Function In Rabbits Research Articles

Diagnostic Endocrinology: Blood Steroid Concentrations in Neutered Male and Female Rabbits

Abstract There is a growing interest in rabbits as pets, and many pet rabbits are neutered to prevent pregnancy and avoid behavioral issues. Behaviors such as mating and aggression in neutered rabbits may suggest incomplete gonadectomy, adrenal disease, or other conditions. Information on adrenal steroid concentrations, including progestins and androgens, in neutered rabbits is not readily available in the literature. In this study, we determined concentrations of the adrenal steroids progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, and cortisol in 29 neutered rabbits. Results revealed no significant differences in hormone concentrations between neutered male and female rabbits. Mean ± standard error and relative percent concentrations of hormones were progesterone 0.25 ± 0.02 ng/mL (1.5%), 17-hydroxyprogesterone 6.40 ± 1.35 ng/mL (39.2%), androstenedione 2.47 ± 0.22 ng/mL (15.0%), testosterone 0.02 ± 0.00 ng/mL (0.12%), and cortisol 7.28 ± 0.40 ng/mL (44.2%). Steroid hormone concentrations determined in this study are an initial step in gaining more information about endocrine function in rabbits and may be useful in diagnostic evaluation of incomplete gonadectomy and adrenal disease in rabbits.

High infusion pressure in conjunction with vitreous surgery alters the morphology and function of the retina of rabbits

To investigate the effects of high infusion pressure in conjunction with pars plana vitrectomy (PPV) on retinal morphology and function in rabbits. Pars plana vitrectomy was performed under urethane (0.8 mg/kg) anaesthesia in the right eye of albino rabbits following phacoemulsification and aspiration (PEA). The left eyes were not touched. After PEA, the animals were divided into two groups. In six eyes, intraocular pressure (IOP) was increased to 80 mmHg for 30 mins (high-pressure group) and in five eyes IOP was maintained at 40 mmHg for 30 mins (low-pressure group). The IOPs were regulated by the height of the bottle of balanced salt solution (BSS) and monitored with a pressure transducer. After the pressure elevation, vitreous fluid was collected to measure the glutamate concentration. Then, PPV was performed for 15 mins in both groups under an infusion pressure of 40 mmHg. In five additional rabbits, PEA alone was performed in the right eye, and vitreous fluid was collected (PEA group). Functional alterations were assessed by recording visual evoked potentials (VEPs) and electroretinograms (ERGs). Ten days after the IOP changes, the animals were killed with intravenous pentobarbital sodium and the eyes were prepared for histological analysis. Damage to retinal ganglion cells (RGCs) was quantified by counting the number of cells in the ganglion cell layer (GCL). The contralateral eyes in the high-pressure group served as controls (n = 6). The mean implicit time (IT) of the VEPs in the high-pressure group was significantly longer than that before the IOP elevation, by 114-124% (p < 0.05, paired t-test), and also than that of control eyes (p < 0.05, anova followed by t-test). No significant changes in the VEPs were detected in either the low-pressure group or the PEA group. There were significantly fewer cells in the GCL in the high-pressure group (24.7/mm) than in the control animals (41.4/mm; p < 0.05, Dunnett's test). The number of cells in the GCL in the low-pressure and PEA groups did not significantly differ to that in the controls. The amplitudes of the ERG a- and b-waves were not significantly changed (p > 0.05, paired t-test). These results suggest that high infusion pressure in conjunction with PPV leads to morphological and functional changes in the retina. The absence of ERG changes and presence of VEP changes suggest that these changes were due to damage to RGCs, which supports the morphological observations.

Voglibose, an Anti-diabetic Drug, Reduces Myocardial Infarct Size and Improves Left Ventricular Function in Rabbits

Purpose: We previously reported that α-glucosidase inhibitors miglitol and acarbose reduce the myocardial infarct size. Therefore, we hypothesized that voglibose also has an effect to reduce the myocardial infarct size.

Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction

Adipose-derived stem cells (ADSCs) are capable of differentiating into cardiomyogenic and endothelial cells in vitro. We tested the hypothesis that transplantation of ADSCs into myocardial scar may regenerate infracted myocardium and restore cardiac function. ADSCs were isolated from the fatty tissue of New Zealand white rabbits and cultured in Iscoves modified dulbeccos medium. Three weeks after ligation of left anterior descending coronary artery of rabbits, either a graft of untreated ADSCs (UASCs, n = 14), 5-azacytidine-pretreated ADSCs (AASCs, n = 13), or phosphate buffer saline (n = 13) were injected into the infarct region. Transmural scar size, cardiac function, and immunohistochemistry were performed 5 weeks after cell transplantation. ADSCs in culture demonstrated a fibroblast-like appearance and expressed CD29, CD44 and CD105. Five weeks after cell transplantation, transmural scar size in AASC-implanted hearts was smaller than that of the other hearts. Many ADSCs were differentiated into cardiomyocytes. The AASCs in the prescar appeared more myotube-like. AASCs in the middle of the scar and UASCs, in contrast, were poorly differentiated. Some ADSCs were differentiated into endothelial cells and participate in vessel-like structures formation. All the ADSC-implanted hearts had a greater capillary density in the infarct region than did the control hearts. Statistical analyses revealed significant improvement in left ventricular ejection fraction, myocardial performance index, end-diastolic pressure, and peak +dP/dt, in two groups of ADSC-implanted hearts relative to the control hearts. AASC-implanted hearts had higher peak -dP/dt values than did control, higher ejection fraction and peak +dP/dt values than did UASC-implanted hearts. ADSCs transplanted into the myocardial scar tissue formed cardiac islands and vessel-like structures, induced angiogenesis and improved cardiac function. 5-Azacytidine pretreatment before implantation is desirable for augmenting myogenesis. Transplantation of 5-azacytidine-treated ADSCs into the myocardial scar was more efficient than that of untreated ADSCs in preservation of cardiac function.

Daily Rhythms of Liver-Function Indicators in Rabbits

Serum concentrations of urea and cholesterol were used as indicators of liver function in rabbits in an investigation of the responsiveness of the daily rhythm of liver function to phase shifts in the environmental light-dark cycle. Locomotor activity was simultaneously monitored by actigraphy. Serum urea and cholesterol concentrations exhibited robust daily rhythmicity with opposite phases. Both indicators of liver function phase shifted in response to phase shifts of the light-dark cycle. The phase shifts in liver function appeared to be parallel to phase shifts in locomotor activity, but the data were not sufficiently strong to confirm that the liver relies on the secondary effect of photic phase shift on ingestive behavior in order to be phase-shifted by light as previously indicated by gene expression studies in laboratory rodents.

Chlorpyrifos induces cardiac dysfunction in rabbits

This study was carried out to evaluate the effects of organophosphate (OP) insecticide chlorpyrifos on cardiac morphology and function in rabbits using echocardiography. Twenty New Zealand male rabbits were divided equally into four groups. Rabbits were exposed to chlorpyrifos in drinking water at concentrations of 0, 125, 250 or 375 ppm for 90 days. The comparison among the groups indicated that 375 ppm chlorpyrifos resulted in significant decrease ( p < 0.05) in heart rate (HR), cardiac output (CO), left ventricular fractional shortening (FS), left ventricular ejection fraction (EF), percentage thickening of left ventricle posterior wall (PWT), and significant increase ( p < 0.05) in left atrial diameter (LA), left ventricular internal diameter in end diastole (LVIDD), left ventricular end diastolic (EDV) and end systolic volumes (ESV) compared to those of the control group. These results showed that chlorpyrifos induces cardiac dysfunction in rabbits.

Simvastatin improves left ventricular function after myocardial infarction in hypercholesterolemic rabbits by anti-inflammatory effects

Hypercholesterolemia contributes to coronary artery disease progression but little is known about its effect on left ventricular (LV) function after myocardial infarction (MI). The aim of this study was to investigate the effects of hypercholesterolemia and statin treatment in rabbits with experimental MI. New Zealand White rabbits on a normal or cholesterol-rich diet for 4 weeks, underwent permanent coronary artery ligation. Starting on the first day post-MI rabbits were treated with either placebo or simvastatin (5 mg/kg/day) for 9 weeks. Hypercholesterolemia itself did not affect LV function in sham-operated animals but further impaired LV systolic (dP/dtmax -42%) and diastolic (dP/dtmin -47%) function in MI rabbits on placebo. Simvastatin treatment not only prevented deterioration of LV function associated with hypercholesterolemia but improved LV function (dP/dtmax +130%; dP/dtmin +144%, P < 0.05). Simvastatin also attenuated the depression of LV function in normocholesterolemic MI rabbits (dP/dtmax +46%; dP/dtmin +53%, P < 0.05). Hypercholesterolemia in MI rabbits coincided with a significant increase in C-reactive protein levels (marker of inflammation) and Rac1-GTPase activity (marker of oxidative stress), and a reduction in cardiac sarcoplasmic-reticulum calcium ATPase-2 expression and endothelial nitric oxide synthase protein phosphorylation, all of which were normalised by simvastatin treatment. Elevated serum cholesterol levels were only partially reduced by simvastatin. Hypercholesterolemia further impaired the depressed LV function in rabbits post-MI. Statin treatment reversed this effect, and conferred additional protection, as in normocholesterolemic animals. Our study suggests that anti-inflammatory and anti-oxidative effects of simvastatin substantially contribute to its beneficial effects on cardiac function after MI.

Reevaluation of Gray and White Matter Injury after Spinal Cord Ischemia in Rabbits

Although gray matter injury has been well characterized, the available data on white matter injury after spinal cord ischemia (SCI) in rabbits are limited. The current study was conducted to investigate the evolution of ischemia induced injury to gray and white matter and to correlate this damage to hind-limb motor function in rabbits subjected to SCI. Thirty-eight rabbits were randomly assigned to 24-h, 4-day, or 14-day reperfusion groups or a sham group (n = 9 or 10 per group). SCI was induced by occlusion of the infrarenal aorta for 16 min. Hind-limb motor function was assessed using the Tarlov scale (0 = paraplegia, 4 = normal). The gray matter damage was assessed on the basis of the number of normal neurons in the anterior spinal cord. White matter damage was assessed on the basis of the extent of vacuolation and accumulation of amyloid precursor protein immunoreactivity. Tarlov scores gradually decreased and reached a nadir 14 days after reperfusion. There were no significant differences in the number of normal neurons among the 24-h, 4-day, and 14-day groups. The extent of vacuolation, expressed as a percent of total white matter area, was significantly greater in the 4-day and 14-day groups in comparison with the sham group. By contrast, there was no difference in vacuolation between the sham and 24-h groups. Amyloid precursor protein immunoreactivity was greater in the 4-day and 14-day groups. The results in the current study show that SCI induced white matter injury as well as gray matter injury in a rabbit model of SCI. The time course for 14 days after reperfusion may differ among the gray and white matter damages and hind-limb motor function in rabbits subjected to SCI.

Retinal Function in Rabbits Does Not Improve 4–5 Months after Terminating Treatment with Vigabatrin

We have previously reported changes in retinal function and histopathology in rabbits treated with vigabatrin. The purpose of the present study was to evaluate retinal function and histopathology of retina in rabbits 4-5 months after terminating vigabatrin medication. Five rabbits were treated with a daily per oral dose of vigabatrin during 12-13 months. After terminating treatment an observation period of 4-5 months followed. Six rabbits receiving water served as controls. Standardized full-field electroretinograms were performed every 6-8 weeks, using a Burian-Allen bipolar contact lens. After 18 months the rabbits were sacrificed and the morphology of the sectioned retina was studied. The antibodies used for staining were GABA, GFAP, GAD, and vimentin. After 12-13 months of treatment the full-field ERG was reduced in all rabbits treated with vigabatrin. There was a statistically significant difference in the dark adapted cone b-wave amplitude between treated animals and controls (Wilcoxon signed-rank test, p = 0.043). This difference was consistent also 4-5 months after terminating treatment. Immunohistology of the sectioned retina demonstrated no significant difference in immunoreactivity between treated animals and controls. All treated rabbits demonstrated elevated serum concentration of the drug during medication. Four to five months after terminating treatment with vigabatrin the rabbit full-field ERG remains reduced in isolated cone b-wave amplitude indicating that vigabatrin induced retinal dysfunction may be irreversible. However, immunohistology is normal after a period without treatment, implying that the previously described changes in retinal morphology and glial cell activity are reversible, and probably exist only during treatment.

Balance of Activity of Sympathetic, Parasympathetic, and Serotoninergic Divisions of the Autonomic Nervous System in Rabbits

We studied the balance of activity of sympathetic, parasympathetic, and serotoninergic divisions of the autonomic nervous system in the regulation of the heart function in rabbits. High activities of the sympathetic and parasympathetic system are associated with antagonistic interactions between them. Moderation of activity of these systems could be accompanied by activation of the serotoninergic system. Physiological sympathectomy and parasympathectomy lead to hyperfunction of the serotoninergic system and pathology.

Effect of captopril on the nervous function in rabbits exposed to vibration

To study the effect of captopril on the nervous function in rabbits exposed to vibration. Rabbits were divided into vibration group, intervention group, and control group. Vibration group and intervention group were exposed to (tested by) vibration. Captopril was given to intervention group from the 11th day of vibration exposure. Somatosensory evoked potential (SEP) and motor nervous conduction function (MCF) were measured and analyzed in each group before and after vibration exposure. The latent periods of N1, P1 and N2 of SEP in vibration group after vibration exposure were (30.76 +/- 4.26), (41.91 +/- 6.67), and (45.29 +/- 5.81) ms respectively, and in intervention group after vibration exposure were (27.00 +/- 3.04), (35.07 +/- 4.20) and (41.15 +/- 3.19) ms respectively. Compared with intervention group before and after exposure, and control group, the latent periods of each wave of SEP were delayed significantly (P < 0.05). The nervous conduction velocity, the distant wave amplitude, and the distant potential period of sciatic nerve in vibration group after vibration exposure were significantly different from those in intervention group [(35.69 +/- 4.37) m/s, (1.55 +/- 0.73) microV, (8.16 +/- 0.71) ms respectively vs (52.20 +/- 5.13) m/s, (2.89 +/- 0.36) microV, (7.26 +/- 0.77) ms respectively (P < 0.01)]. Captopril may improve the impairment of nervous functions to a certain degree in rabbits exposed to vibration.

The protective effects of L-arginine on the peripheral vascular functions in rabbits exposed to vibration

目的 探讨L-精氨酸对后肢接振家兔外周血管功能的保护作用及意义.方法将家兔随机分为单纯接振组(A组),L-精氨酸组(B组)和对照组(C组),并进行接振试验.从试验第11天起,每隔2d给予B组L-精氨酸20mg/kg,分别测定各组血浆一氧化氮(NO)、内皮素(ET)浓度进行测定分析.结果试验前及试验后第10天、20天、30天,A组NO浓度分别为(172.400±12.350)μmol/L、(167.915±7.879)μmol/L、(150.088±7.453)μmol/L、(132.313±8.747)μmol/L,ET浓度分别为(43.575±8.166)μg/L、(46.213±5.448)μg/L、(53.788±6.037)μg/L、(66.613±9.485)μg/L;B组浓度分别为(172.850±13.323)μmol/L、(167.788±10.531)μmol/L、(164.125±8.380)μmol/L、(161.813±7.639)μmol/L,ET浓度分别为(43.513±4.901)μg/L、(47.175±7.481)μg/L、(47.025±5.026)μg/L、(47.600±4.883)μg/L.随接振时间延长,A组NO浓度有明显降低、ET浓度有明显升高趋势(P<0.01);B组也有类似变化,但变化幅度较小. 结论 L-精氨酸可通过影响接振家兔血管内皮活性物质而保护外周血管功能。

Cardiac systolic and diastolic dysfunction after a cholesterol-rich diet.

Although hypercholesterolemia is a well-established risk factor for coronary artery disease, little is known regarding its direct effects on cardiac function. We examined the effects of cholesterol feeding (0.5%) on cardiac function in rabbits. After 10 weeks, both systolic shortening and diastolic relaxation rates were impaired without any change in aortic pressure or ventricular hypertrophy. However, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA)-2 mRNA levels were reduced within 4 days after initiation of cholesterol feeding. After this effect, SERCA-2 protein and SERCA-mediated Ca uptake into sarcoplasmic reticulum vesicles were impaired, and the ratio of MHC-beta to MHC-alpha mRNA increased 5-fold. Suppression of the SERCA-2 message correlated temporally with enrichment of the cardiac sarcolemma with cholesterol. These data demonstrate that dietary hypercholesterolemia induces a "cholesterol cardiomyopathy" characterized by systolic and diastolic dysfunction. These alterations were independent of vascular disease and demonstrate a dietary link to cardiac dysfunction.

Localization of electroreceptive function in rabbits

The detection process by which animals react to the presence of electromagnetic fields (EMFs) may be a form of sensory transduction. However, the anatomic location of signal transduction in most species is unknown. Attempts to solve this problem by applying local EMFs and registering the resulting changes in the electroencephalogram (EEG) have not succeeded because of the nonstationarity of the EEG and the insensitivity of linear methods of analysis. We approached the problem of localizing electroreception in rabbits by using recurrence quantification analysis (RQA), a novel method of nonlinear analysis designed to detect small deterministic changes in a larger signal irrespective of considerations involving stationarity. When 2.5 G, 60 Hz was applied to the entire body, increased determinism in the EEG was found in all 10 animals studied, as evidenced by statistically significant increases in two RQA quantifiers. A similar result occurred when the field was applied only to the front half of each animal, but no effect on the EEG was seen when the field was applied only to the back half. When the field was localized to the head, the effect on the determinism in the EEG was again seen. When the field was further localized to the eye, the effect did not occur. Overall, the results indicated that detection of the field occurred in cells or extracellular structures in the head, probably the brain, although the methods used did not have the resolution to discriminate between specific brain structures. Thus, our results showed that the presence of transient deterministic brain states induced by an EMF signal could be documented using dynamical analysis, thereby allowing us to infer the approximate anatomic location of the signal's transduction.

High methionine and cholesterol diet abolishes endothelial relaxation.

High plasma cholesterol or homocysteine is a risk factor for atherosclerosis. Cholesterol and methionine, the precursor of homocysteine, are rarely eaten separately. Thus, the aims of this study were to determine neointima formation, aortic reactivity, and factors involved in endothelial function in rabbits fed high dietary cholesterol, methionine, or a combination of the two for 12 weeks. Rabbit dietary groups were randomized into the following: control (Con), 0.5% cholesterol (Chol), 1% methionine (Meth), and 1% methionine+0.5% cholesterol (MethChol). Aortic reactivity was studied by isometric tension techniques, aortic volumetric analysis was determined by stereological techniques, and immunohistochemistry was used to localize endothelial and inducible NO synthases, superoxide dismutase, macrophages, and nitrotyrosine. Atherosclerosis was present in the Chol and MethChol groups. Endothelium-dependent relaxation was virtually abolished in the MethChol group compared with control. Such decrease in relaxation was not attributable to a vascular smooth muscle cell defect or to a decrease in endothelial NO synthase or superoxide dismutase content. Macrophages and inducible NO synthase immunoreactivity were present in Chol and MetChol groups. The combination of high dietary cholesterol plus methionine virtually abolishes endothelium-dependent relaxation, underscoring the importance of multiple risk factors in the development of cardiovascular disease.

Rosiglitazone Improves Endothelial Function in Rabbits with Hypercholesterolemia by Reducing Oxidative Stress and Preserving NO/cGMP Signaling

Rosiglitazone Improves Endothelial Function in Rabbits with Hypercholesterolemia by Reducing Oxidative Stress and Preserving NO/cGMP Signaling

A lipoprotein lipase-promoting agent, NO-1886, improves glucose and lipid metabolism in high fat, high sucrose-fed New Zealand white rabbits.

The synthetic compound NO-1886 is a lipoprotein lipase activator that lowers plasma triglycerides and elevates high-density lipoprotein cholesterol (HDL-C). Recently, the authors found that NO-1886 also had an action of reducing plasma glucose in high-fat/high-sucrose diet–induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 on insulin resistance and β-cell function in rabbits. Our results showed that high-fat/high-sucrose feeding increased plasma triglyceride, free fatty acid (FFA), and glucose levels and decreased HDL-C level. This diet also induced insulin resistance and impairment of acute insulin response to glucose loading. Supplementing 1% NO-1886 into the high-fat/high-sucrose diet resulted in decreased plasma triglyceride, FFA, and glucose levels and increased HDL-C level. The authors also found a clear increased glucose clearance and a protected acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 suppresses the elevation of blood glucose in rabbits induced by feeding a high-fat/high-sucrose diet, probably through controlling lipid metabolism and improving insulin resistance.

An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion

Background: We hypothesized that systemic ATL-146e, an adenosine A2A agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome. Methods: Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 μg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining. Results: There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05). Conclusions: Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.(J Vasc Surg 2001;34:482-8.)

Effects of environmental antiandrogens on reproductive development in experimental animals

Chemicals that act as androgen receptor (AR) agonists and antagonists or inhibit fetal steroidogenesis can induce reproductive malformations in humans and laboratory animals. Several environmental chemicals disrupt development in rats and/or rabbits at fetal concentrations at, or near, exposure levels seen in some segments of the human population. In rats, fetal tissues concentrations of 10–20 p.p.m. of the DDT metabolite, p,p'‐DDE, are correlated with reproductive abnormalities in male offspring. These concentrations are similar to those measured in first‐trimester human fetal tissues in the late 1960s. The pesticides vinclozolin, procymidone, linuron and DDT are AR antagonists. They reduce male rat anogenital distance, and induce areolas at relatively low dosages. Hypospadias, agenesis of the sex accessory tissues and retained nipples are seen in the middle dosages, while undescended testes and epididymal agenesis are seen in the highest doses. Phthalate esters (PE) inhibit testosterone synthesis during fetal life, but do not appear to be AR antagonists. Prenatal administration of a single low dose of dioxin (50–1000 ng TCDD/kg) alters the differentiation of androgen‐dependent tissues at p.p.t. concentrations, but the mechanism of action likely involves interaction with a hormone‐like nuclear transcription factor, the hormone‐like receptor AhR, rather than AR. p,p'‐DDT and p,p'‐DDE, vinclozolin and di‐n‐butyl phthalate affect reproductive function in rabbits when administered during prenatal and/or neonatal life. Cryptorchidism and carcinoma in situ‐like (CIS) testicular lesions were seen in male rabbits treated during development with p,p'‐DDT or p,p'‐DDE. Extrapolation of effects from rodents to humans would be enhanced if future studies incorporate determination of tissue concentrations of the active metabolites. Knowledge of the tissue concentrations of the active toxicants also would provide an important link to in‐vitro studies, which provide more useful mechanistic information when they are executed at relevant concentrations.

Chronic aristolochic acid toxicity in rabbits: A model of Chinese herbs nephropathy?

Chinese herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.