Inbred Rat Model Research Articles

Association of Alcohol Craving With α‐Synuclein (SNCA)

Studies have found that genomic variation in the gene SNCA, which encodes the protein alpha-synuclein, may contribute to the variation in alcohol consumption in an inbred rat model of alcohol preference. Studies in humans have provided support for an association between SNCA and craving for alcohol. To examine the role of this gene in alcohol dependence and related phenotypes, 30 single nucleotide polymorphisms (SNPs) were genotyped across the SNCA gene in a sample of 219 multiplex alcoholic families of European American descent. Two phenotypes, alcohol dependence and alcohol craving, were analyzed using the pedigree disequilibrium test. There was no evidence of association between any of the SNCA SNPs and alcohol dependence (p>or=0.13). In contrast, 8 SNPs provided evidence of association (p<0.05) with the phenotype of alcohol craving. Haplotype analysis further supported evidence of an association with alcohol craving; a haplotype encompassing SNPs in intron 4 through the region downstream of the gene was overtransmitted to cravers and a second haplotype was overtransmitted to noncravers. These results suggest that variation in SNCA contributes to alcohol craving, a common, although not uniform, feature of alcohol dependence.

Effect of orthotopic small bowel transplantation on mineral metabolism in an experimental model

Numerous experimental models have been described for investigation of short bowel syndrome. The aim of this study was to examine the effect of orthotopic small bowel transplantation (OSBT) on universal metabolism in an inbred rat model, with particular emphasis on mineral metabolism. Jejunoileal resection and syngeneic OSBT was performed in 12-week-old male Lewis rats. Metabolic studies were performed over the following 16 weeks. Bones were analysed by physicochemical methods, dual X-ray absorptiometry, biomechanical procedures and histomorphometry. Biochemical markers of bone turnover were also measured. Jejunoileal resection induced severe short bowel syndrome with profoundly reduced food efficiency, bone size, fracturing energy and bone mineral content, but no cancellous bone osteopenia. After OSBT rats showed normal growth; bones were of normal size, and bone mineral content and fracturing energy were similar to those in sham-operated controls. However, tibial, but not vertebral, cancellous bone osteopenia was found after transplantation. OSBT with portal venous drainage achieves almost optimal mineral and bone metabolism. In the absence of immunosuppressive therapy, OSBT does not appear to have major untoward side-effects on bone in rats.

A &lt;I&gt;TASK3&lt;/I&gt; Channel (&lt;I&gt;KCNK9&lt;/I&gt;) Mutation in a Genetic Model of Absence Epilepsy

Childhood absence epilepsy is an idiopathic, generalized, nonconvulsive epilepsy with a multifactorial genetic etiology. The KCNK9 gene coding for the TASK3 (Twik-like acid-sensitive K</U)+) channel is present on chromosome 8 at position 8q24, a locus that has shown positive linkage to the human absence epilepsy phenotype. Sequencing of the KCNK9 gene in the genetic absence epilepsy rats from Strasbourg (GAERS), a well established genetic model of this disease, reveals an additional alanine residue in a polyalanine tract within the C-terminal intracellular domain. This additional alanine is absent in the inbred nonepileptic control (NEC) strain, Wistar, and Wistar albino Glaxo strain bred in Rijswijk, another inbred rat model of absence epilepsy. Expression of the mutant channel in CHO cells produces a K+ current that is blocked by acidic pH and millimolar concentrations of barium or ruthenium red and is not different from the wild-type channel. In brain slices, thalamic neurons display a prominent pH-sensitive tonic K+ current, but no difference was observed between GAERS and NEC or Wistar rats. Ruthenium red had no effect in cortical, reticular thalamic, or sensory thalamic neurons in either GAERS or NEC, indicating that the TASK3 homodimer is not present in these structures. Twik-like acid-sensitive K+(TASK3) channels, therefore, are probably associated with TASK1 to form ruthenium red-insensitive heterodimers in these neurons. Finally, no difference was found between GAERS and NEC rats in the modulation of the leak K+ current following activation of muscarinic receptors. These studies describe the first mutation found in a genetic model of absence epilepsy. Although our experiments showed no difference in the leak K+ current between GAERS and NEC rats, further work is needed to ascertain whether this mutation contributes to the generation of absence seizures, possibly by mechanisms related to the expansion of the polyalanine run.

Mapping the genetic determinants of hypertension, metabolic diseases, and related phenotypes in the lyon hypertensive rat.

The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.

METANEPHROS TRANSPLANTATION BETWEEN NON-HISTOCOMPATIBLE RATS RESULTS IN REJECTION WHILST INBRED TRANSPLANTS ARE NOT REJECTED AND DEMONSTRATE MEASUREABLE FUNCTION.

P1203 Aims: Loss of kidney function resulting in end-stage renal failure is a major clinical problem with a wide variety of causes. One potential approach is transplantation of foetal kidney rudiments with subsequent, microsurgical connection of the transplant ureter to the recipient excretory tract. Methods: We have transplanted E14-E15.5 metanephroi to the abdominal cavity of more than 100 inbred (Lewis) rats. These animals were reexplored after 17-21 days and microsurgical anastamosis of the transplant ureter to the host excretory tract performed wherever possible. At a third procedure urine of metanephric origin was collected after diversion or removal of remaining host renal tissue. Glomerular filtration rates were estimated. Using identical methodology, we transplanted 126 E14-E15.5 sprague-dawley (outbred) metanephroi into the abdominal cavity of 36 sprague-dawley rats. In addition, we transplanted 10 sprague-dawley metanephroi to 2 nude rats. Outbred transplants were assessed after 7, 12, 16, 21 and 25 days following implantation Results: Inbred transplants undergo growth and differentiation with essentially normal renal histology. The transplants develop cystic dilatation of their excretory tracts which contain fluid with a more than 10-fold higher concentration of urea than plasma consistent with production of urine. Following successful microsurgical connection of transplant ureters to the recipient urinary tract, we have also demonstrated metanephric urine production and measureable glomerular filtration of up to 62.6 (+/- 6.8) μls/min/100g body weight. All transplants between outbred animals were identifiable at 7 and 12 days whilst thereafter, decreasing proportions were identifiable with only 61% of transplants present after 25 days. Histology showed all normal renal components present in all transplants after 7 days, whilst at the later time points, there was progressive immunological rejection with destruction of renal tissue architecture. This is confirmed on immunostaining for a variety of markers including MHC, macrophages and the T cell receptor. After 25 days, those transplants still identifiable showed near total rejection or fibrosis. No outbred transplants exhibited cystic dilatation and, whilst in 7 animals anatomical connection of the transplant ureter to the host ureter was possible, none made metanephric urine. Transplants of sprague-dawley metanephroi to nude rats showed normal growth and histology without any demonstrable rejection. Conclusions: These findings are in keeping with many previous experiments on the transplantation of embryonic tissues but distinct from previous reports of abdominal metanephros transplantation utilising outbred or non-histocompatible rat strains. The severity and kinetics of the rejection observed in our model is in keeping with that seen in solid organ transplants. Reproduceible transplant growth and function is demonstrated in an inbred rat model. Extensive data exists on the effects of current, clinical immunosuppressives on renal development from the offspring of mothers receiving immunosuppression but in such cases the developing metanephros is separated from the circulating drug by two circulations and a placenta. The direct effects of these drugs on the growth and development of metanephric transplants are largely unknown. These findings suggest that a permissive immunosuppressive regime will be necessary for successful transplantation of foetal anlagen between non-identical individuals.

Hepatic cholangiodysplastic pseudocirrhosis with multiple disseminated intrahepatic nodules of pancreatic tissue

We developed an inbred rat model of diabetic embryopathy, in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Our aim was to find genes controlling the embryonic maldevelopment in a diabetic environment.We contrasted the fetal outcome in inbred Sprague-Dawley L rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats (denoted W, no skeletal malformations in diabetic pregnancy). We used offspring from the backcross F1 × L to probe for the genetic basis for malformation of the mandible in diabetic pregnancy. A set of 186 fetuses (93 affected, 93 unaffected) was subjected to a whole genome scan with 160 micro satellites. Analysis of genotype distribution indicated 7 loci on chromosome 4, 10 (3 loci), 14, 18, and 19 in the teratogenic process (and 14 other loci on 12 chromosomes with less strong association to the malformations), several of which contained genes implicated in other experimental studies of diabetic embryopathy. These candidate genes will be scrutinized in further experimentation.We conclude that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations.

Localization, cDNA sequence and genomic organization of the rat seipin gene (Bscl2) and sequence analysis in inbred rat models of Type 2 diabetes mellitus

Mutations in the gene encoding seipin cause Berardinelli-Seip congenital lipodystrophy 2, with symptoms including near-absence of adipose tissue and altered glucose tolerance. Radiation hybrid analysis localized the seipin gene (Bscl2) in rat to a major quantitative trait locus in rat chromosome 1 linked to glucose intolerance in the Goto-Kakizaki (GK) rat model of Type 2 diabetes. We determined the genomic organization of Bscl2 and screened coding exons and flanking intron sequences for mutations in GK, Wistar and Brown Norway rats, as well as in the Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rat. Two silent single nucleotide polymorphisms that were identified also were found in non-diabetic rat strains. We conclude that mutations in the gene for seipin are unlikely to contribute to diabetes in GK and OLETF rats.

Controlled Hypertension, a Transgenic Toggle Switch Reveals Differential Mechanisms Underlying Vascular Disease

A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.

Variability in skeletal mass, structure, and biomechanical properties among inbred strains of rats.

The aim of this study was to assess the usefulness of the inbred rat model for studies of genetic influences on skeletal fragility. We characterized bone mass, geometry, and skeletal biomechanics in 11 inbred strains of rats. This study showed that considerable variation exists in bone structure, areal bone mineral density (aBMD), and fragility phenotypes among inbred strains of rats. Interestingly, the variability in skeletal phenotypes in rats was site specific, suggesting that no single gene regulates skeletal fragility at all sites. For instance, the Copenhagen 2331 (COP) strain had the greatest biomechanical properties in the femoral neck but only modest bone strength at the femoral midshaft, compared with other strains. Consequently, COP rats appear to have alleles that specifically enhance femoral neck biomechanical properties and may serve as a model for studying genetic influences on hip strength. The Brown Norway (BN) and Fischer 344 (F344) strains may provide models for vertebral fragility because each has relatively fragile lumbar vertebrae. The F344 rats also had the most fragile femora and, thus, appear to carry alleles that cause overall skeletal fragility. We identified two inbred rat crosses that will facilitate the study of genetic influences on skeletal fragility at clinically relevant skeletal sites: Lewis (LEW) with F344 (primarily for vertebral fragility) and COP with DA (primarily for femoral neck fragility). The results strongly suggest that selected crosses of inbred strains of rats will provide useful models for studying genetic influences on bone strength and structure.

Cytokine and chemokine expression kinetics after corneal transplantation.

Allogeneic rejection is the most common cause of corneal graft failure. The aim of this work was to establish the kinetics of cytokine and chemokine mRNA expression before and after onset of corneal graft rejection. Intracorneal cytokine and chemokine mRNA levels were investigated in the Brown Norway-->Lewis inbred rat model in which rejection onset is observed at 8/9 days after grafting in all animals. Nongrafted corneas and syngeneic (Lewis-->Lewis) corneal transplants were used as controls. Donor and recipient cornea was examined by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) for hypoxyanthine phosphoribosyltransferase (HPRT), CD3, CD25, interleukin (IL)-1beta, IL-1RA, IL2, IL-6, IL-10, interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), transforming growth factor (TGF)-beta1, and macrophage inflammatory protein (MIP)-II and by nonquantitative RT-PCR for IL4, IL-5, IL-12 p40, IL-13, TGF-beta2, monocyte chemotactic protein-1 (MCP-1), MIP-1alpha, MIP-1beta, and RANTES (for regulated upon activation normal T cell expressed and secreted). A biphasic expression of cytokine and chemokine mRNA was found after transplantation. During the early phase (days 3-9), there was an elevation of the majority of the cytokines examined, including IL-1beta, IL-6, IL-10, IL-12 p40, and MIP-II. There was no difference in cytokine expression patterns between allogeneic or syngeneic recipients at this time. In syngeneic recipients, cytokine levels reduced to pretransplant levels by day 13, whereas levels of all cytokines rose after observed rejection onset in the allografts, including TGF-beta1, TGF-beta2, and IL-1RA. The T cell-derived cytokines IL-4, IL-13, and IFN-gamma were detected only during the rejection phase in allogeneic recipients. There is an early cytokine and chemokine response to the transplantation process, evident in syngeneic and allogeneic grafts, that probably drives angiogenesis, leukocyte recruitment, and affects leukocyte functions. After an immune response has been generated, allogeneic rejection results in the expression of Th1 cytokines (IL-2, IL-12 p40, IFN-gamma), Th2 cytokines (IL-4, IL-6, IL-10, and IL-13), and antiinflammatory/Th3 cytokines (TGF-beta1/2 and IL-1RA).

Genetic analysis of essential hypertension in Japanese populations.

The reverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the genetic cause of essential hypertension. Using the rat cross model, studies of the genetically hypertensive inbred rat model indicated several candidate loci on the rat chromosome responsible for blood pressure, but failed to identify the exact causal gene. Moreover, it was not certain that the rat data really reflect the human case. Thus, we shifted our focus to human genetics and carried out case control studies using the candidate gene approach. We mainly focused on gene components of the renin-angiotensin system as candidates, finding that angiotensinogen gene polymorphisms are genetic predisposing factors for hypertension. However, the results obtained from case-control studies using Japanese subjects were not consistent, suggesting that there was a problem in control sampling. In our recent study, we recruited more than 5,000 residents of an urban community as a general population and examined the association between genetic factors and their health status. Our results indicate that angiotensin-converting enzyme gene polymorphism is a male-specific genetic risk for essential hypertension. In light of our previous investigations, we present a discussion concerning the design of future studies of the genetics of hypertension.

Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity.

The Dark Aouti (DA) inbred strain of rats has superior aerobic treadmill running capacity compared with the Copenhagen (COP) strain of inbred rats. This difference in aerobic capacity provides a model to explore the genetic basis of variation in this trait. The present study evaluated intermediate phenotypic differences between 10 male COP inbred rats and 10 male DA inbred rats that might contribute to the difference in aerobic capacity between the strains. Five autonomically regulated cardiovascular variables were evaluated during rest or exercise by measuring the response to autonomic antagonists. The DA rat had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. Specifically, at rest the DA rats had significantly more sympathetic (123 +/- 8 vs. 99 +/- 7 beats/min) and parasympathetic (35 +/- 5 vs. 12 +/- 3 beats/min) tonus for heart rate control and more sympathetic support of blood pressure (70 +/- 7 vs. 38 +/- 6 mmHg) compared with the COP rats. During three graded levels of treadmill exercise the DA rats had higher blood pressures (16% on average) and higher heart rates (4% on average) relative to the COP rats. In addition, the DA rats had a 27% greater heart weight-to-body weight ratio compared with the COP strain of rats (3.63 +/- 0.08 vs. 2.85 +/- 0.07 g/kg). All five of these intermediate phenotypes could participate as variables causative of the difference in treadmill running capacity between the DA and COP strains of rats.

From animal models to humans.

1. Essential hypertension is a mixture of several 'hypertensions' with different aetiologies. Analyses of inbred rat models of hypertension have so far provided several candidate loci and genes that may be responsible for hypertension. Among them, SA and alpha-adducin were evaluated in humans both by linkage and association analyses. However, the results are still controversial. Two major reasons may account for these discrepancies. 2. Heterogeneity of human essential hypertension still keeps us from comprehensive conclusions. Comparative analysis of more than one homogeneous population may be necessary to overcome this problem. 3. As in the case of SA, a lack of information on the physiological or pathophysiological roles of candidate genes makes it difficult to evaluate them in human hypertension. Efforts to find good intermediate phenotypes regulated directly by putative hypertension genes are essential to dissect a heterogeneous mixture of 'hypertensions'. In this context, physiological studies on congenic strains as well as conventional rat models will become important.

Complement Activation Accelerates Glomerular Injury in Diabetic Rats

A known inhibitor of the complement cascade (K-76 COONa) was administered to an inbred diabetic rat model to investigate whether the complement system may play a role in the progression of diabetic glomerulosclerosis. Drinking water containing K-76 COONa was available continuously to inbred diabetic rats (Otsuka Long-Evans Tokushima Fatty, OLETF) from the age of 25 to 55 weeks (Group L). Drinking water without K-76 COONa was similarly available to OLETF rats (Group H) and nondiabetic control rats (Long-Evans Tokushima Otsuka, LETO) (Group C). The levels of plasma glucose (mg/dl) at the 55th week were 156 ± 16 in Group C, 252 ± 18 in Group L and 349 ± 93 in Group H. There was no significant difference in the degree of diabetes between Group L and Group H. The levels of urinary protein at 55 weeks of age (mg/day) were 2.1 ± 0.4 in Group C, 11.6 ± 1.5 in Group L and 18.0 ± 2.8 in Group H. The level of urinary protein was significantly decreased by the administration of K-76 COONa. Histological examination of renal specimens from the sacrificed rats at 55 weeks of age revealed diffuse mesangial expansion in almost all glomeruli in Group H, exudative lesions in 30% of glomeruli in Group H, and only mild mesangial expansion was recognized in Group L. Immunofluorescence study revealed brilliant staining of C3 and immunoglobulins (Ig) in Group H; trace staining of Ig and no staining of C3 were recognized in Group L. The incubation study with guinea pig serum and glomeruli from rats revealed that Ig and complement components also bound to injured glomeruli in vitro. These data indicate that the complement cascade is activated by injured glomeruli and this activation exacerbates diabetic glomerulosclerosis.

The effects of liver transplantation and cyclosporine on bile formation and lipid composition: an experimental study in the rat

Background/Aims: Hepatic graft dysfunction is a major management problem in the early post-liver transplantation period. Our aims were to study how liver transplantation per se affects bile formation, and to investigate the role of cyclosporine in the pathogenesis of early graft dysfunction. Methods: Syngeneic liver transplantation used male Lewis rats. Two weeks after transplantation, the rats were randomly assigned to receive either daily subcutaneous injections of cyclosporine 10 mg/kg for 1 week ( n=8), or daily saline injections (Placebo, n=8). 24-h bile collections were performed 18 h after the last injection. Eight non-transplanted rats served as controls. Results: Liver transplantation per se (Placebo) significantly increased basal bile flow (51%), particularly that portion which was bile salk-independent flow (81%), but did not impair bile kinetics or biliary lipid composition. Cyclosporine reduced basal bile flow and bile salt-independent flow by 41% and 30%, respectively. Bile salt synthesis was 52% suppressed, leading to a 22% decrease in the bile salt pool size. The recycling frequency of the bile salt pool was unaffected. The drug inhibited bile salt (37%) and phospholipid (23%) outputs; cholesterol secretion remained unaltered. This significantly elevated the cholesterol saturation of bile (25%). Conclusions: Liver transplantation per se is choleretic and does not impair bile formation or lipid composition in this inbred rat model. Parenteral administration of high-dose cyclosporine induces cholestasis by inhibiting bile salt secretion and BSIF. Bile salt synthesis is down-regulated and the bile salt pool size decreased. The drug adversely affects biliary lipid composition by differential inhibition of bile salt and phospholipid outputs relative to an unchanged cholesterol secretion.

Higher Frequency of Aberrant Crypt Foci in Rapid Than Slow Acetylator Inbred Rats Administered the Colon Carcinogen 3,2′-Dimethyl-4-aminobiphenyl

Humans and other mammals such as rats exhibit a genetic polymorphism in acetyltransferase (NAT2) capacity, yielding rapid and slow acetylator phenotypes. The rapid acetylator phenotype has been associated with increased incidence of human colorectal cancer in some, but not all, epidemiological studies. In order to investigate this possible association, a rapid (F-344) and slow (WKY) acetylator inbred rat model was utilized to investigate the role of the acetylator genotype (NAT2) in the formation of aberrant crypt foci (ACF) following administration of colon carcinogens. Age-matched (retired breeder) female rapid and slow acetylator inbred rats received two weekly injections (50 or 100 mg/kg, sc) of 3,2′-dimethyl-4-aminobiphenyl (DMABP) or a single 50 mg/kg, sc, injection of 1,2-dimethyl-hydrazine (DMH). The rats were euthanized at 10 weeks and ACF were evaluated in the cecum, ascending, transverse, and descending colon, and rectum. ACF were observed in the colon and rectum, but not the cecum of rapid and slow acetylator inbred rats administered DMABP or DMH. ACF were more concentrated in the descending colon. ACF frequencies were significantly higher in colons of rapid than slow acetylator inbred rats administered DMABP, a colon carcinogen which is activated viaO-acetylation catalyzed by polymorphic acetyltransferase (NAT2). At 50 mg/kg, ACF frequency in the distal colon was 2.29 ± 0.57 in rapid acetylators versus 0.38 ± 0.18 in slow acetylators. At 100 mg/kg, ACF frequency was 4.11 ± 1.06 in rapid versus 1.57 ± 0.48 in slow acetylators. ACF frequency did not differ significantly between rapid and slow acetylator inbred rats administered DMH, a colon carcinogen which is not metabolized by polymorphic acetyltransferase. The two inbred rat strains did not differ in hepatic microsomal phenacetin deethylase activity, which is a marker for CYP1A2 activity important for the activation of aromatic amines. These results support the hypothesis that rapid acetylator (NAT2) genotype is a risk factor in aromatic amine-induced colon carcinogenesis.

Current Inbred and Hybrid Rat and Mouse Models for Gereontological Research.

Animal models are commonly used in aging research because they allow researchers to obtain data that are difficult or impossible to obtain from humans. Some studies that can, in principle, be done in humans are much easier to do in animals because of their shorter life spans. For example, measurements of changes over entire life spans, which would take many decades to complete in humans, can be accomplished in rodents in 2 to 3 years. Other kinds of experiments cannot, even in principle, be done with humans. Using rodents, researchers can manipulate breeding, extract tissues, administer bioactive agents, control diets, and perform surgical manipulations—procedures that would be unethical or excessively hazardous using humans. Rats and mice are the species of choice for most animal aging studies for a number of reasons: Techniques for breeding and housing them are well developed; they age rapidly; and a very large body of knowledge about their biology and behavior exists, which provides a solid base for future advances. Rats and mice thus provide indispensable tools for the study of mammalian aging and the development of methods for ameliorating aging-related diseases in humans. The scientific issue is not whether to study rats and mice but instead, which rats and mice should be studied. The discussion that follows reviews the factors that determine the choice of strain and species. This discussion is limited to mice and rats; other species are discussed by Sprott and Austad(1996).

Hepatocyte fine structure during maturation and senescence

Aging is accompanied by a myriad of changes in cell structure, function, and composition. The fact that much of the information concerning age-related alterations in cellular morphology is qualitative precludes meaningful correlations with biochemical changes in order to enhance data interpretation. The mammalian liver has been subjected to both qualitative and quantitative evaluations of hepatocyte structure as a function of aging, i.e., development, maturation, and senescence. Although these data are characterized by considerable variability and, in some instances, blatant contradictions, there exists sufficient agreement in several parameters to permit a consensus in the inbred rat model. Certainly the volume of individual hepatocytes increases with age, and many of the organelle compartments reflect this change. While old rats exhibit a high incidence of polyploidy, there is no definitive evidence to demonstrate a concomitant increase in the binuclear hepatocyte index. Several specific hepatocellular organelles undergo changes in their relative volume or surface area that appear to correlate with functional alterations. The volume density of the lysosomal compartment enlarges significantly during senescence and is accompanied by increased activities of several constituent hydrolases. The hepatic concentration of smooth-surfaced endoplasmic reticulum declines markedly with aging, as does the yield of liver microsomes and the activities of several microsomal enzymes, e.g., mono-oxygenases and glucose-6-phosphatase. However, the responses of the majority of hepatocyte organelles to aging is varied and inconsistent based on the limited data currently available.

Metabolic aspects of small bowel transplantation in inbred rats

An inbred rat model of small bowel transplantation was used to study the metabolic consequences of systemic venous drainage of the graft. Lewis rats received either Lewis (isograft) or Lewis X Brown Norway F1 (allograft) small bowel grafts. Venous drainage of the isografts was to either the portal vein or the inferior vena cava. Allograft recipients underwent systemic venous drainage and were treated with a 4-week course of tapering cyclosporine. Ammonia levels in systemically drained isografts (108 ± 5 μM/100 ml) were more than twice those in portally drained isografts (38 ± 3, P < 0.001), while amino acid analysis showed significant elevations in glycine, serine, asparagine, histidine, phenylalanine, and tyrosine. Ammonia levels decreased and amino acid alterations were generally corrected when animals were fed a modified protein diet low in aromatic and high in branched chain amino acids. Recipients of both systemically and portally drained isografts grew normally, while weight gain in allograft recipients was impaired. We conclude that (1) systemic venous drainage of small bowel grafts results in altered ammonia and amino acid levels that resemble those found in models of hepatic encephalopathy; (2) these changes can be significantly ameliorated by dietary modification; and (3) the compromised growth seen in systemically drained allografted animals results from chronic rejection and/or cyclosporine rather than the partial porto-systemic shunt.

Anti-Inflammatory Activity of Superoxide Dismutases: Studies on Adjuvant Induced Polyarthritis in Rats

The anti-arthritic activities of various superoxide dismutases and of liposomal bovine Cu-SOD have been compared in the adjuvant induced Lewis Inbred Rat model. Various approaches, including plethysmometric measurements, red cell sedimentation rates, while cell counts, levels of IgA and IgG immunoglobulins and scoring by visual, radiographic and scintigraphic techniques all concord in a demonstration of different activities for different SODs. The most efficient are liposomal bovine Cu-SOD and E. coli Mn-SOD, a moderate activity being shown by free bovine Cu-SOD. Poor or zero results are obtained with human Mn-SOD, human Cu-SOD or the homologous rat Cu-SOD.