Renal responses to chronic cold exposure

The aim of this study was to assess our hypothesis that the release of antidiuretic hormone (ADH), the renal concentrating response to ADH, or both is decreased by prolonged cold exposure. Six groups (n = 6/group) of rats were used. Three groups were exposed to cold (5 degrees C), whilethe remaining three groups were kept at room temperature (25 degrees C). It was found that urine osmolality decreased significantly and serum osmolality increased significantly during cold exposure. The ratio of water/food intake was not affected by prolonged cold exposure. However, prolonged cold exposure increased the ratio of urine output/food intake in the cold-exposed rats, indicating that more urine flow is required by the cold-exposed rats to excrete the osmotic substance at a given food intake. The difference between water intake and urine output decreased significantly in the cold-exposed rats. Thus, prolonged cold exposure increases water loss from excretion. Renal concentrating responses to 24-h dehydration and Pitressin were decreased significantly in the cold-exposed rats. Plasma ADH levels remained unchanged, but renal ADH receptor (V2 receptor) mRNA was decreased significantly in the cold-exposed rats. The results strongly support the conclusion that cold exposure increases excretive water loss, and this may be due to suppression of renal V2 receptors rather than inhibition of ADH release.     

Role of vasopressin in rats with bilateral ureteral obstruction

After unilateral release of bilateral ureteral obstruction (BUO), there is a significant increase in renal vasoconstriction that accounts for the marked decrease in glomerular filtration rate and effective renal plasma flow seen in this setting. We examined the potential role of antidiuretic hormone (ADH), a vasoconstrictor of the renal circulation, on renal hemodynamics in female Sprague-Dawley rats with BUO of 24-hr duration. Rats with BUO had significantly higher plasma values of ADH 65.1 +/- 12.2 vs. 12.1 +/- 4.1 pg/ml), sodium (145.4 +/- 0.91 vs 138.6 +/- 1.06 mEq/liter), and osmolality (375.6 +/- 2.0 vs 310.1 +/- 3.6 mOsm/kg) than sham-operated rats. Rats with BUO pretreated with enalapril, an angiotensin-converting enzyme inhibitor, before obstruction had somewhat higher, but not significantly different, plasma values for ADH (84.6 +/- 20.8 pg/ml) than rats with BUO not given enalapril. Rats with unilateral ureteral obstruction of 24-hr duration had plasma levels of ADH (8.2 +/- 1.3) not different from those in sham-operated rats. Rats with BUO pretreated with a specific antagonist of the V1-type receptor for ADH had significantly greater values for the glomerular filtration rate (2.31 +/- 0.24 vs 1.44 +/- 0.08 ml/min/kg body wt) and the effective renal plasma flow (8.95 +/- 0.71 vs 3.81 +/- 0.44 ml/min/kg body wt) and significantly lower values for mean arterial pressure (140.3 +/- 2.0 vs 159.1 +/- 5.5 mm Hg) than did BUO rats not given the antagonist. The results indicate that high levels of ADH play an important role in the decrease in the glomerular filtration rate and effective renal plasma flow observed in rats with BUO of 24 hr. The significant increase in ADH levels after BUO of 24-hr duration may be due to an increase in osmotic stimulation as a consequence of hypernatremia. Activation of the renin-angiotensin axis, known to occur after BUO or unilateral ureteral obstruction of 24-hr duration, does not appear to have a role in the increased circulating levels of ADH.     

Circulating antidiuretic hormone in the X-irradiated rat

Male rats exposed to 500 R of whole-body x-irradiation were allowed food and water ad libitum and housed in metabolism cages; water and food intake and urinary and fecal excretion were recorded daily. Urine output increased 200% during the first 24 hours after irradiation. No significant changes occurred in daily sodium, potassium, urea, or total solute excretion, although calcium excretion approximately doubled after irradiation. The marked increase in free water excretion implicates antidiuretic hormone (ADH) in this phenomenon. Application of a sensitive bioassay for ADH permitted measurement of plasma ADH concentrations in undisturbed, unanesthetized rats before and after irradiation. ADH levels were lower and frequently not detectable 24 hours after exposure. High ADH levels, however, could be provoked in irradiated rats by hemorrhage, indicating that the receptor cells and secretory ability of the posterior pituitary remained intact. Furthermore, irradiated rats responded normally to small intravenous injections (4 to 8 microU) of exogenous ADH. Rats with congenital diabetes insipidus given daily injections of Pitressin showed no postirradiation diuresis. Lastly, increased urinary calcium excretion may result from hypercalcemia which is known to induce diuresis through calcium-vasopressin antagonism. These results further suggest that the diuretic response is due to decreased circulating ADH.     

Effect of central adrenergic alpha receptor blockader IEM-611 on the activity of alcohol and aldehyde dehydrogenase in rat liver

The effect of IEM-611 (30 mg/kg) on alcohol consumption in rats under the conditions of voluntary choice between water and 15% ethanol was studied as that on alcohol dehydrogenase (ADH) in postmitochondrial supernatant and in NAD-dependent aldehyde dehydrogenases (A1DH) in liver mitochondria. Administration of IEM-611 during 6 or 12 days reduces ethanol consumption by 29 and 30%, respectively, activates ADH and appreciably decreases overall activity of NAD-dependent A1DH. At the same time the ADH/A1DH ratio increases. Activation of ADH and A1DH and the decreased ADH/A1DH ratio were disclosed in alcohol preferring rats as compared to water preferring animals. IEM-611 shifts enzymatic activity of ethanol metabolism towards the level characteristic for water preferring rats. It is suggested that variation of the ADH/A1DH ratio is one of the mechanisms responsible for the decreased ethanol consumption in rats.     

Role of renal prostaglandins in the fall in urine osmolality after papillary micropuncture

The effect of micropuncture of the renal papilla through an intact ureter on urinary concentrating ability of rats was examined. Micropuncture of the renal papilla caused a fall in urine osmolality in the punctured kidney from 1718 +/- 106 to 1035 +/- 79 mosmol/kg X H2O. In order to investigate the role of renal prostaglandins in this process, PGE2 excretion was measured and found to increase from 63.4 +/- 14.0 to 205.5 +/- 57.1 pg/min. Urine osmolality and PGE2 excretion from the contralateral kidney were not significantly altered. In animals given meclofenamate (2 mg/kg X hr), renal PGE2 excretion was reduced to 22.3 +/- 5.1 pg/min prior to micropuncture and it remained low at 8.9 +/- 1.8 pg/min after papillary micropuncture. Meclofenamate also blocked the fall in urine osmolality caused by micropuncture of the renal papilla, with urine osmolality averaging 1940 +/- 122 before and 1782 +/- 96 mosmol/kg X H2O after the micropuncture. These results indicated that papillary micropuncture through an intact ureter increased renal PGE2 excretion and that a rise in renal production of PGE2 or some other prostanoid is associated with a fall in urine concentrating ability.     

Redistribution of intrarenal blood flow following adh administration: Lack of inhibition by blockade of prostaglandin cyclooxygenase

The effect of prostaglandin synthesis inhibition on the redistribution of renal cortical blood flow in response to antidiuretic hormone (ADH) was examined using radioactive microspheres in water loaded, thiopental-anesthetized dogs. Microsphere injections were made during a control and an ADH infusion period (0.35 mU/kg/min following a 20 mU/kg bolus) both before and after indomethacin pretreatment (8 mg/kg intravenously). Urinary prostaglandin E₂ (PGE₂) excretion in each period was measured by gas chromatography-mass spectrometry. ADH caused a marked redistribution of flow toward inner cortical zones from 19±1 to 25±2 ml/min (mean^± SE, p < 0.01). Fractional flow to inner zones was also significantly increased. Indomethacin pretreatment had no effect on the ADH-induced redistribution (17±2 vs. 24±2 ml/min, p < 0.01), although urinary PGE₂ excretion was suppressed by indomethacin by 60%. It is concluded that prostaglandins do not mediate the redistribution of intrarenal blood flow accompanying ADH administration.     

Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease

Impaired glomerular filtration rate (GFR) is a risk factor for the development of hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD). However, markers of tubular function were not tested whether they are linked to hypertension or blood pressure (BP) level. The aim of our study was to investigate the relationship between renal concentrating capacity and BP in children with ADPKD. Fifty-three children (mean age 11.8+/-4.4 years) were investigated. Standardized renal concentrating capacity test was performed after nasal drop application of desmopressin, BP was measured by ambulatory BP monitoring (ABPM). Renal concentrating capacity was decreased in 58 % of children. The prevalence of hypertension was significantly higher in children with decreased renal concentrating capacity (35 %) than in children with normal renal concentrating capacity (5 %) (p<0.05). Significant negative correlations were found between renal concentrating capacity, ambulatory BP and number of renal cysts (r = -0.29 to -0.39, p<0.05 to p<0.01). In conclusion, the concentrating capacity is decreased in about half of the patients and is linked to BP. Decreased renal concentrating capacity should be considered.     

Losartan corrects abnormal frequency response of renal vasculature in congestive heart failure

In congestive heart failure, renal blood flow is decreased and renal vascular resistance is increased in a setting of increased activity of both the sympathetic nervous and renin-angiotensin systems. The renal vasoconstrictor response to renal nerve stimulation is enhanced. This is associated with an abnormality in the low-pass filter function of the renal vasculature wherein higher frequencies (> or =0.01 Hz) within renal sympathetic nerve activity are not normally attenuated and are passed into the renal blood flow signal. This study tested the hypothesis that excess angiotensin II action mediates the abnormal frequency response characteristics of the renal vasculature in congestive heart failure. In anesthetized rats, the renal vasoconstrictor response to graded frequency renal nerve stimulation was significantly greater in congestive heart failure than in control rats. Losartan attenuated the renal vasoconstrictor response to a significantly greater degree in congestive heart failure than in control rats. In control rats, the frequency response of the renal vasculature was that of a first order (-20 dB/frequency decade) low-pass filter with a corner frequency (-3 dB, 30% attenuation) of 0.002 Hz and 97% attenuation (-30 dB) at > or =0.1 Hz. In congestive heart failure rats, attenuation did not exceed 45% (-5 dB) over the frequency range of 0.001-0.6 Hz. The frequency response of the renal vasculature was not affected by losartan treatment in control rats but was completely restored to normal by losartan treatment in congestive heart failure rats. The enhanced renal vasoconstrictor response to renal nerve stimulation and the associated abnormality in the frequency response characteristics of the renal vasculature seen in congestive heart failure are mediated by the action of angiotensin II on renal angiotensin II AT1 receptors.     

Effect of captopril or enalapril on renal prostaglandin E2

Since one of the hypotensive mechanisms of angiotensin-converting enzyme inhibitor (ACEI) has been suggested to be mediated through the renal kinin-prostaglandin (PG) axis, the present study was designed to investigate the effect of captopril (C) or enalapril (E) on renal PGE2 excretion or synthesis. Wistar male rats (BW 200-250 g) were given orally captopril at 30 mg/kg/day or enalapril at 10 or 30 mg/kg for one week. Before and after ACEI, blood pressure (tail cuff method) as well as PRA and urinary PGE2 excretion was determined. Renopapillary slices were obtained from some of the rats including controls and incubated to determine PGE2 synthesis. C or E administration resulted in a blood pressure decrease of 21 to 36 mm Hg with an increase in PRA. Urine volume and sodium excretion increased after daily treatment with C or E at 30 mg/kg. Urinary PGE2 excretion increased 1.4-fold in response to C, but not to E. Papillary PGE2 synthesis demonstrated a marked decrease 2 h after in vivo administration of either ACEI compared to controls. However, when C or enalaprilat was added in vitro to renal slices obtained from controls, only C at 10(-5) M showed a significant 2-fold increase in renal PGE2 synthesis. These results suggest that (1) renal PGE2 synthesis may be dependent on circulating angiotensin II. (2) C, but not enalaprilat, has a direct stimulatory effect on renal PGE2 synthesis and (3) renal PGE2 may not be involved very much in the hypotensive effect of ACEI.     

Changes in cAMP reception in the cytosol of the developing rat kidney

The age-dependent changes in the cAMP-binding activity of renal papillary cytosol were studied in intact rats and in animals with experimental delay in development of the concentrating renal function induced by hydrocortisone injection in early postnatal period. The age dynamics of specific cAMP binding in the experimental group differ significantly from that in intact and control (sham injected) animals. It is suggested that the developmental changes in experimental animal kidneys are due to disturbances in hormonal regulation of renal tissue differentiation caused by the changes in intracellular receptors of cAMP. Another possible reason for the observed delay of development of the renal function is the weakening of the stimulating effect of endogenous cAMP on the genome function due to cAMP receptor deficiency in the cell.     

Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla

Chloroquine, a widely used anti-malaria drug, has gained popularity for the treatment of rheumatoid arthritis, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV). Unfortunately, chloroquine may also negatively impact renal function for patients whose fluid and electrolyte homeostasis is already compromised by diseases. Chronic administration of chloroquine also results in polyuria, which may be explained by suppression of the antidiuretic response of vasopressin. Several of the transporters responsible for concentrating urine are vasopressin-sensitive including the urea transporters UT-A1 and UT-A3, the water channel aquaporin-2 (AQP2), and the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). To examine the effect of chloroquine on these transporters, Sprague-Dawley rats received daily subcutaneous injections of 80 mg·kg(-1)·day(-1) of chloroquine for 4 days. Twenty-four hour urine output was twofold higher, and urine osmolality was decreased by twofold in chloroquine-treated rats compared with controls. Urine analysis of treated rats detected the presence chloroquine as well as decreased urine urea and cAMP levels compared with control rats. Western blot analysis showed a downregulation of AQP2 and NKCC2 transporters; however, UT-A1 and UT-A3 abundances were unaffected by chloroquine treatment. Immunohistochemistry showed a marked reduction of UT-A1 and AQP2 in the apical membrane in inner medullary collecting ducts of chloroquine-treated rats. In conclusion, chloroquine-induced polyuria likely occurs as a result of lowered cAMP production. These findings suggest that chronic chloroquine treatment would exacerbate the already compromised fluid homeostasis observed in diseases like chronic kidney disease.     

Enhanced natriuretic effect of ADH in rats loaded with NaCl

ADH at doses 20 μU/100 g and 100 μU/100 g or 20 μU/100 g and 200 μU/100 g was injected intravenously into pentobarbital and alcohol anaesthetized rats loaded with either water or isotonic solution consisting of NaCl, glucose and ethanol. At the dose of 20 μU/100 g ADH retained water in both water and NaCl loaded animals. At high doses 100 μU/100 g in NaCl loaded rats and 200 μU/100 g in water loaded rats, ADH retained water and increased the renal excretion of Na⁺. That the natriuretic effect of ADH at the dose 20 μU/100 g was enhanced in NaCl loaded rats suggests that ADH is probably important in the regulation of Na⁺ content in the body when it is loaded with NaCl.     

Influence of naloxone on hypothalamic L-aminopeptidase activity in the normal and ovariectomized rat

The effect of naloxone on the L-leucinaminopeptidase (LAP) activity has been determined in the hypothalamus of normal female rats or after different periods of time from ovariectomy (15th or 30th day). Castration at 15th and 30th days produced a not very important fall of LAP activity. The naloxone injections (2.5 or 5 mg/kg vía i.p.) determined a significant decrease in LAP activity in the intact and ovariectomized rats, greater for 5 mg/kg. A significant LAP activity decrease was found only after a 30 day postcastration period when naloxone treated intact animals were compared with the castrated rats. These data are discussed in relation to the physiological significance of brain peptidases and the pharmacological effect of naloxone on the function of the hypothalamic-pituitary-gonadal axis.     

Role of pressor mechanisms from the NTS and CVLM in control of arterial pressure

In the present study, we investigated the effects of inhibition of the caudal ventrolateral medulla (CVLM) with the GABA(A) agonist muscimol combined with the blockade of glutamatergic mechanism in the nucleus of the solitary tract (NTS) with kynurenic acid (kyn) on mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances. In male Holtzman rats anesthetized intravenously with urethane/chloralose, bilateral injections of muscimol (120 pmol) into the CVLM or bilateral injections of kyn (2.7 nmol) into the NTS alone increased MAP to 186 +/- 11 and to 142 +/- 6 mmHg, respectively, vs. control: 105 +/- 4 mmHg; HR to 407 +/- 15 and to 412 +/- 18 beats per minute (bpm), respectively, vs. control: 352 +/- 12 bpm; and renal, mesenteric and hindquarter vascular resistances. However, in rats with the CVLM bilaterally blocked by muscimol, additional injections of kyn into the NTS reduced MAP to 88 +/- 5 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Moreover, in rats with the glutamatergic mechanisms of the NTS blocked by bilateral injections of kyn, additional injections of muscimol into the CVLM also reduced MAP to 92 +/- 2 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Simultaneous blockade of NTS and CVLM did not modify the increase in HR but also abolished the increase in renal vascular resistance produced by each treatment alone. The results suggest that important pressor mechanisms arise from the NTS and CVLM to control vascular resistance and arterial pressure under the conditions of the present study.     

Acute renal response to LPS: impaired arginine production and inducible nitric oxide synthase activity

We have previously shown in rats that lipopolysaccharide (LPS) causes both decreased renal perfusion and kidney arginine production before nitric oxide (NO) synthesis, resulting in a >30% reduction in plasma arginine. To clarify the early phase effects of LPS, we asked the following two questions: 1) is the rapid change in renal arginine production after LPS simply the result of decreased substrate (i.e., citrulline) delivery to the kidney or due to impaired uptake and conversion and 2) is the systemic production of NO limited by plasma arginine availability after LPS? Arterial and renal vein plasma was sampled at 30-min intervals from anesthetized rats with or without citrulline or arginine (2 micromol.min(-1).kg(-1) iv) a dose with no effect on MAP, renal function, or NO production. Exogenous citrulline was quickly converted to arginine by the kidney, resulting in plasma levels similar to equimolar arginine infusion. Also, the increase in citrulline uptake resulted primarily from increased filtered load and reabsorption. In a separate series, citrulline was infused after LPS administration, verifying that citrulline uptake and conversion persists during impaired kidney function. Last, in rats given LPS, the elevation of plasma arginine had no discernable impact on mean arterial pressure, kidney function, or systemic NO production. This work demonstrates how arginine synthesis is normally "substrate limited" and explains how impaired kidney perfusion quickly results in decreased plasma arginine. However, contrary to in vitro studies, the significant reduction in extracellular arginine during the early phase response to LPS in vivo is not functionally rate limiting for NO production.     

The effect of angiotensin II and ADH on the secretion of atrial natriuretic factor

Studies in intact animals have suggested that angiotensin II (AII) and antidiuretic hormone (ADH) increase the plasma concentration of atrial natriuretic factor (ANF). The purpose of these studies was to examine the effects of AII and ADH on ANF secretion in a rat heart-lung preparation under conditions where aortic pressure could be regulated and other indirect effects of these hormones eliminated. ANF secretion was estimated as the total amount of ANF present in a perfusion reservoir at the end of each 30-min period. A pump was used to deliver a fluorocarbon perfusate to the right atrium at rates of either 2 or 5 ml/min. In a time control series where venous return was maintained at 2 ml/min for three 30-min periods ANF secretion was 672 +/- 114, 794 +/- 91, and 793 +/- 125 pg/min (n = 6, P greater than 0.05). When venous return was increased from 2 to 5 ml/min ANF secretion increased from 669 +/- 81 to 1089 +/- 127 pg/min (P less than 0.01). The addition of AII to the perfusate in concentrations of 50, 100, or 200 pg/ml (n = 6 in each group) had no significant effect on basal ANF secretion or the ANF response to increasing venous return. Similarly, the addition of ADH to the perfusate in concentrations of 5, 25, or 100 pg/ml had no significant effect on ANF release from the heart. These results suggest that the ability of AII and ADH to increase plasma ANF concentration in vivo may be due to the effects of these hormones on right or left atrial pressure.     

Glucocorticoids modulate baroreflex control of renal sympathetic nerve activity

Experiments were performed to determine the effects of glucocorticoids on arterial baroreceptor reflex control of renal sympathetic nerve activity (RSNA). Intravenous infusions of phenylephrine and nitroprusside were used to produce graded changes in arterial pressure (AP) in Inactin-anesthetized male Sprague-Dawley rats. Baroreflex control of RSNA was determined during a baseline period and 2 and 3 h after administration of the glucocorticoid type II receptor antagonist Mifepristone (30 mg/kg sc) or vehicle (oil). Corticosterone (cort) treatment (100 mg cort pellet sc for 2-3 wk) increased baseline AP from 115 +/- 2 to 128 +/- 1 mmHg. Cort treatment also decreased the gain coefficient and increased the midpoint of the baroreflex curve. Treatment of cort rats with Mifepristone decreased AP within 2 h and increased the gain coefficient and decreased the midpoint of the baroreflex function curve back toward values measured in control rats. Mifepristone altered the baroreflex function curve even when AP was maintained at baseline levels. Therefore, these data demonstrate for the first time that glucocorticoids can modulate baroreflex control of RSNA by a mechanism that is, in part, independent of changes in AP.     

Renal cytoplasmic proteasome proteinase activities are altered in chronic renal failure

The effect of uremia on renal cortex cytoplasmic proteasomes was examined by comparing proteasomes isolated from 5/6th nephrectomy rats 3-months post-surgery and age-matched control rats with normal renal function. ATP-dependent proteasome activity was reduced 50% in chronic renal failure rats (CRF) 3-months post-surgery compared to age-matched control rats. Trypsin-like (T-like) proteasome activity was decreased 90% compared to 70% for caspase-like activity (PGPHase) and 30% for chymotrypsin-like activity (C-like). ATP-independent proteasome activity was decreased 60% in CRF rats 3-months post-surgery. ATP-independent renal cortex proteasome T-like activity in CRF rats was 4% of age-matched control rats. C-like and PGPHase activities were 60% and 50% of age-matched controls, respectively. Uremia was associated with decreased 26S proteasome beta subunits. CRF rat 26S proteasomes had decreased levels of beta1, beta3, alpha4, and alpha7 abundances. Compared to age-matched control rats with normal renal function, CRF rats had a 25% increase in ubiquitinated cytoplasmic proteins. Decreased renal cytoplasmic proteasome activity may play a role in renal tubule hypertrophy common to renal diseases associated with decreased functioning nephrons.     

Comparison of the effectiveness of 2,3-dimercaptopropanol (BAL) andmeso-2,3-dimercaptosuccinic acid (DMSA) as protective agents against mercuric chloride-induced nephrotoxicity in rats

The effectiveness of 2,3-dimercaptopropanol (BAL) andmeso-2,3-dimercaptosuccinic acid (DMSA) on HgCl₂-induced nephrotoxicity was studied in the rat. Seven groups of adult male rats were given a single sc toxic dose of HgCl₂ (0.68 mg/kg) followed by 0.9% saline (positive control group), BAL (15, 30, and 60 mg/kg) or DMSA (50, 100, and 200 mg/kg) administered ip at 0, 24, 48, and 72 h thereafter. Although the renal function of HgCl₂-exposed rats was slightly improved after BAL administration, Hg concentrations in the kidney were only reduced at 60 mg/kg. In addition, the protective effect of BAL was not dose-related. In contrast to BAL, DMSA was effective in increasing the urinary excretion of Hg and in reducing the renal Hg content. These results show that DMSA would be more effective than BAL in preventing or in protecting against inorganic Hg-induced nephrotoxicity.     

Physiological consequences of early neonatal growth retardation: effects of alpha-difluoromethylornithine on renal growth and function in the rat

The physiological consequences of early neonatal growth retardation in the kidney were investigated using alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines. We administered by s.c. 500 mg/kg/day DFMO, or saline, to Sprague-Dawley rat pups from the day of birth through postnatal day (PD) 6 and evaluated renal function on PD 4, 7, 10, and 13 using tests of basal renal clearance and urinary concentrating ability. Kidney weights and gross pathology were also obtained. On PD 39, serum chemistries and organ weights were determined. In a second experiment, we evaluated concentrating ability on PD 7-10, and basal renal function, concentrating ability, diuretic response, serum chemistries, and organ weights on PD 132-140. DFMO selectively inhibited renal growth but did not inhibit glomerular and tubular functional maturation. In fact, the rates of filtration and reabsorption (per g renal tissue), and concentrating ability were increased in treated pups. These changes were associated with long-term effects on renal function, including uremia, glucosuria, and male-specific concentrating deficits in adulthood. Several hypotheses can be developed concerning the physiological mechanisms underlying these changes (e.g., altered renal urea metabolism), which in turn may reflect either a direct role of ODC in the regulation of maturation or secondary consequences of inhibition of ODC.(ABSTRACT TRUNCATED AT 250 WORDS)