasis. So far few comparative evaluations of the various animal models of CRC have been made. CONCLUSION: Animal studies cannot replace human clinical trials, but they can be used as a pre-screening tool, so that human trials become more directed, with greater chances of success. The orthotopic transplantation of colon cancer cells into the cecum of syngeneic animals or intraportal inoculation appears to resemble the human metastatic disease most closely, providing a model for study of the treatment of metastases. Which model(s) to choose depends on the goal(s) of the experiment(s). The review published here can provide help in selecting the most optimal CRC model(s) for a certain purpose and in preventing unnecessary duplication of animal experimentation.

Adenocarcinoma↗
PubMed2004

Strain differences in diazepam metabolism at its three metabolic sites in sprague-dawley, brown norway, dark agouti, and wistar strain rats.

Knowledge of strain differences in drug metabolism is important for the selection of animals for pharmacokinetic, pharmacodynamic, and toxicological studies. Hepatic microsomes from Sprague-Dawley (SD) and Brown Norway (BN) rats had 300-fold higher diazepam p-hydroxylation activity than Dark Agouti (DA) and Wistar (W) rats at a low diazepam concentration (3 microM). Kinetic studies indicated that diazepam p-hydroxylation in SD and BN rats proceeded with lower K(m) and higher V(max) values than it did in DA and W rats. However, the expression levels of cytochrome P450 CYP2D1, the reported enzyme for diazepam p-hydroxylation, did not cosegregate with the activity. These results suggest the presence of a new high-affinity diazepam p-hydroxylation enzyme other than CYP2D1 in SD and BN rats. DA rats showed 3- and 2-fold higher diazepam 3-hydroxylation and N-desmethylation activities, respectively, than the other rat strains. In agreement with this, DA rat liver microsomes had a higher expression of CYP3A2, which is responsible for diazepam 3-hydroxylation and partly responsible for N-desmethylation. Values of CL(int) (V(max)/K(m)) indicated that p-hydroxy-diazepam is the major metabolite in SD and BN rats, whereas 3-hydroxy-diazepam is the major metabolite in DA and W rats. The sum of the CL(int) in each strain was in the order of DA > SD = BN >> W. Strain differences in the pharmacodynamics of diazepam between SD and DA rats may be due to these differences in diazepam metabolism. We found that both the rate of elimination of diazepam and the major metabolic pathways in diazepam metabolism differed among the different rat strains due to polymorphic expression of the two enzymes involved in diazepam metabolism.

Alcohol Oxidoreductases↗
PubMed1989

Pharmacokinetic characteristics of the obese overfed rat.

The present study was undertaken to examine the appropriateness of the obese overfed rat and the obese Zucker rat as animal models for evaluating drug disposition changes in human obesity. It was found that 11 of 12 characteristics that control or influence drug clearance and volume of drug distribution in obese humans were qualitatively reproduced in the obese overfed rat. In contrast, existing literature shows that the obese Zucker rat resembles the obese human in only five of 12 characteristics, with meaningful discrepancies in fat-free mass, creatinine clearance, and thyroid function. Perhaps of greatest significance were changes in hepatic cytochrome P-450, which increased in proportion to total body mass in the obese overfed rat but remain unchanged in the Zucker rat. Although P-450 status in human obesity is unknown, the overfed rat model provides an opportunity for examining increased oxidative drug elimination that appears as an established feature of human obesity. In conclusion, the obese overfed rat appears to be superior to the obese Zucker rat as an animal model for evaluating the pharmacological consequences of human obesity, particularly those in which reproducing drug pharmacokinetics is an important consideration.

Animals↗
PubMed1987

The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells.

Athymic nude rats (PVG.rnu/rnu) were injected at 6 to 10 wk of age with 1 to 200 million thoracic duct lymphocytes (TDL) containing 40 to 60% mature T cells. Thereafter TDL-injected nude recipients were monitored for evidence of T cell function for up to 2 yr. W3/25+ T helper (Th) cells in lymph nodes (LN) increased from 7% at 2 wk to 30% at 8 wk after TDL transfer. The percent of W3/25+ cells remained elevated for the life of the recipient (up to 2 yr), approximating normal levels. The total size of the recirculating pool expanded in TDL-injected nude rats to reach 2/3 the level of euthymic controls by 16 wk, an increase of 10-fold to 15-fold in W3/25+ cells. The expansion of the W3/25+ population was independent of initial TDL dose. With time spleen and LN acquired a normal histological appearance including the development of germinal centres and a marked increase in cellularity in T cell traffic areas. TDL-injected nude rats rejected skin allografts with near normal kinetics. In addition graft vs host (GVH) responsiveness, assessed by the popliteal LN assay, progressively increased reaching a level 9 mo to 1 yr after replacement that resembled the GVH activity in euthymic controls.

Animals↗