Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein.
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We previously have reported corpus callosum defects in transgenic mice expressing the beta-amyloid precursor protein (betaAPP) with a deletion of exon 2 and at only 5% of normal levels. This finding indicates a possible involvement of betaAPP in the regulation or guidance of axon growth during neural development. To determine to what degree the betaAPP mutation interacts with genetic background alleles that predispose for forebrain commissure defects in some mouse lines, we have assessed the size of the forebrain commissures in a sample of 298 mice. Lines with mixed genetic background were compared with congenic lines obtained by backcrossing to the parental strains C57BL/6 and 129/SvEv. Mice bearing a null mutation of the betaAPP gene also were included in the analysis. We show that, independently of genetic background, both lack and underexpression of betaAPP are associated with reduced brain weight and reduced size of forebrain commissures, especially of the ventral hippocampal commissure. In addition, both mutations drastically increase the frequency and severity of callosal agenesis and hippocampal commissure defects in mouse lines with 129/SvEv or 129/Ola background. (+info)
Contribution of baroreceptors and chemoreceptors to ventricular hypertrophy produced by sino-aortic denervation in rats.
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1. To test whether sino-aortic denervation (SAD)-induced right ventricular hypertrophy (RVH) is a consequence of baroreceptor or chemoreceptor denervation, we compared the effects of aortic denervation (AD), carotid denervation (CD), SAD and a SAD procedure modified to spare the carotid chemoreceptors (mSAD), 6 weeks after denervation surgery in rats. A sham surgery group served as the control. 2. The blood pressure (BP) level was unaffected by AD, CD or SAD, but increased (9 %) following mSAD. The mean heart rate level was not affected. Short-term BP variability was elevated following AD (81 %), SAD (144 %) and mSAD (146 %), but not after CD. Baroreflex heart rate responses to phenylephrine were attenuated in all denervation groups. 3. Significant RVH occurred only following CD and SAD. These procedures also produced high mortality (CD and SAD) and significant increases in right ventricular pressures and haematocrit (CD). 4. Significant left ventricular hypertrophy occurred following CD, SAD and mSAD. Normalized left ventricular weight was significantly correlated with indices of BP variability. 5. These results suggest that SAD-induced RVH is a consequence of chemoreceptor, not baroreceptor, denervation. Our results also demonstrate that a mSAD procedure designed to spare the carotid chemoreceptors produced profound baroreflex dysfunction and significant left, but not right, ventricular hypertrophy. (+info)
Resistance to remnant nephropathy in the Wistar-Furth rat.
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The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164+/-5 [Wistar-Furth] versus 184+/-7 [Wistar] mm Hg mean arterial pressure), with sham animals remaining normotensive (134+/-6 mm Hg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7+/-4.2 [Wistar-Furth] versus 97.4+/-22.6 [Wistar] mg/d per 100 g body wt, P<0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P<0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144+/-8 mm Hg [Wistar] versus 157+/-7 mm Hg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction. (+info)
Growth hormone promotes somatic and skeletal muscle growth recovery in rats following chronic protein-energy malnutrition.
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The efficacy of recombinant human growth hormone (GH) and/or a diet enriched in protein and energy to improve growth recovery following prolonged malnutrition was examined in male rats food-restricted from birth until 120 d of age. At d 121, restricted rats were randomly assigned to recovery groups receiving either a control or enriched diet with or without daily subcutaneous injections of GH. Rats were killed after 16 or 47 d of recovery. At d 16, GH treatment stimulated liver, heart, plantaris, soleus, carcass and body weight gain and inhibited fat gain when compared to recovery controls. Rats receiving GH also exhibited the highest serum insulin-like growth factor-I (IGF-I) concentrations and total muscle protein. At d 47, GH effects on body and muscle recovery were minimal, and differences among recovery groups in serum IGF-I concentration and total muscle protein were no longer present. Consumption of an enriched diet increased fat pad and liver mass, but did not promote muscle recovery. There were no differences among treatment groups in skeletal muscle IGF-I mRNA levels at d 16 or 47. In summary, GH had positive effects on somatic and skeletal muscle growth early in the recovery process, possibly via endocrine IGF-I-stimulated protein accretion. In contrast, the enriched diet promoted fat deposition with no impact on skeletal muscle growth recovery. (+info)
Increased fecal bile acid excretion and changes in the circulating bile acid pool are involved in the hypocholesterolemic and gallstone-preventive actions of psyllium in hamsters.
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The lipid-lowering effect of psyllium (PSY) is well established. Enhanced fecal bile acid excretion and a stimulation of hepatic bile acid synthesis are discussed as primary mechanisms of this action. To further examine the effect of bile acid excretion and specifically of compositional alterations in the bile acid pool on the cholesterol-lowering and gallstone-preventing action of PSY, male golden Syrian hamsters were fed lithogenic diets containing 5 g/100 g fat, 0.4 g/100 g cholesterol and 0 (control), 4 or 6% PSY or 1% cholestyramine (CHY). PSY significantly lowered plasma total cholesterol and triacylglycerol at a magnitude comparable to that induced by CHY. Although hepatic cholesteryl ester accumulation was completely inhibited by CHY, PSY did not prevent the hepatic storage of esterified cholesterol. PSY and CHY caused distinct alterations in the bile acid profile. PSY caused a selective reduction of taurine-conjugated bile acids, especially of taurochenodeoxycholate. As a result, the glycine:taurine conjugation and the cholate:chenodeoxycholate ratios were significantly higher in PSY-fed hamsters. PSY and CHY normalized the lithogenic index and prevented cholesterol gallstone formation compared with controls. Daily fecal bile acid excretion was approximately 400% greater in hamsters fed 6% PSY, whereas CHY caused an 11-fold increase. Daily neutral sterol excretion did not differ in PSY-fed hamsters but was >100% greater in those fed CHY than in controls. These data emphasize the potent lipid-lowering effect of PSY. Increased fecal bile acid excretion and alterations of the circulating bile acid pool by removal of dihydroxy bile acids (e.g., taurochenodeoxycholate) appear to be main modulators of the hypocholesterolemic action of PSY by leading to an up-regulation of hepatic bile acid synthesis. (+info)
Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits.
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The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308+/-39) and lowest in the TE group (61+/-12), but was intermediate in the DHEA (155+/-30), TU (191+/-43), and sham operation (162+/-29) groups (ANOVA, P<0.0001). ANCOVA indicated that the androgen effect on aortic atherosclerosis was only in part explained by the changes in lipoproteins. Aortic estrogen receptor contents were significantly lower in the androgen-treated groups than in the control groups, whereas there was no difference in aortic androgen receptor contents between groups. Natural androgens inhibit aortic atherosclerosis in castrated male rabbits only partly through a lipid-mediated effect. (+info)
The effects of glutamine on intestinal epithelial cell proliferation in parenterally fed rats.
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BACKGROUND: Several papers have indicated that glutamine is a preferred fuel for the enterocyte and that it can increase intestinal epithelial cell proliferation. AIMS: To investigate the effects of glutamine on intestinal epithelial cell proliferation in the parenterally fed rat. METHODS: Five groups of six rats were fed parenterally; a group of orally fed rats was also studied. Crypt cell proliferation was studied after six days using native mitoses in microdissected crypts and bromodeoxyuridine labelling. RESULTS: No effect of treatment was seen on intestinal weight; however, the weights of the small intestine, caecum, and colon were all significantly heavier in the orally fed group than in the total parenteral nutrition groups (p<0.001). There was no effect of any of the glutamine treatments on mitotic activity in the small intestine. In the colon there was a small increase in native mitoses with glutamine (p=0.03). There was also an indication of increased proliferative activity in the first fifth of the small intestine and colon with glutamine. Little effect of glutamine on bromodeoxyuridine labelling in either site was observed, but there was a small but significant reduction in growth fraction of the colon of the glutamine treated group. The labelling distribution curve from sections and the mitotic distribution curve obtained from crypt squashes showed a good correlation. CONCLUSION: Glutamine has a small, but significant effect on mitotic activity but only in the colon. Modest effects on the distribution of labelled cells were also seen. (+info)
Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice.
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Heme oxygenase (HO) catalyzes the oxidation of heme to generate carbon monoxide (CO) and bilirubin. CO increases cellular levels of cGMP, which regulates vascular tone and smooth muscle development. Bilirubin is a potent antioxidant. Hypoxia increases expression of the inducible HO isoform (HO-1) but not the constitutive isoform (HO-2). To determine whether HO-1 affects cellular adaptation to chronic hypoxia in vivo, we generated HO-1 null (HO-1(-/-)) mice and subjected them to hypoxia (10% oxygen) for five to seven weeks. Hypoxia caused similar increases in right ventricular systolic pressure in wild-type and HO-1(-/-) mice. Although ventricular weight increased in wild-type mice, the increase was greater in HO-1(-/-) mice. Similarly, the right ventricles were more dilated in HO-1(-/-) mice. After seven weeks of hypoxia, only HO-1(-/-) mice developed right ventricular infarcts with organized mural thrombi. No left ventricular infarcts were observed. Lipid peroxidation and oxidative damage occurred in right ventricular cardiomyocytes in HO-1(-/-), but not wild-type, mice. We also detected apoptotic cardiomyocytes surrounding areas of infarcted myocardium by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) assays. Our data suggest that in the absence of HO-1, cardiomyocytes have a maladaptive response to hypoxia and subsequent pulmonary hypertension. J.Clin. Invest. 103:R23-R29 (1999). (+info)