Ciclosporin administration during pregnancy induces ultrastructural changes on pancreatic beta-cells of newborn rats

Ciclosporin (CS) is an immunosuppressive agent used in the prevention of graft rejections and in the management of type 1 diabetes. However, the drug is not without side effects. The aim of this study was to evaluate eventual cytotoxic phenomena in the pancreas of newborn rats whose mothers had been treated with therapeutic doses of CS. For this purpose, 25 female Wistar rats were used, 20 of which were subjected to daily injections of 10 mg/kg BW/day i.p. of CS dissolved in Intralipid, administered during the whole gestational period. The results obtained indicated that CS did not arrest fetal development, even though the number of newborns per mother was reduced when compared to controls. Moreover, mothers and newborn rats were subjected to vacuolation of kidney proximal tubular cells and of the insulin-secreting pancreatic beta-cells. This alteration was more evident in the islet beta-cells of newborn rats. Therefore, CS is not only toxic to the mothers' endocrine beta-cells but also to those of any eventual offspring.     

Zea mays L. extracts modify glomerular function and potassium urinary excretion in conscious rats

Diuretic and uricosuric properties have traditionally been attributed to corn silk, stigma/style of Zea mays L. Although the diuretic effect was confirmed, studies of the plant's effects on renal function or solute excretion were lacking. Thus, we studied the effects of corn silk aqueous extract on the urinary excretion of water, Na+, K+, and uric acid. Glomerular and proximal tubular function and Na+ tubular handling were also studied. Conscious, unrestrained adult male rats were housed in individual metabolic cages (IMC) with continuous urine collection for 5 and 3 h, following two protocols. The effects of 25, 50, 200, 350, and 500 mg/kg body wt. corn silk extract on urine volume plus Na+ and K+ excretions were studied in water-loaded conscious rats (2.5 ml/100 g body wt.) in the IMC for 5 h (Protocol 1). Kaliuresis was observed with doses of 350 (100.42 +/- 22.32-120.28 +/- 19.70 microEq/5 h/100 g body wt.; n = 13) and 500 mg/kg body wt. (94.97+/- 29.30-134.32 +/- 39.98 microEq/5h/100 g body wt.; n = 12; p<0.01), and the latter dose resulted in diuresis as well (1.98 +/- 0.44-2.41 +/- 0.41 ml/5 h/100 g body wt.; n = 12; p<0.05). The effects of a 500 mg/kg body wt. dose of corn silk extract on urine volume, Na+, K+ and uric acid excretions, and glomerular and proximal tubular function, were measured respectively by creatinine (Cler) and Li+ (ClLi) clearances and Na+ tubular handling, in water-loaded rats (5 ml/100 g body wt.) in the IMC for 3 h (Protocol 2). Clcr (294.6 +/- 73.2, n = 12, to 241.7 +/- 48.0 microl/ min/100 g body wt.; n = 13; p<0.05) and the Na+ filtered load (41.9 +/- 10.3, n = 12, to 34.3 +/- .8, n = 13, p<0.05) decreased and ClLi and Na+ excretion were unchanged, while K+ excretion (0.1044 +/- 0.0458, n=12, to 0.2289 +/- 0.0583 microEq/min/100 body wt.; n = 13; p<0.001) increased. For Na+ tubular handling, the fractional proximal tubular reabsorption (91.5 +/- 3.5, n = 12, to 87.5 +/- 3.4%; n = 13; p<0.01) decreased, and both fractional distal reabsorptions--I and II--increased (96.5 +/- 1.5, n = 12, to 97.8 +/- 0.9%; n = 13; p<0.01; and 8.2 +/- 3.5, n = 12, to 12.2 +/- 3.4%, n = 13, p<0.01, respectively). To summarize, in water-loaded conscious rats (2.5 ml/100 body wt.), corn silk aqueous extract is diuretic at a dose of 500 mg/kg body wt. and kaliuretic at doses of 350 and 500 mg/kg body wt. In water-loaded conscious rats (5.0 ml/100 g body wt.), corn silk aqueous extract is kaliuretic at a dose of 500 mg/kg body wt., but glomerular filtration and filtered load decrease without affecting proximal tubular function, Na+, or uric acid excretion.     

Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats

Hypobaric hypoxia (HH) induces oxidative stress (OS) and is associated with the generation of reactive oxygen species (ROS). Vitamin C is an efficient antioxidant, and it is used in a high-altitude environment to reduce the OS. The present study explores the role of vitamin C on some HH-induced changes of immune parameters in rats which were exposed to HHc condition at 18,000 ft in a simulated chamber for 8 h/day for 6 days with and without vitamin C administration at three different doses (200, 400, and 600 mg/kg body wt). The phagocytic activity of circulating blood WBC was increased, and the cytotoxic activity of splenic mononuclear cell (MNC) and the delayed type of hypersensitivity (DTH) responses to bovine serum albumin (BSA) were decreased in rats exposed to HHc condition, but these immune changes were blocked after administration of vitamin C at 400 mg/kg body wt. The leukocyte adhesive inhibition index (LAI) was not altered either in HHc condition or after administration of vitamin C in HHc condition. The serum corticosterone (CORT) concentration was increased in rats exposed to HHc condition which was blocked after administration of vitamin C (400 mg/kg body wt). The immune parameters and serum CORT concentration, however, did not show any recovery after administration of vitamin C at the dose of 200 and 600 mg/kg body wt. The present study indicates that administration of vitamin C at a dose of 400 mg/kg body wt may prevent the HH-induced immunological changes but not at the lower dose (200 mg/kg body wt) or higher dose (600 mg/kg body wt) in rats.     

Protective effects of Anthocleista djalonensis A. Chev root extracts against induced testicular inflammation and impaired spermatogenesis in adult rats

This study was designed to explore the protective effects of methanol (Meth, 200 mg kg^?1 body wt) and aqueous ethanol (Eth-OH, 200 mg kg^?1 body wt) extracts of Anthocleista djalonensis roots on testicular inflammation induced by lipopolysaccharide (LPS, 5 mg/kg body wt) and depletion of tubular germ cells induced by busulfan (15 mg/kg body wt) in rats after 60 days of oral administration. As expected, LPS stimulation of the animals significantly increased serum and intra-testicular interleukin-6 and serum nitrite levels which were significantly inhibited in the Eth-OH?+?LPS and Meth?+?LPS animals. The increase in testicular and not serum myeloperoxidase activity that was induced by LPS treatment was synergistically increased in the Eth-OH?+?LPS animals, whereas it was inhibited in the Meth?+?LPS animals compared to LPS-treated animals. Furthermore, the administration of the Eth-OH or Meth extracts protected against busulfan-induced depletion of tubular germ cells and promotes the re-population of the seminiferous tubules with germ cells (spermatogonia, spermatocytes and round spermatids) at different stages of development. The extracts were found to contain 7′-oxaspiro [cyclopropane-1,4′-tricyclo [3.3.1.0 (6,8)] nonan-2′-one], cis,cis-7,10-hexadecadienal, hexadecanoic acid, methyl ester, hexadecanoic acid, ethyl ester, 9,12-octadecadienoic acid, methyl ester, and 9,12-octadecadienoic acid (Z,Z)–) which may partly explain the observed anti-inflammatory effects. In conclusion, Meth extracts of A. djanonesis have better anti-inflammatory effects than the Eth-OH extract for the management of impaired testicular function due to inflammation. However both extracts exhibited protective effect on the histology of the testis allowing for the recovery of spermatogenesis.

     

Effect of mannitol, dextran (macrodex), allopurinol, and methylprednisolone on the morphology of the proximal tubule of the rat kidney made ischemic in vivo.

Rats were anesthetized and their lift kidneys were made ischemic for 1 h by clamping of the aorta just above the left renal artery. Mannitol (2.5 g/kg), Dextran 70 (0.6 g/kg), methylprednisolone (50 and 100 mg/kg), and allopurinol (100 mg/kg body weight) were administered before, during, or after the ischemia period in order to test the effect of each of these drugs upon this model of renal injury. At 24 h after the release of the aortic clamp the left kidneys of the drug treated animals wwere perfusion fixed and processed for light and electron microscopy. Dextran administration to animals with ischemic kidneys gave rise to a pronounced vacuolization ("osmotic nephrosis"), in the entire proximal tubule and especially in the pars recta. This was in contrast to dextran administration to rats with nonischemic kidenys, which showed no or very mild "osmotic nephrosis." This demonstrates that ischemia makes rat kidneys more susceptible to the development of "osmotic nephrosis." In controls (no drug treatment) one hour of renal ischemia gave partial necrosis of pars recta of the proximal tubule, while the pars convoluta tubule survived. Mannitol treatment significantly reduced the amount of necrosis of the pars recta, whereas dextran, methylprednisolone, and allopurinol had no or a negative effect on the survival of the cells of the pars recta segment. It is suggested that mannitol protects against the development of necrosis by increasing medullary blood flow in combination with a counteractive influence on the cellular swelling, which is known to occur in ischemia.     

Induction of hepatic drug metabolizing enzymes by DL-methionine in rats

A single intraperitoneal injection of DL-methionine (500 mg/kg body wt.) to adult male Wistar rats was shown to significantly induce all the components of the hepatic microsomal mixed function oxidase system such as NADPH cytochrome C reductase activity, cytochromes P-450 and b₅, as well as activities of drug metabolizing enzymes such as aminopyrine demethylase and uridine 5′ -diphosphate-glucuronosyltransferase. Combined administration of nicotinamide (250 mg/kg body wt.) and DL-methionine (500 mg/kg body wt.) was shown to bring about an additional increase (25-30%) in the activities of these enzymes as compared to their induction on independent administration of the two endobiotics. In rats bearing Yoshida sarcoma (ascites) tumour as well as in normal rats injected with serum from tumour bearing animals, the decreased activities of hepatic mixed function oxidases could be restored to their normal levels by administration of DL-methionine (500 mg/kg body wt.) to these rats. Whereas actinomycin D (1 mg/kg body wt.) had no effect on the increased incorporation of [¹⁴C] labelled leucine into microsomal proteins following administration of nicotinamide, the enhanced incorporation of the label following DL-methionine administration was completely inhibited by the same dose of actinomycin D. Administration of cycloheximide (0·5 mg/kg body wt.) to rats could completely inhibit the increased incorporation of [¹⁴C] leucine into hepatic microsomal proteins following independent administration of nicotinamide and DL-methionine. Similar inhibitory pattern with actinomycin D and cycloheximide was also demonstrated in case of induction of NADPH cytochromeC reductase activity by both these endobiotics.     

Morphological effects of cadmium on proximal tubular cells in rats

Twenty-four male rats of the Wistar strain divided into four groups were injected sc with a dose of 0.8, 1.5, and 3.0 mg Cd/kg body wt as CdCl₂ in saline, and saline alone to the control rats, three times a week for 3 wk. Cadmium levels of whole kidney homogenate, supernatant (cytosol), precipitate, and metallothionein (MT) fraction were measured. Histological changes of the renal proximal tubules were investigated by optical and electron microscopy. In the kidneys, Cd levels were increased with the increment of Cd dosage; 80–90% of Cd was contained in cytosol, and 55–75% was in MT fraction. Non-MT-Cd reached a maximum in the 1.5 mg Cd group, whereas that of the 3.0 mg Cd group showed some decline. With increasing Cd doses, the size of nuclei and nucleoli in the cells of proximal tubule showed significant enlargement and also an increase in the number of nucleoli on light microscopy. At higher doses, chromatin condensation of the tubular nuclei and vacuolar degeneration of the tubular cells were evident. On electron microscopy, perichromatin granules of the proximal tubular nuclei were increased in number, especially in the rats of Cd 0.8 mg and 1.5 mg/kg groups. As the Cd doses increased, ring-shaped nucleoli were increased in number and nucleolar segregation was observed more clearly. Moreover, in the 3.0 mg/kg Cd group, nuclear indentation and nucleoli containing compact dense granules were observed. In the cytoplasm, there was an increase of lysosomes, myelin bodies, ring-shaped mitochondria, and vesiculation; ultimate changes were degeneration and cell necrosis. The injured cells were heterogenously distributed in each nephron and this heterogeneity was attributed in the difference in Cd content and cell cycle in each cell of the nephron.     

Anti-diabetic potential of Barleria lupulina extract in rats.

We have undertaken a study to evaluate the anti-hyperglycemic effect of a methanol extract of aerial parts of Barleria lupulina Lindl. (Acanthaceae) in streptozotocin-diabetic rats, based on folkloric reports its use as an anti-diabetic agent. The extract exerted significant (p < 0.05) anti-hyperglycemic efficacy at all levels tested from 4 h after its administration, as compared with the control group, and the effect was also prolonged up to 12 h. The extract at doses of 200 mg kg(-1) body wt. and above exhibited a maximum activity (p < 0.001) at 12 h after administration. The most significant activity (15.35% blood glucose reduction) was observed for the group administered 300 mg kg(-1) body wt. at 12 h after administration, while the standard drug glibenclamide (10 mg/kg(-1) body wt.) showed an 18.80% reduction of blood glucose at the same time interval. Based on our current results, it appears that the methanol extract of aerial parts of Barleria lupulina Lindl. shows a pronounced blood-glucose-lowering potential in streptozotocin hyperglycemic rats, and is thus provided with a pharmacological support of the folklore claims of anti-diabetic activity.     

Maleate effects on kidney peptidases and proteinuria of male and female rats. Histochemical and biochemical studies

The effects of maleate on membrane-bound and lysosomal peptidases were studied histochemically in the kidney and biochemically in the kidney and the urine of male and female rats 6 h after the administration of two different doses of sodium maleate (150 and 300 mg/kg body weight). Additionally, the proteinuria of experimental animals was electrophoretically analysed to detect maleate-induced alterations in the urinary protein composition. The histochemistry of the brush-border peptidases (aminopeptidase A, gamma-glutamyltransferase) showed dose-dependent maleate effects in the late pars convoluta and the pars recta of the proximal tubule (blurring of the brush-border enzyme reaction pattern). The female animals were more severely affected by both maleate doses. After maleate treatment, enzyme-activity measurements in the kidney homogenate supernatant and urine indicated dose-dependent structural destruction of the proximal tubule, especially of brush-border membranes, and revealed an increase in enzyme excretion. Both the maleate-induced enzyme excretion and proteinuria were more pronouncedly increased in females than in males. Electrophoretic analysis of urinary proteins revealed alterations in the urinary-protein composition after maleate treatment, which favoured the excretion of proteins with a molecular weight higher than 20,000 daltons. Again, sex-related differences in the maleate effects were demonstrated. The results indicate that maleate causes alterations in the brush-border membranes and, especially at higher doses, results in cellular destruction selectively in the late proximal tubule of rat kidneys. Selectivity was also encountered in the maleate effects on urinary-protein composition, suggesting that the tubular alterations lead to an inhibition of the reabsorption of mainly high-molecular-weight proteins. Although the nature of the effects was independent of sex, it appears that females are less well protected against tubular damage caused by maleate.     

Toxicity of endosulfan on kidney of male rats in relation to drug metabolizing enzymes and microsomal lipid peroxidation

Endosulfan administration (po, 15 and 30 days at 7.5 and 10 mg/kg body wt respectively) inhibited the activity of microsomal mixed function oxidases in kidney tissue of male rats. Microsomal and cytosolic protein contents of kidney were significantly increased following 30 days endosulfan exposures. Profound induction in the activity profiles of alcohol dehydrogenase and cytosolic glutathione s-transferase was noticed, however, no such change was apparent in the activity of aldehyde dehydrogenase. Microsomal preparations from treated animals showed a dose and duration dependent increase in spontaneous lipid peroxidation. The observed biochemical changes persisted even after 7 days normalcy allowance provided after the endosulfan (10 mg/kg body wt) withdrawl. The results suggest a substantial renal toxicity of endosulfan to male rats in relation to microsomal mixed function oxidases and associated functions which possibly resulted from lipid peroxidative damage of microsomal membrane in treated animals.     

Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic rats.

To examine the role of changes in myocardial metabolism in cardiac dysfunction in diabetes mellitus, rats were injected with streptozotocin (65 mg/kg body wt) to induce diabetes and were treated 2 wk later with the carnitine palmitoyltransferase inhibitor (carnitine palmitoyltransferase I) etomoxir (8 mg/kg body wt) for 4 wk. Untreated diabetic rats exhibited a reduction in heart rate, left ventricular systolic pressure, and positive and negative rate of pressure development and an increase in end-diastolic pressure. The sarcolemmal Na+-K+-ATPase activity was depressed and was associated with a decrease in maximal density of binding sites (Bmax) value for high-affinity sites for [3H]ouabain, whereas Bmax for low-affinity sites was unaffected. Treatment of diabetic animals with etomoxir partially reversed the depressed cardiac function with the exception of heart rate. The high serum triglyceride and free fatty acid levels were reduced, whereas the levels of glucose, insulin, and 3,3',-5-triiodo-L-thyronine were not affected by etomoxir in diabetic animals. The activity of Na+-K+-ATPase expressed per gram heart weight, but not per milligram sarcolemmal protein, was increased by etomoxir in diabetic animals. Furthermore, Bmax (per g heart wt) for both low-affinity and high-affinity binding sites in control and diabetic animals was increased by etomoxir treatment. Etomoxir treatment also increased the depressed left ventricular weight of diabetic rats and appeared to increase the density of the sarcolemma and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a shift in myocardial substrate utilization may represent an important signal for improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic rat hearts with impaired glucose utilization.     

Schistosoma haematobium: Amoscanate and adult worm ultrastructure

Amoscanate, when administered orally as an aqueous or “formulated” preparation, induced pronounced ultrastructural abnormalities in male and female Schistosoma haematobium. Higher dose levels of the aqueous suspension (300 mg/kg body wt) had to be administered to achieve the full range of effects induced by formulated doses of 2.5–8 mg/kg body wt. Worms were recovered from hamsters between 1 and 120 hr after treatment. Although the amount of amoscanate-induced damage varied considerably between worms, an overall pattern of damage emerged. Initially, 1 hr after treatment, amoscanate caused tegumental vacuolation and oedema. As the drug treatment period was extended to 24 hr, blebbing, exudation, collapse of sensory organelle bases, and abnormal mitochondria became increasingly evident. With exposure to higher drug doses (50–300 mg/kg body wt), the tegument became further distorted with the appearance of necrotic structures and myelin whorls, which appeared to represent various stages in lysosomal formation and digestion. Eventually, erosion of surface layers resulted in the breakdown of tegumental integrity. The caeca and vitellaria were also adversely affected by drug treatment. Basal vacuolation and the formation of myelin whorls occurred in the gastrodermis. In the mature S4 vitelline cells, coalesced vitelline droplets and myelin whorls were evident.     

Alleviation of lindane induced toxicity in testis of Swiss mice (Mus musculus) by combined treatment with vitamin C, vitamin E and alpha-lipoic acid

Mitigation of lindane induced toxicity in testis of Swiss mice by combined treatment with vitamin C, vitamin E and alpha-lipoic acid has been evaluated. Male healthy mice (40), 8-10 weeks old were randomly selected and divided into 4 groups, control (C); lindane (L); antioxidant (A) and antioxidant plus lindane (A+L). Group C animals were administered only the vehicle (olive oil); in group L lindane was administered orally at a dose of 40 mg/kg body wt.; in group A combination of antioxidants at a dose of 125 mg/kg body wt.(vitamin C: 50 mg/kg body wt., vitamin E: 50 mg/kg body wt. and alpha-lipoic acid: 25 mg/kg body wt.) was administered orally; in group A+L both antioxidants (125 mg/kg body wt.) and lindane (40 mg/kg body wt.) were administered at their respective doses. In group A+L antioxidants were administered 1 h prior to lindane administration. All treatments were continuously given for 60 days. Histopathological changes due to lindane intoxication indicated shrunken and distorted seminiferous tubules, sparse Leydig cells and blood vessels and atrophy in the tissue. The testis weight also decreased significantly. Lindane treated group showed increased lipid peroxidation, whereas glutathione, glutathione peroxidase, superoxide dismutase, catalase and protein were significantly decreased compared to control. Lindane induced damage was minimized by administration of antioxidants. Results suggest that combined pretreatment with antioxidants can alleviate the damage caused to testis by lindane.     

Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential

Methanolic extract of P. amarus was found to have potential anti-oxidant activity as it could inhibit lipid peroxidation, and scavenge hydroxyl and superoxide radicals in vitro. The amount required for 50% inhibition of lipid peroxide formation was 104 microg/ml and the concentrations needed to scavenge hydroxyl and superoxide radicals were 117 and 19 microg/ml respectively. The extract was found to reduce the blood sugar in alloxan diabetic rats at 4th hr by 6% at a dose level of 200 mg/kg body wt and 18.7% at a concentration of 1000 mg/kg body wt. Continued administration of the extract for 15 days produced significant (P < 0.001) reduction in blood sugar. On 18th day after alloxan administration values were almost similar to normal in the group taking 1000 mg/kg body wt.     

Kidney regeneration through nephron neogenesis in medaka

Although renal regeneration is limited to repair of the proximal tubule in mammals, some bony fish are capable of renal regeneration through nephron neogenesis in the event of renal injury. We previously reported that nephron development in the medaka mesonephros is characterized by four histologically distinct stages, generally referred to as condensed mesenchyme, nephrogenic body, relatively small nephron, and the mature nephron. Developing nephrons are positive for wt1 expression during the first three of these stages. In the present study, we examined the regenerative response to renal injury, artificially induced by the administration of sublethal amounts of gentamicin in adult medaka. Similar to previous reports in other animals, the renal tubular epithelium and the glomerulus of the medaka kidney exhibited severe damage after exposure to this agent. However, kidneys showed substantial recovery after gentamicin administration, and a significant number of developing nephrons appeared 14 days after gentamicin administration (P < 0.01). Similarly, the expression of wt1 in developing nephrons also indicated the early stages of nephrogenesis. These findings show that medaka has the ability to regenerate kidney through nephron neogenesis during adulthood and that wt1 is a suitable marker for detecting nephrogenesis.     

Production of hypotaurine, taurine and sulfate in rats and mice injected with L-cysteinesulfinate

Summary. We studied in vivo production of taurine, hypotaurine and sulfate following subcutaneous administration of L-cysteinesulfinate (CSA) to rats and mice. When 5.0 mmol/kg of body weight of CSA was injected to rats, increased urinary excretions of taurine, hypotaurine and sulfate in 24 h urine were 617, 52 and 1,767 μmol/kg, respectively. From these results together with our previous data, sulfate production was calculated to be 1.6 times greater than taurine production. Increased contents (μmol/g of wet tissue) over the control of taurine and hypotaurine in mouse tissues at 60 min after the injection of 5.0 mmol/kg body weight of CSA were: liver, 3.5 and 9.9; kidney, 0.3 and 5.2; heart, 3.7 and 0.2; blood plasma, 0.4 and 0.2, respectively. Upon loading of hypotaurine or taurine, tissue contents of these amino acids in liver and kidney increased greatly. Our results indicate that liver is the most active tissue for taurine production, followed by kidney, and that external CSA, hypotaurine and taurine are easily taken up by these tissues.     

Effect of route of administration on phenytoin teratogenicity in A/J mice

Acute administration of the anticonvulsant drug, phenytoin (PHT) has been shown to result in embryotoxicity and teratogenicity in several strains of mice. The A/J strain is reported to be most susceptible to the effects of the drug including an increased incidence of resorptions and orofacial clefts in treated animals. When administered chronically, the drug has been shown to be teratogenic in the absence of maternal toxicity and embryolethality in Swiss Webster mice [Hansen and Billings, 1985]. In this paper, we have compared the embryopathic effects of chronic and acute administrations of PHT to A/J mice. PHT was administered to pregnant females by intraperitoneal (i.p.) injection on day 10 of gestation at a dose of either 60 or 75 mg/kg body weight. Alternatively, PHT was added to ground chow and fed to animals prior to and throughout gestation; animals received a daily dose of either 60 or 75 mg/kg body weight. Pregnant animals were sacrificed on day 18 or 19 of gestation, and fetuses were examined for the presence of orofacial clefts and other anomalies. There was a significant increase in the frequency of cleft lip and palate in animals receiving the drug by i.p. administration, but there was no increase in the incidence of clefts if the drug were added to the diet. The results of this study reiterate the importance of the route of administration of a drug in determining its embryopathic effect.     

Decreased tubular uptake of L-3,4-dihydroxyphenylalanine in streptozotocin-induced diabetic rats.

BACKGROUND/AIMS: This study determined alterations in renal dopamine production in streptozotocin-treated rats and explored the mechanisms underlying this alteration. METHODS: Streptozotocin (65 mg/kg) or vehicle was administered to 3-month-old male Wistar rats. Treated animals had hyperglycemia, glycosuria and increased diuresis, natriuresis and excretion of L-dopa. Urinary dopamine and dihydroxyphenylacetic acid were similar to those in control animals. The production of dopamine by renal cortex slices from treated rats was significantly less than that from control animals. The addition of glucose (8.4-18.4 mM) to the incubation medium decreased about 40% the uptake of L-dopa by isolated proximal tubular cells. Scatchard analysis of the saturation curves obtained in this condition showed a decrease in the V(max) without changes in the K(m). RESULTS: Our results confirm previous studies suggesting a renal dopaminergic deficiency in insulin-dependent diabetes and provide evidence strongly suggesting that a decrease in the number of tubular L-dopa transport sites is the underlying defect of this deficiency. CONCLUSION: These results highlight the role of the uptake of dopa as an important modulator of renal dopamine synthesis.     

Protective effect of selenium treatment on diabetes-induced myocardial structural alterations

One of the main causes leading to mortality in diabetes is myocardial disease. Using streptozotocin (STZ)-induced diabetic animals, it has been possible to characterize diabetes-induced myocardial abnormalities. Interstitial and microvascular disorders are known to be a characteristic part of the diabetic cardiomyopathy and partly resist insulin therapy. Because diabetic damage is partly attributed to oxidative stress, antioxidant treatment may be able to reduce this damage. The aim of this study was to investigate the cardioprotective effect of sodium selenite, known as an antioxidant agent. The diabetes was induced by ip injection of 50 mg/kg body wt STZ. The duration of diabetes was 5 wk. The protected group received (ip) 5 μmol/kg body wt/d sodium selenite (Na₂SeO₃) over 4 wk following diabetes induction. Electron and light microscopic morphometry of heart samples revealed typical diabetic alterations consisting in an increase in collagen content, vacuolation, diminishing of the cardiomyocyte diameter, alteration in myofilaments and Z-lines of myofibers, and myofibrillary degeneration. Sodium selenite treatment could prevent the loss of myofibrills and reduction of myocyte diameter. In the sodium-selenite-treated diabetic rat heart, alterations of the discus intercalaris and nucleus were corrected, and degenerations seen in myofilaments and Z-lines were reversed by this treatment. Under these findings, one can suggest that sodium selenite treatment may alleviate late diabetic complications when it is used under control conditions.     

An increase in superoxide dismutase counteracts islet vascular alterations in low-dose streptozocin-treated mice

A decrease in superoxide dismutase (SOD), the first cellular defence against free radicals, occurs at about the same time as the activation of macrophages within the islets of low-dose streptozocin (LDS)-treated mice. Furthermore, a decrease in the total islet capillary area also has been shown to occur by 10 days after the first streptozocin (STZ) injection and this decline in capillary area is concomitant with the activation of macrophages as is the fall in SOD. Intracellular levels of SOD have been shown to increase after administration of acetyl-homocysteine-thiolactone (citiolone); therefore, the aim of the present study was to observe any relationship between the citiolone-induced increase in SOD levels and islet microvasculature area during LDS-induced diabetes. C57BL6/J male mice were pretreated with daily intramuscular injections of 50 mg citiolone/kg body wt. for 30 days and were then rendered diabetic with 45 mg STZ/kg body wt. given for 5 days; citiolone was given until the animals were killed (days 6, 11 and 18 after the first STZ injection). Further animals were used as non-diabetic and diabetic (STZ-only) controls. The results show that LDS-treated animals when given citiolone: (1) were generally normoglycaemic; (2) had SOD levels that were higher than those of STZ-only control animals; (3) had an islet capillary area that was larger than that of LDS-treated mice. Therefore, the administration of a free radical scavenger, namely citiolone, is able partly to counteract and delay the reduction of islet vascular area and oedema formation in LDS-treated mice.