Jenny T. Bond

cis-Dichlorodiammineplatinum nephrotoxicity: Time course and dose response of renal functional impairment☆

Abstract Although administration of cis -dichlorodiammineplatinum (CDDP) is known to induce acute proximal tubular necrosis, more subtle functional damage of the kidney could occur. This study was initiated to examine the renal functional correlates of CDDP nephrotoxicity in male F-344 rats receiving a single iv dose of 0, 1.25, 2.5, 5, 10, or 15 mg/kg CDDP. When compared to pair-fed controls, the following effects were observed 2 days following CDDP treatment: (a) increased 24-hr uv (5, 10, and 15 mg/kg), (b) reduced U osm (2.5 and 5 mg/kg), (c) increased 24-hr urinary K + excretion (10 and 15 mg/kg), (d) glucosuria, accompanied by hyperglycemia (10 and 15 mg/kg), and (e) elevated BUN (15 mg/kg). On Day 4, increased 24-hr uv and reduced U osm persisted in surviving drug treated animals (2.5 or 5 mg/kg). In addition, glucosuria, unaccompanied by hyperglycemia, was observed in the 2.5 and 5 mg/kg group and an elevated BUN was apparent only in the latter treatment group. C inulin (GFR) and C PAH (ERPF) were significantly compromised in drug-treated animals (5 mg/kg) on Day 4, findings consistent with the increased BUN. CDDP administration did not impair the ability of renal cortical slices to accumulate a prototype organic anion ( p -aminohippurate) or cation (tetraethylammonium) in vitro on Day 4. However, accumulation of these organic ions was significantly depressed in kidney slices obtained from untreated animals when 500 or 600 μg/ml CDDP was added to incubation medium. Inasmuch as alterations in urinary excretory function, but not BUN, were apparent in the lower dosage groups on Day 2, these results suggest that urine analyses may provide a more sensitive test for the early detection of CDDP nephrotoxicity than the commonly used measurement of BUN.

Bone mineral analysis of the rat femur by direct photon absorptiometry

SummaryThis report describes a method using direct photon absorptiometry (DPA) for determination in vivo of the bone mineral content to bone width ratio (BMC/W) in the rat femur. A significant correlation was noted between measurements by DPA and whole femur dry weight and ash weight. Measurements were reproducible within repeated determinations of both the same and successive days. Soft tissue, rotation of the femur, or slight differences in the longitudinal positioning of the femur did not significantly affect usefulness of the measurements. A significant positive correlation was seen between body weight and the femur BMC/W, indicating that the method accurately reflected expected physiological changes in bone mineral. The method is suitable for the rapid, simple, accurate, and reproducible measurement of bone mineral in the anesthetized rat and is applicable to serial measurements.

Zinc deficiency and behavior: A developmental perspective

Abstract Zinc deficiency was induced in 35 and 300 day-old male Holtzman rats. Group ZDA was fed ad lib a diet deficient in zinc (1 ppm), ZSP controls were pair-fed a diet supplemented with zinc (50 ppm) and ZSA controls were fed ad lib a diet supplemented with zinc (50 ppm). Physical status and six open-field behaviors were evaluated. Food intake, body weight and plasma zinc concentrations were significantly reduced in both age groups. Expanded use of the open-field revealed significantly lower latencies to explore the novel environment and significantly lower ambulation scores in the young and older zinc deficient rats. Older rats spent significantly less time grooming than their controls. Rearing was significantly less in young zinc deficient rats and “kangaroo-like” posture was evident. Young rats made deficient during critical periods of growth and development, were at greater risk for most parameters tested, compared to the older deficient rats. These results do demonstrate, however, that feeding low-zinc diets to older, fully developed animals results in significant physical and behavioral impairment.

The effects of cisplatin and other divalent platinum compounds on glucose metabolism and pancreatic endocrine function

Three divalent platinum compounds, cis-dichlorodiammineplatinum (cis-DDP), trans-dichlorodiammineplatinum (trans-DDP), and ammonium tetrachloroplatinate, were examined for their effects on glucose metabolism in male F-344 rats. Rats were treated with a single iv dose of cis-DDP (0, 2.5, or 5 mg/kg), trans-DDP (0, 5, 7.5, or 15 mg/kg) or tetrachloroplatinate (0, 6, or 18 mg/kg). Glucose tolerance was evaluated 2, 4, 7, and 14 days following platinum treatment by serially measuring plasma glucose before and following an ip glucose load. Administration of 5 mg/kg cis-DDP impaired glucose tolerance on Days 2 and 4, but not on Days 7 and 14. Plasma immunoreactive glucagon (IRG) was elevated at all times following cis-DDP treatment and thus was not correlated with the transient impairment in glucose tolerance. Plasma immunoreactive insulin (IRI) response to a glucose load was deficient relative to the degree of hyperglycemia in cis-DDP-treated (5 mg/kg) animals on Days 2 and 4. However, neither histopathological damage of the pancreas nor pancreatic stores of IRI were affected by cis-DDP treatment. In contrast to cis-DDP, equimolar or greater than equimolar doses of trans-DDP or tetrachloroplatinate did not significantly affect glucose tolerance at any time examined. These results indicate that cis-DDP-mediated glucose intolerance is unique to the geometry of the complex and is related to properties other than the presence of a divalent platinum atom. Furthermore, glucose intolerance following cis-DDP treatment appears to be related to a relative deficiency in insulin secretion.

Glucose intolerance following cis-platinum treatment in rats.

cis-Dichlorodiammineplatinum (cis-Pt) is a heavy metal complex used in cancer chemotherapy. Since this drug has been shown to induce hyperglycemia in rats, these studies were initiated to elucidate the effects of cis-Pt on carbohydrate tolerance and insulin and glucagon secretion. Two days following i.v. cis-Pt (2.5 or 7.5 mg/kg, 5 ml/kg) or vehicle administration to male F-344 rats, plasma glucose, immunoreactive insulin (IRI) and glucagon (IRG) concentrations were determined in the basal state and serially following a glucose load (2 g/kg, i.p.). Since cis-Pt induces a dose-related anorexia, a pair-fed control group was also studied. Administration of 7.5 mg/kg cis-Pt was associated with plasma glucose concentrations 2.5-5 times greater than ad-libitum and pair-fed controls at every time point during the 2-h glucose tolerance test. Although basal plasma IRI concentrations of the 7.5-mg/kg group were comparable to ad-libitum fed controls, they were significantly greater than those of pair-fed partners. Furthermore, the appropriate IRI response to a glucose stimulus observed in both controls and the 2.5-mg/kg group was absent in the 7.5-mg/kg group. Basal plasma IRG concentrations of the 7.5-mg/kg group were approximately 3-4 times greater than ad-libitum and pair-fed controls and were not suppressed following a glucose load. These results suggest that cis-Pt induces marked glucose intolerance in association with an impaired IRI response and abnormal glucagon response to a glucose stimulus.

Hyperglucagonemia following cisplatin treatment

These studies were initiated to determine (1) if cisplatin (cis-DDP)-induced hyperglucagonemia is related to decreased hormone degradation, (2) the relationship between impaired kidney function associated with cis-DDP nephrotoxicity and hyperglucagonemia, and (3) the contribution of cis-DDP-induced hyperglucagonemia to disturbances in glucose metabolism in male F-344 rats. Administration of 5 or 7.5, but not 2.5, mg/kg cis-DDP iv increased fasting plasma immunoreactive glucagon (IRG) concentrations. Hyperglucagonemia following cis-DDP treatment was characterized by an increase in the biologically active or true pancreatic form of IRG as well as an increase in an extrapancreatic component. cis-DDP treatment (5 mg/kg) resulted in a prolonged half-life and a reduced rate of plasma disappearance of exogenous glucagon. Reducing cis-DDP nephrotoxicity, via mannitol pretreatment, resulted in a significant reduction in total, true pancreatic, and extrapancreatic plasma IRG. Other nephrotoxicants, such as glycerol or gentamicin, also resulted in hyperglucagonemia, indicating that the effects of cis-DDP on glucagon metabolism are also characteristic of other nephrotoxicants and, therefore, may be secondary to kidney toxicity. Despite marked hyperglucagonemia following cis-DDP treatment, neither severe fasting hyperglycemia nor increased hepatic and renal gluconeogenic enzyme activity was apparent in treated animals. This apparent discrepancy cannot be attributed to glucagon resistance at the target tissue level since cis-DDP-treated animals responded appropriately to exogenous glucagon. These results indicate that hyperglucagonemia following cis-DDP treatment (1) may be related to decreased glucagon degradation associated with impaired renal function and (2) does not markedly disrupt glucose homeostasis.

Influence of rural-urban migration on adult women's food patterns and adequacy of their children's diet, in ecuador

Twenty‐four hour dietary recalls were collected from eighty‐five school aged children eight to ten years of age in Cotocollao Alto, Quito, Equador. Socioeconomic, food frequency, and dietary history data were also collected from the food system gatekeeper of each childs family. Mean proportions of the 1974 FAO/WHO Recommended Nutrient Intakes adjusted for sex and age were 50% or greater. Migrating women and their children did change their dietary patterns when they moved from rural to urban areas of Ecuador. These changes were examined to describe potentially positive, negative, or neutral effects on the dietary adequacy of the children.

In vitro renal transport functions of the progeny of rats with streptozotocin-induced diabetes.

Abstract The effect of streptozotocin-induced gestational diabetes in the rat on the development of renal tubular functions of progeny was determined using in vitro kidney slice techniques. Accumulation of p-aminohippuric acid (PAH) by renal cortical slices (PAH S/M ratios) from progeny of diabetic mothers (PDMs) was lowest at Day 1 of age and increased from 1 to 28 days of age. For PDMs, PAH S/M ratios were similar to those observed for progeny of control mothers (PCMs) except at 10 days of age when they were significantly lower. Accumulation of α-methylglucoside (MG) by renal cortical slices from PDMs (MG S/M ratios) was similar to that reported for PCMs, except at 10 days of age when accumulation was significantly depressed in PDMs. Accumulation of N-methylnicotinamide (NMN) by renal cortical slices (NMN S/M ratios) from PDMs was similar to that of PCMs. NMN S/M ratios were lowest at birth and increased with age. Accumulation of α-amino-isobutyric acid (AIB) by renal cortical slices (AIB S/M ratios) from PDMs was no different than that from PCMs. AIB S/M ratios were highest at birth and decreased with age. It was concluded that gestational diabetes differentially affected renal tubular transport functions in the progeny.

Psychobiological impairment in rats following late-onset protein restriction

Mature rats were kept on protein-deficient diets to test the hypothesis that late-onset protein restriction results in deficits and to determine the feasibility of doing nutrition-behavior research with old naive animals. A 3% low-protein (LP) group and a 24% adequate-protein (AP) pair-fed control were used. Body weights and plasma protein concentrations were lower and exploratory behavior and motor coordination were poorer for LP rats. Both groups preferred the 24% protein diet. LP rats habituated slower and failed to overcome an initial black preference on an oddity discrimination learning task. Nutrition-behavioral research with older rats is feasible, and late-onset protein restriction produces psychobiological deficits.