Nitric oxide metabolism following unilateral renal ischemia/reperfusion injury in rats.

Renal ischemia/reperfusion (I/R) injury results in decreased glomerular filtration and renal blood flow (RBF) and increased urine output, characterized by natriuresis and impaired concentrating ability. We studied unilateral I/R in rats to assess renal handling of nitric oxide (NO). Prior to I/ R, we measured urine flow rate (V), inulin clearance (C[IN]), para-aminohippuric acid clearance (C[PAH]), NO clearance (C[NOx] determined from metabolites NO2 and NO3), tubular transport of NOx (T[NOx], filtered load +/- urinary excretion), urine sodium and potassium excretion (U[Na]V, U[K]V), fractional excretion of sodium (FENa), and fractional excretion of NOx (FENOx) in each kidney. The left renal artery was then ligated for 30 min, followed by 30 min of reperfusion, and all measurements were repeated. C(IN) and C(PAH) were decreased in I/R kidneys compared with the contralateral kidney or pre-ischemia controls. V, FENa, and U(K)V were all significantly increased in I/R kidneys. Plasma NOx concentration was lower after injury in all animals (23.3 +/- 2.8 post injury vs. 30.4 +/- 7.7 microM pre injury, P < 0.05). C(NOx) was significantly higher in I/R kidneys (0.14 +/- 0.05 ml/min per g kidney weight) than in pre-injury kidneys (0.03 +/- 0.02 right, 0.04 +/- 0.30 left) or the contralateral controls (0.04 +/- 0.02) (P < 0.05 for all three controls). T(NOx) showed net tubular reabsorption of NOx in all kidneys (11 +/- 6 in post-ischemic left kidneys vs. 25 +/- 20 in left pre-ischemia, 33 +/- 13 in right pre-ischemia, and 21 +/- 4 right post-ischemia, nM/min per g kidney weight, P = NS). FENOx was higher in injured kidneys (28% +/- 18) than in pre-injury (3% +/- 0.6, 5% +/- 3) or contralateral controls (6% +/- 3) (P < 0.05 for all three controls). Renal NOx excretion and clearance are increased despite decreased plasma levels of NO metabolites after I/R injury. This increased excretion is not dependent on RBF or glomerular filtration, but may be related to impaired tubular reabsorption of NOx combined with increased intra-renal NO production.

The renal handling of IgG in the aging rat and in experimental kidney disease.

The urinary excretion of total protein, low-MW proteins, albumin, high-MW proteins, and intact IgG was measured in male Wistar rats between the ages of 5-52 weeks, and in rats with experimentally induced glomerular or tubular proteinuria. About 25% of aging rats spontaneously developed focal glomerulosclerosis and a mild glomerular proteinuria. By age 52 weeks, total protein excretion in rats with glomerulosclerosis exceeded that of unaffected rats by a factor of seven (39.5 vs 5.4 mg/24 hr x 100 g body wt), and albumin excretion was seven times higher than IgG excretion in affected rats (21.2 vs 2.9 mg/24 hr x 100 g body wt). Rats with chromate toxicity exhibited a reversible tubular proteinuria, with low-molecular weight protein excretion reaching 16.8 mg/24 hr x 100 g body wt (75% of total protein excretion) at the time of peak toxicity. IgG excretion remained less than 0.6 mg/24 hr x 100 g body wt. Aminonucleoside induced a massive but reversible glomerular proteinuria (204 mg/24 hr x 100 g body wt), with IgG excretion reaching 11.4 mg/24 hr x 100 g body wt (6% of total protein excretion) at the time of peak toxicity. Biochemical and immunochemical studies showed that, while some intact IgG is present in normal rat urine, most IgG immunoreactivity is derived from low-molecular weight catabolic fragments of IgG which interfere with the immunoassay of intact urinary IgG. One of these fragments, probably Fc fragment, may be involved in the pathogenesis of focal segmental glomerulosclerosis.

Nitric oxide-inhibitory effect of aminoguanidine on renal function in rats.

Inhibition of nitric oxide (NO) synthesis by structural analogues of L-arginine reduces glomerular filtration, renal blood flow, sodium excretion, and urine output. N(G)-nitro-L-arginine methyl ester (L-NAME) inhibits constitutive and inducible isoforms of NO synthase, while aminoguanidine (AG) selectively inhibits inducible isoforms of NO synthase. We assessed the NO-inhibitory activity of AG on renal function. Rats were treated with aminoguanidine 50 mg/kg daily for 2 months, followed by L-NAME (25 mg/kg/day) for 1 week to inhibit all NO synthase isoforms. After treatment with L-NAME, we performed baseline renal function measurements, then infused L-arginine (2.5 mg/100 g BW x min) to reverse NO inhibition and assessed whether AG exerted NO-inhibitory activity independently of L-NAME. Prior to L-arginine infusion, AG-treated rats did not differ from controls with respect to body weight, kidney weight, systolic blood pressure, urine flow rate, urinary protein or albumin excretion, or urinary excretion of NO metabolites. After L-arginine infusion, all animals showed a 10-15% decrease in mean arterial blood pressure. L-Arginine-induced increases in urine flow, inulin clearance, PAH clearance, sodium excretion, and NO metabolite excretion were blunted in aminoguanidine-treated animals. To assess long-term effects of aminoguanidine, rats were treated for 12 months. Urinary excretion of NO metabolites was lower than controls. Inulin clearance was higher than controls. Aminoguanidine blunts the effect of L-ariginine on renal hemodynamics independently of the nitric oxide synthase inhibitor, L-NAME. However, the use of aminoguanidine for 12 months in rats did not adversely affect renal function.

Sex chromosomes do not influence renal injury in borderline hypertensive rats.

The present study was undertaken to investigate whether the development of proteinuria in the borderline hypertensive rat (BHR) is influenced by the Y chromosome and to determine if the onset of proteinuria in the BHR is delayed when blood pressure is lowered with enalapril, an angiotensin I converting enzyme inhibitor. Male F1, rats were the first-generation offspring of the mating of spontaneously hypertensive (SHR) females and Wistar-Kyoto (WKY) males and the mating of SHR males and WKY females. At 20 weeks of age, enalapril (125 mg/l) was added to the drinking water. Untreated BHR and enalapril-treated BHR (BHRE) were followed to 90-100 weeks of age. Urine was collected every 10-20 weeks for determination of protein, albumin, and nitric oxide (NO2/NO3) metabolite excretion. Indirect blood pressure in BHR from both crosses was approximately 175 mm Hg from 20 to 90-100 weeks of age. Enalapril lowered blood pressure by about 30 mm Hg, but was ineffective in reducing urinary protein or albumin excretion rates at any age. Urinary excretion of nitric oxide metabolites was similar in all groups at all time periods. There were significant differences in the percent of glomerulosclerosis between the two matings. Based on these results, renal injury in the BHR is not associated with the Y chromosome and can be dissociated from hypertension. Further studies using congenic and transgenic technology will be necessary to identify functions of genes and associations with hypertension in order to understand the kidney disease in this model of hypertension.

Resistance to glomerular injury in the diabetic biobreeding rat.

This study was designed to determine whether the diabetic BioBreeding rat develops significant renal injury following long-term moderate to severe hyperglycaemia. Diabetic and control rats were followed from the onset of diabetes (2-4 months) to 18 months of age. Frank proteinuria and/or albuminuria were always absent. Glomerular filtration rate, measured by inulin clearance (ml min-1 (100 g body weight)-1), was significantly higher in diabetic rats than in controls at 10, 12 and 18 months of age. Advanced glycosylation end-product cross-links assessed by percentage solubility of tail tendon collagen were moderately increased in diabetic compared with control animals. Urinary excretion of advanced glycosylation end-products in unfractionated urine and in urine fractionated for low molecular mass peptides (< 10 kDa) was 11-fold greater in the diabetic rats than in the control group. Urinary excretion of nitric oxide metabolites (nmol NO2- and NO3- (24 h)-1) were significantly (P < 0.05) greater in diabetic rats than in controls after 8 months of age. Mild histopathology resembling human diabetic nephropathy, including increased mesangial volume and glomerular basement membrane thickness, was detected at 18 months of age. The findings of hyperfiltration and mild glomerular morphological changes in diabetic BioBreeding rats are similar to the abnormalities seen in stage 2 human diabetic nephropathy. We hypothesize that two factors which may contribute to the resistance or tolerance to renal injury in the BioBreeding diabetic rat are increased nitric oxide production and the decreased accumulation of advanced glycosylation end-products.

Nephrotoxicity of ifosfamide in rats.

Renal proximal tubule cell injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. We investigated the effect of this medication on kidney function in rats. Animals received either 40 or 80 mg kg(-1) ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four treatment courses. Ifosfamide-treated rats had significantly lower body weight and hematocrit than sterile water-treated control rats. Animals receiving 40 mg kg(-1) ifosfamide developed isolated phosphaturia after their fourth and final treatment course. Rats receiving 80 mg kg(-1) ifosfamide had low-grade glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate, creatinine clearance, urinary sodium and potassium excretion and kidney glutathione and malondialdehyde content were not affected by ifosfamide at either dose. These findings indicate that ifosfamide produces abnormalities in rat renal function resembling subclinical Fanconi syndrome.

Single nephron hemodynamics in spontaneously hypertensive rats.

This study was designed to determine whether glomerular hypertension develops as a function of age in the spontaneously hypertensive rat (SHR). Male SHR and age-matched Wistar-Kyoto (WKY) normotensive controls were divided into three groups for measurements of whole kidney and single nephron hemodynamics at 5, 10, and 15 months of age. As reported previously, SHR developed significant proteinuria which was predominantly an albuminuria, after 5 months of age. There were no differences in whole kidney or single nephron glomerular filtration rates between SHR and WKY. Afferent glomerular capillary hydraulic pressure (PGC) was slightly increased in SHR compared with WKY at 10 months of age. At 15 months of age, PGC in SHR was significantly lower than WKY. Our studies indicate that increased capillary pressure is not a major factor in the development and progression of renal injury in the spontaneously hypertensive rat.

Dietary cholesterol supplementation in the spontaneously diabetic rat.

Dietary cholesterol supplementation was used to increase serum cholesterol concentration in diabetic and non-diabetic rats. With the use of numerous dietary formulations, extremely elevated serum cholesterol concentrations and gastrointestinal intolerance were found. We conclude that there are unacceptable side effects with a vast number of exogenous cholesterol supplemented diets which preclude standard and long-term usage.

Somatic parameters, organ growth, and plasma substrates in weanling rats with lateral hypothalamic lesions one month postoperatively.

Somatic and some metabolic aspects of the syndrome that follows bilateral destruction of the lateral hypothalamic area (LHA) have been studied primarily in mature rats. Fewer data are available for the weanling rat. Weanling Sprague-Dawley rats received small (10 mC) bilateral electrolytic lesions (LHAL). Sham-operated controls were pair-gained to LHAL rats (CON-PG) or fed ad lib (CON-ADLIB). All rats were killed 1 month after LHAL. Both LHAL and CON-PG weighed less, had less carcass fat, and were shorter than CON-ADLIB. Also, LHAL were somewhat, but significantly (SIGN), shorter than CON-PG. Rats with LHAL has less carcass protein than CON-ADLIB in percent but not in absolute terms. Liver, epididymal fat pads, diaphragm, kidneys adrenals, testes, spleen, and heart grew SIGN smaller in LHAL vs. CON-ADLIB, but in no instance was there a SIGN difference between LHAL and CON-PG. In body weight percentage, some of these differences (liver, kidneys, heart) were not SIGN. Both LHAL and CON-PG had larger adrenals than CON-ADLIB and both LHAL and CON-PG had SIGN less protein in their livers, epididymal fat pads, and diaphragm than CON-ADLIB. In organ weight percentage, however, LHAL rats had more protein in their livers and fat pads than CON-ADLIB and LHAL rats had less protein in fat pads than CON-PG in absolute but not in percent organ weight terms. Plasma glucose was similar in all groups, but LHAL had SIGN lower triglycerides and total cholesterol than CON-ADLIB.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of aging, diet, and sex on plasma glucose, fructosamine, and lipid concentrations in barrier-raised Fischer 344 rats.

We studied the relationships of plasma glucose, fructosamine, triglycerides, and cholesterol as a function of age, gender, and diet in barrier-raised Fischer 344 rats aged 5 to 26 months, fed a diet either ad libitum or restricted to 60% of the ad libitum caloric intake. The complex relationships of these plasma levels to age, gender, and diet led to the development of a model with age, diet, and sex as covariates. Overall, fasting plasma glucose concentrations were reduced by approximately 25% in rats on the restricted diet, compared to ad libitum-fed animals. There was a significant age-dependent decline in glucose levels in male animals, whereas in females there was an increase in plasma glucose with aging. Plasma fructosamine levels in calorie-restricted animals, overall, were reduced by 7% compared to levels in animals fed ad libitum. There was a significant positive correlation between plasma glucose and fructosamine levels. Mean plasma triglyceride content was decreased by 50% in calorie-restricted rats compared to ad libitum-fed animals. A significant decrease in triglyceride levels with increasing age was seen in male animals, and an increase with aging in females. There was a significant positive correlation between plasma glucose and triglyceride levels. Plasma cholesterol levels in calorie-restricted animals were reduced by 7% compared to levels in ad libitum-fed animals. An increase of cholesterol concentration with aging was significant in both males and females. Analysis of the data showed that there were significant differences between male and female Fischer 344 rats in the response of plasma glucose and fructosamine to aging and calorie restriction. Changes of plasma triglyceride and cholesterol with aging and dietary calorie restriction were also different in males and females. Studies of the effect of aging on glycemia and blood lipid content should take into account the contributions of animal sex.

The effect of dorsomedial hypothalamic nucleus lesions on kidney function and structure after 1 and 12 months.

According to the Dillman theory (17), aging results from a deterioration of metabolism that begins with an elevation of hypothalamic receptor thresholds for feedback signals from the periphery. Three hypothalamic areas are known to contain such receptors: the ventromedial and dorsomedial hypothalamic nuclei (DMN) and the lateral hypothalamic area. We have hypothesized that selective destruction of those hypothalamic areas might be followed by physiological changes associated with aging. Electrolytic bilateral DMN lesions were produced in male and female weanling rats. These rats were maintained for up to 13 months of age. Sham-operated rats served as controls. Food intake and body weight were monitored postoperatively and prior to sacrifice. Before sacrifice, tail blood and a 24-h urine samples were obtained. In accordance with previous findings, rats with DMN lesions showed dramatic reductions of ponderal growth and food intake but had normal body composition. Total protein and albumin excretion rates were significantly lower in rats with lesions. The fractional contribution of albumin to total urinary protein was also decreased in rats with lesions. Histological examination of the kidneys showed significantly less pathology in the kidneys of rats with DMN lesions; the severity of renal pathology was correlated directly with proteinuria. These changes were seen as early as 1 month after production of the lesion. The attenuation of age-related changes in kidney functions and structure in rats with lesions could be due to reduced food intake (dietary restriction is known to produce similar results), and/or a direct effect of the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of cyclosporin A on disease progression in proliferative immune complex glomerulonephritis.

In rats with the proliferative immune complex glomerulonephritis of chronic serum sickness, kidney function deteriorates in three discrete and readily distinguishable stages: Mild, Moderate, and Severe. The mononuclear cell composition of glomerular inflammation is also different in each stage. The immunosuppressive drug, cyclosporin A, was administered to rats with chronic serum sickness in order to investigate the relationship between glomerular immunopathology and pathophysiology in proliferative immune complex nephritis. When introduced after the onset of proteinuria, daily treatment with cyclosporin A failed to prevent the progression from Moderate to Severe nephritis, which is characterized by the abnormal differentiation and local proliferation of glomerular macrophages, as well as grave deterioration in kidney function. In contrast, when cyclosporin A therapy started before the onset of proteinuria, the course of proliferative glomerulonephritis was altered significantly. Although the levels of proteinuria and macrophage accumulation that are characteristic of the Moderate stage of nephritis were not reduced, progression to Severe nephritis did not occur. The number of glomerular macrophages appeared to increase in two separate phases in this chronic serum sickness model of proliferative immune complex glomerulonephritis. The first phase, which coincided with the onset of proteinuria, did not require T cells and culminated only in moderate hypercellularity and proteinuria. The second increase in the number of glomerular macrophages, which was accompanied by the expression of abnormal macrophage phenotypes, was closely linked to the development of severe kidney insufficiency. The protective effect of cyclosporin A therapy was consistent with, although not conclusive proof for, the hypothesis that local T cell activation may contribute to the progression of proliferative immune complex glomerulonephritis. Since cyclosporin A can also directly influence the responses of macrophages and mesangial cells, the effect of the drug on the course of nephritis in this model might not be related to its immunosuppressive action.

Endogenous creatinine clearance in the rat: strain variation.

The clearance of endogenous creatinine was examined in five strains of rats (Wistar, Wistar Kyoto, Spontaneously Hypertensive Rats, Biobreeding/Worcester diabetic prone and diabetic resistant rats). Creatinine clearance was compared with inulin clearance as the standard. Conditions for clearance measurements were also varied (anesthesia with constant infusion, overnight collection of urine, fed vs. unfed state, single-injection technique). The clearance of creatinine adequately reflects the glomerular filtration rate in three strains (Wistar, Wistar-Kyoto and the Spontaneously Hypertensive Rat). In the two strains of the Biobreeding/Worcester rat creatinine clearance is consistently lower than the inulin clearance. When creatinine clearance is measured from an overnight collection of urine with food withheld it is always lower than when food is present. This clearance should always be validated by comparison with inulin clearance measured simultaneously or under comparable conditions. The ease with which endogenous creatinine clearance can be measured makes it a reasonable method when large numbers of repeated determinations of glomerular filtration rate are required.

Calorie restriction decreases microalbuminuria associated with aging in barrier-raised Fischer 344 rats.

Renal function as a sensitive biomarker of aging has been studied in specific pathogen-free (SPF) Fischer 344 rats (n = 211), and results are presented according to animal age (5, 8, 12, 18, 24 mo), sex, and diet (ad libitum vs. 40% calorie restriction). Plasma creatinine concentration, endogenous creatinine clearance, total protein excretion, and albumin excretion were measured. Kidney histology was evaluated by light microscopy. In both calorie-restricted and ad libitum-fed animals, kidney weight (KW) and body weight (BW) showed parallel changes with age. The KW-to-BW ratio was unaffected by age in all groups. There was no alteration in plasma creatinine concentration as a function of age or diet. In these SPF animals there was also no change in glomerular filtration rate with age. In animals fed ad libitum, albumin and protein excretion increased with age (females: 0.39 +/- 0.05 at 5 mo vs. 7.4 +/- 2.6 mg protein.24 h-1.g KW-1 at 24 mo; males: 4.1 +/- 0.6 at 5 mo vs. 15 +/- 3 mg protein.24 h-1.g KW-1 at 24 mo). The higher protein excretion rate in all males at 5 mo reflected the excretion of sex-dependent low-molecular-weight proteins that commenced with sexual maturation. Calorie restriction prevented the age-dependent increase in total protein excretion. Kidney histopathology was positively correlated with total protein and albumin excretion. Microalbuminuria preceded the development of lesions detectable by light microscopy. These observations support the concept that microalbuminuria in this model is a sensitive and early biomarker of nephropathy that can be monitored easily and noninvasively.

Effect of cyclosporine on endothelial albumin leakage in rats.

Short-term treatment of rats with cyclosporine (cyclosporine A [CsA]; Sandimmune) results in a marked reduction in intravascular plasma volume, a factor that might contribute to the renal dysfunction associated with this potent immunosuppressant. To examine the role of plasma extravasation in CsA-induced hypovolemia, intravascular plasma volumes (PV), blood volumes, [125I]albumin disappearance, and changes in hematocrit (Hct) were measured in Inactin-anesthetized rats subjected to minimal surgery. The rats were treated for 3 wk with either 25 mg/kg/day of CsA s.c. or vehicle. Plasma creatinine and urea were significantly elevated, and magnesium was reduced in the CsA group (N = 6) as compared with controls (CON) (N = 6). CsA treatment had no effect on urinary protein and albumin excretion. Blood volume was significantly lower in CsA than in CON (8.4 +/- 0.5 versus 10.6 +/- 0.3 mL/100 g body wt) as was PV (4.3 +/- 0.2 versus 5.5 +/- 0.2 mL/100 g body wt). Two hours after injection, plasma [125I]albumin concentration had fallen by 41 +/- 4% in CsA versus 23 +/- 5% in CON. Because Hct, and, hence PV, was unchanged in both groups during these 2 h, these data indicate enhanced endothelial albumin leakage in the CsA group. In two additional groups of six rats each, acute volume expansion with fresh whole blood (2 mL/100 g body wt) resulted in extravasation of plasma. Hct rose by 8.0 +/- 0.2% in CsA versus 3.8 +/- 0.2% in CON after 150 min, corresponding to 27 +/- 3 and 15 +/- 2% decreases in total PV, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term renal handling of sodium and calcium in spontaneously hypertensive rats.

The renal handling of sodium and calcium in spontaneously hypertensive rats (SHR) was investigated over an extended period (10-75 weeks of age) and compared with age-matched normotensive Wistar-Kyoto controls. The animals were fed a standard rat chow except during screening periods when liquid diet that matched the pellet chow was substituted. Sodium balance, urinary excretion of sodium and calcium, fractional excretion of sodium (FENa), and renal cortical dopamine receptors (DA1 and DA2) were measured at 10, 30, 60 and 75 weeks of age. The results showed no difference between the two strains except for FENa, which was significantly higher in the SHR at 75 weeks coincident with decreased glomerular filtration rate. We conclude that a defect in renal handling of sodium and/or calcium is not a major factor in the maintenance of hypertension in the SHR.

Glomerular function in spontaneously diabetic rats.

This study was undertaken to determine whether hyperfiltration exists at the single nephron level and whether albumin excretion is increased early in the course of diabetes in Biobreeding rats. Diabetic rats were studied at 8-12 weeks after the onset of diabetes. Control animals were age-matched, diabetes-resistant rats. Urinary and tubular fluid albumin concentrations were measured by polyacrylamide gel electrophoresis. Clearance and micropuncture techniques were used to determine whole kidney and single nephron glomerular filtration rate, renal blood flow, and glomerular capillary pressure. The urinary albumin excretion rate (1.3 +/- 0.1 mg/24 hr) and the tubular fluid albumin concentration (4.7 +/- 0.7 mg/dl) in the diabetic group were significantly elevated when compared with urinary albumin excretion (0.9 +/- 0.1 mg/24 hr) and tubular fluid albumin concentration (2.5 +/- 0.5 mg/dl) in the control group. There were no significant differences in glomerular hemodynamics (whole kidney or single nephron glomerular filtration rate or glomerular capillary pressure) between diabetic and control rats. The kidney weight and kidney weight to body weight ratio were significantly higher in diabetic rats when compared with control rats. Early diabetes in Biobreeding rats is characterized by mild albuminuria and increased kidney size, but not glomerular hyperfiltration.

Progressive glomerular injury after recovery from acute glomerulonephritis in rats.

To determine if an acute immunologic injury resembling poststreptococcal nephritis could lead to chronic renal injury, rats with immune-complex glomerulonephritis produced with cationic human gammaglobulin were followed for 48 weeks. During Week 1, animals developed severe proteinuria, hypoalbuminemia, and a diffuse proliferative/exudative glomerulitis. Substantial recovery, characterized by a significant decline in urinary protein excretion and normalization of plasma albumin concentration, occurred by Week 4. Subsequently, rats developed significantly elevated blood pressures and increasing proteinuria. Glomerular histology at Week 48 revealed minimal inflammation, significant hypertrophy, and considerable sclerosis. We conclude that chronic, progressive renal disease can evolve after apparent recovery from an acute immunologic insult. Further study of this model should provide clinically relevant information about the mechanisms underlying this process.

Inverse changes in erythroid cell volume and number regulate the hematocrit in newborn genetically hypertensive rats.

Erythrocytosis and microcytosis have been described in strains of genetically hypertensive rats and in essentially hypertensive humans. Published discussion of these phenomena has centered around their relationship to observed alterations in ionic transport and the pathogenesis of hypertension. In presenting data for another strain of spontaneously hypertensive rats in which these findings are exhibited, we note that erythroid cell size decreases concurrently with the increase in cell numbers so that the hematocrit and the mean corpuscular hemoglobin concentration remain constant. Data from the literature support the hypothesis that erythroid cell size is inversely proportional to cell count in a large number of species. Erythrocytosis, as it develops in the neonatal rat, is a consequence of the marked immaturity of this species at birth. Erythrocytosis in the spontaneously hypertensive rat is not due to a difference in the affinity of its hemoglobin for oxygen or to significant tissue anorexia. Microcytosis in the spontaneously hypertensive rat is the consequence of a continuation of the linear volume decrease with age of its erythroid cells seen in the normotensive animals and may be accounted for by the production of smaller cells with concomitant regulation of individual cell volume.

Effects of caloric restriction and aging on erythrocyte membrane Ca(2+)-ATPase activity in specific pathogen-free Fischer 344 rats.

Dietary caloric restriction extends life span in the Fischer 344 rat. The interaction of aging and caloric restriction was examined at the level of the plasma membrane transport-associated enzymes, Ca(2+)-adenosine triphosphatase (ATPase) and Na,K-ATPase, in the Fischer rat. Animals were in four age groups, ranging from 6.1 to 25.0 months, and were specific pathogen-free (SPF, barrier-raised). Results from male and female animals raised on an ad libitum diet were compared with those from rats that received 60% of the age-specific caloric intake of their ad lib littermates. The responses of erythrocyte membrane Ca(2+)-ATPase activity in vitro to thyroid hormone (L-thyroxine [T4]; 3,5,3'-triiodothyronine [T3]) and to purified calmodulin, a Ca(2+)-binding protein activator of Ca(2+)-ATPase, were measured. Erythrocyte membrane Na,K-ATPase was also compared in the two diet groups, as was plasma glucose. Plasma membrane Ca(2+)-ATPase activity in the absence of added thyroid hormone and calmodulin was significantly reduced in calorically restricted rats (-39%, P less than .001), compared with ad lib-fed animals, and the response was similar in the four age groups aged 6.1, 12.7, 17.0, and 25.0 months. In contrast, pooled (all ages) Ca(2+)-ATPase response in vitro to T4 and to T3 in calorically restricted animals was enhanced compared with the ad lib group (+62% and +58%, P less than .001, respectively). Calmodulin responsiveness of the enzyme was increased by 45% (P less than .001) in calorie-deprived animals, similar to the change in T4 and T3 responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)