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PubMed1988

Activation of rat complement by soluble and insoluble rat IgA immune complexes.

The ability of rat monoclonal IgA, specific for 2,4-dinitrophenyl (DNA), to activate the complement (C) system of the rat was investigated using aggregated IgA or IgA immune complexes (IC). IgA was coated onto a solid phase, and tested for its capacity to bind C3 upon incubation at 37 degrees C in normal rat serum (NRS) in the presence of Mg-EGTA. Binding of C3 was observed dependent on the dose of dimeric (d-), polymeric (p-) and secretory IgA tested. In contrast, little C3 fixation was observed in this system with monomeric (m-) rat IgA or with mouse m- and d-IgA (MOPC315). Soluble and insoluble rat IgA IC were prepared using dinitrophenylated rat serum albumin (DNP8RSA) as antigen (Ag), and assessed for C activation. It was shown that insoluble IC (immune precipitates; IP) containing m-, d- or pIgA of rat origin activate the alternative pathway of rat C, as demonstrated by their capacity to induce C consumption in NRS in the presence of Mg-EGTA. When p- and m-IgA IP were compared for their capacity to activate C, it was found that p-IgA activated C four times as efficiently as m-IgA IP (at 2 mg/ml). Soluble rat IgA IC were prepared in an excess of DNP8RSA, fractionated by gel filtration on Sepharose 6B, and analyzed for C activation and antibody (Ab)/Ag ratio. In contrast to m-IgA IP, soluble m-IgA did not activate C. On the other hand soluble d-IgA IC activated C dependent on their concentration and size: at a concentration of 0.1 mg/ml high-molecular weight d-IgA IC with a high Ab/Ag ratio were four times as efficient as low-molecular weight IC with a low Ab/Ag ratio, and twice as efficient as IP prepared at equivalence. To demonstrate the induction by IgA of the assembly of the terminal membrane attack complex, trinitrophenyl (TNP)-conjugated rat red blood cells (TNP-RRBC) coated with d- or p-IgA were shown to be lysed in NRS in the presence of Mg-EGTA. No lysis of m-IgA-coated TNP-RRBC was observed. The results in this study demonstrate that both soluble and insoluble rat IgA IC activate the alternative pathway of homologous rat C. Alternative pathway activation by soluble rate IgA IC is dependent on the size of the IC. The degree of polymerization of the IgA Ab itself also influences C activation.

Animals↗
PubMed1998

Effects of 17 beta-estradiol on serum hormone concentrations and estrous cycle in female Crl:CD BR rats: effects on parental and first generation rats.

The recently passed Food Quality Protection Act of 1996 requires the U.S. EPA to implement screening strategies for endocrine active compounds (EACs) within the next 2 years. Interpreting results from screening tests is complicated by the absence of traditional dietary rodent bioassay data with model estrogenic compounds such as 17 beta-estradiol. Thus, a 90-day/one-generation reproduction study with 17 beta-estradiol was designed to: (1) provide such baseline data; (2) set dose levels for multigeneration reproduction and combined chronic toxicity/oncogenicity studies; and (3) evaluate various mechanistic/biochemical endpoints for inclusion in these follow-up studies. The current article describes the effects of dietary administration of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol on the serum hormone concentrations and estrous cyclicity of female Crl:CD BR rats and evaluates a sampling strategy for measuring serum hormone levels in cycling female rats. Serum hormones were measured at three time points during a 90-day dietary exposure (1 week, 28 days, and 90 days) and in the F1 generation rats on postnatal day 98. Over the course of the 90-day feeding study for the P1 generation and from postnatal days 21 to 98 for the F1 generation, the estrous cycle was monitored daily in 10 rats/group. In P1 generation rats, dietary administration of 2.5, 10, and 50 ppm 17 beta-estradiol produced a dose-dependent increase in serum estradiol (E2) concentrations at all time points. In contrast, administration of 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol produced a dose-dependent decrease in serum progesterone (P4) concentrations on test day 90, which correlated with an absence of corpora lutea and ovarian atrophy. At 10 and 50 ppm 17 beta-estradiol, serum luteinizing hormone (LH) concentrations were consistently decreased at all time points and were decreased at 2.5 ppm on test day 90. Serum prolactin (PRL) concentrations were increased at 50 ppm 17 beta-estradiol on test day 90. Serum follicle stimulating hormone (FSH) concentrations were either similar to the control levels or minimally changed at all time points. No F1 generation rats were produced at 10 or 50 ppm 17 beta-estradiol. In F1 generation rats, serum E2 concentrations were increased and P4 concentrations were decreased at a dietary concentration of 2.5 ppm 17 beta-estradiol, while serum concentrations of LH, FSH, and PRL were similar to the control. Dietary administration of 17 beta-estradiol at concentrations of 2.5 (both generations) and 10 and 50 ppm (P1 generation only) produced marked effects on the estrous cycle: decreased number of cycles, increased mean cycle length, and decreased number of normally cycling rats. The estrous cyclicity of rats fed 2.5 ppm 17 beta-estradiol appeared more severely affected in rats of the F1 generation than in rats of the P1 generation. Whether this increase in severity is related to an in utero exposure and/or greater mean daily intake of 17 beta-estradiol in the F1 generation rats in the postnatal period is unclear. Another goal of this study was to evaluate whether a single time point sampling strategy using cycling female rats could be used to detect compound-related changes in serum hormone concentrations. In evaluating a sampling strategy for measuring serum hormone levels, it appears that detection of compound-related alterations in serum hormone concentrations can be best detected by sampling during diestrus. Since the stage of the cycle dramatically influences hormone concentrations, large sample sizes (n = 50) are needed if serum hormone measurements are not matched with the stage of the cycle. The data indicate that this strategy of measuring serum hormone concentrations has utility in detecting compound-related effects within the confines of a traditional guideline study (subchronic, chronic, or multigenerational reproduction study).

Animals↗
PubMed2007

Effects of ertiprotafib on hepatic cytochrome P450 and peroxisomal enzymes in rats and dogs, and in rat and human primary hepatocytes.

Ertiprotafib (ERTI) significantly increased liver weights in male and female rats, and moderately increased liver weights in male dogs after treatment for 28 days. The present study tested the hypotheses that the organ weight increases were associated with peroxisome proliferation in rats and induction of hepatic enzymes in rats and dogs, and would have limited impacts on humans. At a dosage of 200 mg kg-1 day-1, CYP4A was induced by tenfold in male rats and 2.4-fold in female rats. In male rats, CYP2B was induced by 1.2-fold and CYP3A was induced by 1.7-fold. Palmitoyl CoA oxidase was induced by 5.1-fold in male rats and 2.9-fold in female rats; carnitine acetyltransferase was induced by 10.4-fold in male rats and 5.2-fold in female rats. CYP3A, CYP4A and peroxisomal enzymes were not induced in dogs at 150/200 mg kg-1 day-1. ERTI at 50 microM markedly induced the mRNA level of CYP4A by up to fivefold in rat hepatocytes, but not in human primary hepatocytes. In conclusion, the liver weight increases observed in rats treated with ERTI appears to be due to rodent-specific peroxisome proliferation and the substantial induction of CYP4A1. ERTI is not a potent P450 inducer in dogs or in human hepatocytes. Therefore, ERTI is not expected to exert any significant effects on hepatic drug-metabolizing enzymes in humans.

Animals↗
PubMed1976

Rat sequences of the Kirsten and Harvey murine sarcoma virus genomes: nature, origin, and expression in rat tumor RNA.

Two murine sarcoma viruses, the Kirsten and the Harvey, were isolated by passage of mouse type C leukemia viruses through rats. These sarcoma viruses have genomes containing portions of their parental type C mouse leukemia virus genomes, in stable association with specific rat cellular sequences that we find to be quite likely not those of a rat type C leukemia virus. To determine if these murine sarcoma viruses provide a model relevant to the events occurring in spontaneous tumors, we have hybridized DNA and RNA prepared from rat tumors and normal rat tissues to [3H]DNA prepared from the Kirsten murine sarcoma virus. We have also hybridized these rat tissue nucleic acids to [3H]DNA prepared from a respresentative endogenous rat type C leukemia virus, the WFU (Wistar-Furth). Sarcoma-viral rat cellular sequences and endogenous rat leukemia viral sequences were detected in the DNA of both tumor and normal tissues, with no evidence of either gene amplification or additional sequences being present in tumor DNA. Sarcoma-viral rat cellular sequences and endogenous rat leukemia viral sequences were detected at elevated concentrations in the RNA of many rat tumors and in specific groups of normal tissues.

Animals↗
PubMed1979

Evidence for Na-retaining humoral agents and vasoconstrictor humoral agents in hypertension-prone Dahl 'S' rats. Prevention of NaCl-induced hypertension in Dahl 'S' rats with thiazide.

Dahl 'S' rats become hypertensive when fed a high NaCl diet but remain normotensive on a low NaCl diet. Dahl 'R' rats are normotensive on either diet. For a given perfusion pressure, isolated 'S' kidneys excrete 50% less Na than 'R' kidneys. Therefore, we searched for a Na-retaining hormone in 'S' rats. Kidneys were isolated without ischemia from normal rats and were continuously perfused at 125 mm Hg with blood from Dahl 'S' and 'R' rats, all on low NaCl diets. Kidneys and adrenals had been extirpated from the perfusing rats. During 15 min of perfusion, the isolated 'normal' kidneys excreted a mean of 164 micronEq of Na/min/100 g during 26 perfusion experiments with blood from 'R' rats. The 'normal' kidneys excreted a mean of 84 micronEq Na during 24 perfusions with blood from 'S' rats. Thus, the normal kidneys excreted half as much Na when perfused with 'S' blood compared with 'R' blood (p less than 0.02). Seemingly, a Na-retaining humoral agent is present in the blood of 'S' rats on a low Na diet in the absence of renal and adrenal tissue. Moreover, in these normal kidneys, perfusion with 'S' blood induced a 16% higher renal vascular resistance than perfusion with 'R' blood (p less than 0.01), indicating vasoconstricting agents in 'S' blood. However, the Na-retaining humoral effect in 'S' blood could lead to Na retention by 'S' kidneys in vivo, which could partially account for the susceptibility of 'S' rats to NaCl hypertension. Hypertension in Dahl 'S' rats can be almost completely prevented by concomitant treatment with thiazide diuretics which act mainly on the kidney to facilitate Na excretion. This result is in agreement with the hypothesis that a shift in the pressure natriuresis curve, reducing Na excretion for a given arterial pressure, is partially responsible for the great sensitivity to NaCl hypertension in the 'S' rat. The Na-retaining hormone may contribute to this shift.

Animals↗
PubMed1987

Stimulation of supranormal growth in prepubertal, adult plateaued, and hypophysectomized female rats by large doses of rat growth hormone: physiological effects and adverse consequences.

A supranormal rate of growth in intact, prepubertal, 26-day-old female rats was evoked by administration of large doses of highly purified rat GH (rGH). In response to daily doses of 1 and 5 mg/rat (13.6 mg/kg BW and 68 mg/kg BW), sc, for 20 days, body weight (BW) gain increased 51% and 73%, and skeletal growth increased 27% and 40%, respectively. Serum rGH in treated rats rose as much as 69-fold greater than that of controls. Feed efficiency, the ratio of weight gained to feed consumed, increased from 19.8% to 32.0%. This rGH treatment depleted pituitary GH content as much as 58% and caused hepatomegaly. These effects, as well as the accelerated growth rate, reverted to normal after cessation of rGH treatment. Onset of puberty in rGH-treated rats was delayed an average of 2.7 days. A similar stimulatory effect on BW gain, but not skeletal growth, as well as depletion of pituitary GH content, and hepatomegaly, was elicited by rGH treatment in adult, plateaued female rats. These effects in plateaued rats reverted to normal after cessation of GH treatment, and 50% of the body weight gain was rapidly lost. The largest dose of rGH used, 5 mg/day, was apparently toxic, resulting in a 20% higher mortality rate in treated prepubertal and plateaued female rats. Antibody formation was not the cause of the toxicity, since antibodies against rGH were undetectable at the lowest dilutions of serum tested. Serum rat insulin-like growth factor I (RIA), 3.5 U/ml in untreated intact prepubertal rats, increased to 4.7 and 5.0 U/ml, respectively, after 20 days of rGH treatment. In hypophysectomized rats, serum rat insulin-like growth factor I (RIA), undetectable in controls, was increased to 1.63 U/ml after 14 days treatment with 1 mg rGH/day. This study demonstrates that greater than normal growth can be stimulated in normal female rats by administration of large doses of homologous GH, but at the risk of serious adverse effects. Possible implications for the administration of GH to non-GH-deficient children, to promote taller stature, are clear.

Animals↗
PubMed1988

N-(2,4-dinitrophenyl)-5-methoxytryptamine, a novel melatonin antagonist: effects on sexual maturation of the male and female rat and on oestrous cycles of the female rat [corrected].

N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] has recently been synthesized and shown to antagonize the inhibitory effect of melatonin on the release of dopamine in vitro from the hypothalamus of female rats. In the present study the ability of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] to inhibit in vivo the following melatonin-mediated effects was investigated: (1) delayed sexual maturation of young male rats, (2) delayed sexual maturation of young female rats, (3) inhibition of ovulation in mature female rats and (4) re-establishment of oestrous cycles in adult female rats maintained in continuous light. The inhibitory effect of daily melatonin injections, given in the afternoon, on the growth of the prostate gland and seminal vesicles and on serum testosterone concentrations in young male rats was prevented by daily injections of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected]. Daily injections of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] alone did not affect sexual maturation of young rats. In young male rats treated through the drinking water with melatonin, the growth of the accessory sex organs, but not that of the testes, was delayed and serum concentrations of testosterone were lower than in untreated rats. Administration of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] through the drinking water increased serum concentrations of testosterone but did not significantly affect the weights of the accessory sex organs. Simultaneous administration of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] and melatonin through the drinking water prevented completely, in a dose-dependent manner, the melatonin-mediated decrease in epididymal weights and in serum concentrations of testosterone and partially inhibited the delayed growth of the prostate glands and seminal vesicles. In young female rats treated with melatonin through the drinking water for 30 days, the growth of the ovaries was inhibited and serum concentrations of oestradiol were lower than in untreated rats. The growth of the uterus was not significantly affected. Administration of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] through the drinking water did not significantly affect uterine and ovarian weights or oestradiol concentrations. Simultaneous administration of melatonin and N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] through the drinking water prevented completely the melatonin-mediated decrease in ovarian weights and in serum oestradiol concentrations. Ovulation during presumptive oestrus was prevented in adult female rats treated through the drinking water for 7 days with melatonin. Administration of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] alone did not significantly affect the average numbers of ova shed and corpora lutea present. Simultaneous administration of N-(2,4-dinitrophenyl)-5-methoxytryptamine [corrected] and melatonin prevented completely the melatonin-mediated inhibition of ovulation; the average number of ova shed was the same as in controls.(ABSTRACT TRUNCATED AT 400 WORDS)

5-Methoxytryptamine↗
PubMed1989

Cholera toxin-induced fluid secretion in rat gut ligated loops: influence of bile from normal or cholera toxin-immunized rats.

Fresh normal rat bile premixed with cholera toxin (CT) did not significantly affect the CT-induced fluid accumulation in rat jejunal ligated loops. Bile from rats intrajejunally (i.j.) immunized three times with CT definitely inhibited CT-induced fluid secretion. Bile duct ligature (BDL) for 1-4 days in unimmunized rats, in contrast with mice, did not significantly affect subsequent CT-elicited fluid secretion in their ligated loops. BDL for 4 days in rats i.j. immunized with CT, only slightly decreased the CT-neutralizing ability of their gut loops. Passive transfer during 24 hr of bile from i.j.-immunized rats, but not from normal rats, into gut of normal recipient rats with BDL, significantly protected loops made in such recipients. The affinity-purified antibodies of immune bile, mixed with CT, neutralized its effect. Our data show that, unlike mice, rat bile acids are not required for expression of the CT effect in gut loops. In addition, bile from i.j.-immunized rats contains enough anti-CT antibodies to be protective on its own, but is not necessary for substantial gut protection against CT in i.j.-immunized BDL rats. Our results confirm a major and complementary role of both biliary and intestinal secretory IgA antibodies in protection of the rat gut mucosa against CT-induced fluid secretion.

Animals↗
PubMed1988

Variant forms of rat epidermal growth factor present in the urine of nude rats bearing human tumors.

Epidermal growth factor (EGF) receptor-binding peptides from the urine of tumor patients have been reported to differ in molecular weight and relative hydrophobicity from those of normal individuals. Nude rats bearing human large cell lung carcinomas or chondrosarcomas and non-tumor-bearing sibling control rats were used to investigate the contributions of tumor and host to urinary EGF-related peptide growth factors. Peptides were adsorbed from urine onto methyl-bonded silica and eluted according to their relative hydrophobicity by a stepwise gradient of aqueous acetonitrile. Total EGF receptor-binding activity relative to urinary creatine was elevated in the urine of only one group of tumor-bearing rats. However, the proportion of relatively hydrophilic activity was increased markedly in all three groups of tumor-bearing rats. Rats bearing a large cell lung cancer excreted unusually hydrophilic Mr 6000 peptides that were chromatographically similar to transforming growth factor alpha on reverse phase high performance liquid chromatography but proved to be rat EGF by radioimmunoassay (RIA). EGF receptor-binding activity that was common to the urine of tumor-bearing animals regardless of tumor type, but more hydrophilic than that from control rats, had Mr 60,000, 30,000, 12,000, and 4,000 to 7,000 components. All reacted fully in the rat EGF RIA and were negative for human EGF and transforming growth factor alpha by RIA. A more hydrophobic fraction of EGF receptor-binding activity, common to control and tumor-bearing animals, contained Mr 33,000, 5,000 to 7,000, and 2,000 to 5,000 components. High performance liquid chromatography and gel electrophoresis of the Mr 33,000 activity revealed a high molecular weight rat EGF comparable to that reported in human urine. No human EGF or transforming growth factor alpha was detected by RIA in any of the active fractions from tumor-bearing rat urine. Thus, all EGF receptor-binding activity appeared to derive from rat EGF produced by the rat host and not by the xenografted tumors.

Animals↗
PubMed1984

Interactions of purified rat factor VIII/von Willebrand factor with rat and human platelets--effect of albumin and ristocetin.

Rat platelets do not respond to ristocetin in their own plasma nor do they aggregate in the presence of bovine or porcine factor VIII von Willebrand factor (F VIII R:WF) or human F VIII R:WF in presence of ristocetin. However, rat plasma supports ristocetin induced aggregation of washed human platelets. In this study we report on purification of rat F VIII R:WF from cryoprecipitate. Similarly to porcine or bovine material, purified rat F VIII R:WF induced aggregation of human washed fixed platelets. This effect was enhanced by addition of ristocetin and was not modified by addition of albumin. Rat washed platelets were aggregated by ristocetin in the presence of rat or human F VIII R:WF provided that high concentrations of ristocetin are added in a system essentially free of extraneous proteins. Increasing concentrations of albumin dramatically reduced the ability of ristocetin to aggregate rat platelets while human platelet aggregation by human or rat F VIII R:WF was only moderately affected. These studies show that rat F VIII R:WF can interact with rat and human platelets. The lack of response of rat platelets to ristocetin in their own plasma is most likely due to a low sensitivity of rat platelets to this drug and to an inhibitory activity of plasma proteins on this reaction.

Animals↗
PubMed1993

The origin of the autoimmune disease-resistant LER rat: an outcross between the buffalo and autoimmune disease-prone Lewis inbred rat strains.

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear. We report the analysis of 19 simple dinucleotide repeat polymorphisms in 13 rat strains including the LEW/N and LER/N rat strains. The LEW/N and LER/N alleles were the same in only 42% of cases. For all of the other polymorphisms, the LER/N and Buffalo (BUF/N) rat strain alleles were identical. These data provide evidence that the LER strain did not arise as a spontaneous mutation in the LEW strain but is the result of an outcross between the LEW and BUF rat strains. The LER rat strain is now a recombinant inbred rat strain. This information should facilitate the genetic analysis of the loci responsible for resistance to experimental autoimmune disease in the LER rat.

Alleles↗
PubMed1990

Homologous type II collagen-induced arthritis in rats. Characterization of the disease and demonstration of clinically distinct forms of arthritis in two strains of rats after immunization with the same collagen preparation.

Arthritis was induced in Lewis and DA rat strains after immunization with native homologous type II collagen (CII). Differences were noted in the clinical signs of arthritis in the 2 rat strains, which were immunized with the same arthritogenic preparation of CII. DA rats showed disease onset characterized by symmetric involvement of the interphalangeal joints of the hind feet. Lewis rats showed disease onset characterized by involvement of only the ankle or knee joints. Moreover, the arthritis tended to be chronic (i.e., persistent and variable redness and swelling seen in interphalangeal joints) in DA rats, but not in Lewis rats. Analysis of the delayed-type hypersensitivity reaction to CII and anti-CII autoantibody production demonstrated the presence of T cell, as well as B cell, reactivity to rat CII in both strains of rat. A spontaneous T cell reactivity to CII, as measured by rat CII-induced ear swelling, was observed in nonimmunized DA rats, but not in nonimmunized Lewis rats. The demonstration that clinical features of arthritis induced with identical arthritogenic stimuli are different depending on the genetic background of the affected animal may be relevant in understanding the heterogeneity of the clinical features of human inflammatory joint disease.

Animals↗
PubMed1994

Glomerular metalloprotease activity in streptozotocin- treated rats and in spontaneously diabetic rats (BB/DP).

Differences in the type and extent of diabetic glomerular injury occur in rats made diabetic with streptozotocin (STZ) and in a spontaneously diabetic rat model of the BB/Wor strain. The diabetes prone (BB/DP) rat develops no mesangial matrix expansion with diabetes, whereas the STZ-treated Sprague Dawley rat does. The present study was performed to determine if glomerular metalloprotease activities were decreased in these two rat models of diabetes. Rats were studied at 8 weeks following the onset of hyperglycemia. All diabetic rats were maintained moderately hyperglycemic (plasma glucose = 350 mg/dL) with daily injection of insulin. Glomerular preparations were made and metalloprotease activities were assayed by hydrolysis of gelatin. Metalloprotease activities were decreased by 40-50% in STZ-treated Sprague Dawley rats, but not in BB/DP rats or diabetes resistant rats (BD/DR--the control for the BB/DP) made diabetic by STZ-injection. These data suggest that the decrease in glomerular metalloprotease activity may contribute to mesangial matrix expansion in the diabetic Sprague Dawley rats.

Analysis of Variance↗