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PubMed1976

[Age dependent differences in the pharmacokinetics of furosemide in rats].

After i.p. administration of 0,60 mg/100 g of furosemide, adult rats excreted 50 to 70% of this diuretic drug unchanged and 10% as desfurylmethylfurosemide. The renal excretion of furosemide is slower in 5- and 15-day-old rats. Age differences in absorption from the abdominal cavity or in the reabsorption rate in the kidney tubules can be excluded. The excretion of furosemide by the kidney is competitively inhibited by p-aminohippuric acid (PAH). The relative small inhibitory effect of PAH in young rats is caused by a smaller participation of tubular secretion in the renal excretion of furosemide in this age group. The half life time of furosemide is 83 min in 5-day-old rats and 47 min in 55-day-old rats. The distribution volume is 146% of body weight in both age groups. The concentration of furosemide in the kidney homogenate is higher in young rats than in adults. The slow renal excretion of furosemide in young rats is in accordance with the prolonged efficacy. The greater efficacy of furosemide in 5- and 15-day-old rats than in adults is caused particularly by differences in the conditions for diuretic effectiveness, especially by the retention of water and electrolytes in young rats.

Absorption↗
PubMed1989

Natriuretic response to volume expansion in polycystic kidney disease.

Hypertension is an early manifestation of autosomal dominant polycystic kidney disease (ADPKD). Whether polycystic kidneys have an intrinsic abnormality that leads to sodium retention, volume expansion, and hypertension is uncertain. We studied the natriuretic response to a 4-hour infusion of physiologic saline at a rate of 6.5 ml/kg per hour in 10 patients with ADPKD who had normal renal function and 10 gender- and age-matched control subjects. Baseline 24-hour urinary excretions of sodium and potassium were similar in both groups. The baseline filtration fraction was significantly higher in the patients with ADPKD than in the control subjects. During the infusion of saline, no significant changes in blood pressure, clearance of inulin, or clearance of p-aminohippuric acid were detected. The increase in fractional excretion of sodium over baseline was significantly higher in the patients with ADPKD than in the control subjects. The pressure-natriuresis regression line was significantly shifted to the right in patients with ADPKD who had hypertension. The fractional excretion of potassium was significantly lower in patients with ADPKD than in control subjects. No significant differences in plasma renin activity, aldosterone, or atrial natriuretic factor were detected between the two groups. These observations suggest the presence of subtle abnormalities in the management of renal sodium that might contribute to the development and maintenance of hypertension in patients with ADPKD.

Adult↗
PubMed2002

Effects of gender on the pharmacokinetics of drugs secreted by the renal organic anions transport systems in the rat.

The importance of considering sex differences in drug handling studies was admitted recently. The present work evaluates the sex influences on the pharmacokinetics of para-aminohippuric acid (PAH), the reference substance for the renal organic anion transports systems, and furosemide (FS), a standard loop diuretic which is also a substrate for this transport system. Female rats displayed a lower PAH and FS systemic clearance, and a lower value of the elimination rate microconstant from the central compartment for both drugs. These results may be explained by the diminution of the renal clearance of both PAH and FS observed in females. In summary, sex modifies the pharmacokinetics of organic anions. Although additional experimental work must be done to bridge the gap between studies using animals and humans, the reported experimental observations may have potentially important pharmacological implications. So, caution must be exercised in administering drugs like organic anions to females.

Animals↗
PubMed1975

Renal tubular excretion of triethylcholine (TEC) in the chicken: enhancement and inhibition of renal excretion of choline and acetylcholine by TEC.

1. [3H]-triethylcholine (TEC) was actively transported by the renal tubule of the chicken at a rate 85% that of simultaneously administered p-aminohippuric acid (PAH). 2. TEC was demonstrated to be transported by the organic cation transport system in the kidney through inhibition with quinine and the bio-cation choline. 3. When the infusion of TEC was increased to 2 times 10(-6) mol kg(-1) min(-1) reaching the infused kidney, the transport of [3H]-TEC was inhibited, suggesting that an excretory transport maximum for TEC in the renal tubules had been reached. 4. The excretion of both choline and acetylcholine was enhanced by TEC loads as low as 1 times 10(-18) mol kg(-1) min(-1). Enhancement continued as TEC infusion was increased up to approximately 1 times 10(-7) mol kg(-1) min(-1) at which point this enhancement was converted to inhibition. 5. Possible mechanisms for the biphasic effect of TEC on organic cation transport are discussed.

Acetylcholine↗
PubMed1989

Peroxidative damage and nephrotoxicity of dichlorovinylcysteine in mice.

Male NMRI mice were treated i.p. with dichlorovinylcysteine (DCVC) in a dosage of 2.5-500 mg/kg-1 and renal cortical slices from naive mice were incubated with 0-125 micrograms/ml-1 DCVC. The effects of DCVC on blood urea nitrogen (BUN), reduced glutathione (GSH) content, malondialdehyde (MDA) production, p-aminohippuric acid (PAH)- and tetraethylammonium (TEA)-accumulation and glucose synthesis (gluconeogenesis) were measured. DCVC depleted GSH in a time- and dose-dependent manner. Depletion of renal cortical GSH by DCVC was more pronounced in the kidney cortex than in the liver. DCVC caused a dose-dependent increase of ethane exhalation and of MDA production in the renal cortex. When animals were kept in a closed system, decrease in oxygen concentration increased the peroxidative damage. No increase of MDA concentration was observed in the liver. Treatment of mice with DCVC induced a dose-dependent increase in BUN and decreased the accumulation of PAH and TEA in renal cortical slices. Pretreatment of mice with aminooxyacetic acid (AOAA) and (+) cyanidanol-3 (CY) caused a significant reduction in DCVC-induced lipid peroxidation and nephrotoxicity. In vitro incubation of renal cortical slices of naive mice with DCVC resulted in a concentration-dependent increase in MDA and a concentration-dependent decrease in the accumulations of PAH, TEA and of gluconeogenesis. In conclusion, the interaction of DCVC and/or its metabolites with membrane lipids may be responsible for lipid peroxidation and nephrotoxicity. The formation of lipid peroxidation products was greater under hypoxic conditions and appeared to be related to the DCVC-induced nephrotoxicity. This data suggests lipid peroxidation as a possible mechanism of DCVC-induced nephrotoxicity.

Animals↗
PubMed1998

Renal blood flow: measurement in vivo with rapid spiral MR imaging.

PURPOSE: To assess the ability of three cine phase-contrast magnetic resonance (MR) imaging techniques to measure normal human renal blood flow (RBF) in vivo. MATERIALS AND METHODS: Eighteen healthy volunteers were studied with three cine phase-contrast MR imaging techniques: breath-hold, segmented k-space, two-dimensional, Fourier transform technique (ie, time-resolved imaging with automatic data segmentation, or TRIADS); a breath-hold rapid spiral acquisition; and a non-breath-hold rapid spiral acquisition that allowed resolution of both cardiac and respiratory cycles. In each case, total arterial RBF and blood flow per unit of renal volume were calculated. For each subject, RBF was measured with a standard technique of p-aminohippuric acid (PAH)-clearance hematocrit on the same day as the MR imaging examination was performed. RESULTS: The range of agreement (2 standard deviations, or 95% confidence interval) between RBF measurements obtained with the PAH-clearance hematocrit technique and the various cine phase-contrast techniques varied from +/- 17.6% to +/- 26.5%. The best agreement was obtained with non-breath-hold rapid spiral data, by using data from the end-expiratory phase of respiration. CONCLUSION: Findings with cine phase-contrast MR imaging employing rapid spiral acquisition are in good agreement with measurements made with PAH-clearance hematocrit and give the promise of clinical measurements of RBF.

Adult↗
PubMed2002

The adverse renal effects of prostaglandin-synthesis inhibitors in the newborn rabbit.

Nonsteroidal anti-inflammatory drugs are frequently used during pregnancy (premature labor, polyhydramnios) and the immediate postnatal period (closure of patent ductus arteriosus). This article evaluates the renal effect of 3 nonspecific COX inhibitors (aspirin, indomethacin, and ibuprofen) in newborn rabbits. Five groups of anesthetized, ventilated, normoxemic 6-day-old rabbits (n = 52) were administered intravenous aspirin (40 mg/kg), indomethacin (2 mg/kg), and ibuprofen (0.02, 0.2, 2.0 mg/kg, respectively). Renal function and hemodynamics as assessed by inulin and para-aminohippuric acid clearances were measured before and in the hour after drug administration. In all groups of animals, the nonselective COX inhibitors induced an increase in renal vascular resistance and a consequent decrease in glomerular filtration rate and renal blood flow. Urine flow rate decreased significantly in all groups, except in the group receiving the lowest dose of ibuprofen. In newborn rabbits, aspirin, indomethacin, and ibuprofen induced intense renal vasoconstriction, which resulted in impaired renal function. This observation illustrates the major renal protective role played by the vasodilatory prostaglandins during the neonatal period, when the kidney is perfused at very low perfusion pressure. We conclude that all COX inhibitors should be administered with the same caution to the preterm neonate.

Animals↗
PubMed1993

Characterization of p-aminohippurate transport from rat kidney which is expressed after injection of size-selected mRNA into oocytes of Xenopus laevis.

First, the existence of an endogenous p-aminohippurate (PAH) transporter in oocytes of Xenopus laevis was demonstrated. When, however, the oocytes were injected with mRNA from rat kidney cortex, an expressed p-aminohippuric acid (PAH) uptake was seen which differed from the endogenous transporter. Both transport systems are saturated at high PAH concentrations, exhibit trans-stimulation by PAH and are partially inhibited by probenecid. The endogenous transport has a rather low affinity for PAH (Km = 0.57 mM) and is about 50% inhibited by probenecid (one apparent inhibition site with half maximal inhibition at 0.5 mM). The expressed PAH transport has a high affinity for PAH (Km = 60 microM) and can be inhibited 80% by probenecid (two apparent inhibition sites with half maximal inhibitions at 1 microM and 2 mM). Expression experiments with fractionated mRNA revealed that the PAH transport expressed from rat kidney cortex is encoded by an mRNA of 1.8 to 2.5 kb.

Animals↗
PubMed1997

Apical-to-basolateral transepithelial transport of Ochratoxin A by two subtypes of Madin-Darby canine kidney cells.

In this study we investigated the transepithelial transport of Ochratoxin A (OTA), a potent nephrotoxin, across monolayers of two collecting duct-derived cells clones (Madin-Darby canine kidney cells (MDCK)-C7 and MDCK-C11 cells, resembling principal and intercalated cells, respectively) either from the apical to the basolateral side or vice versa. We cultured cells on permeable supports and compared the transport rates of OTA, p-aminohippuric acid (PAH) and fluorescein-labelled inulin. Monolayers of both cell clones translocated OTA from the apical to the basolateral side but not in the opposite direction. Transport rate across MDCK-C11 cell monolayers was 2.9-fold the transport rate across MDCK-C7 cell monolayers. OTA transport was temperature-dependent being reduced from 77.5 pmol/cm2 per h to 10.1 pmol/cm2 per h in MDCK-C11 and from 27.0 pmol/cm2 per h to 7.6 pmol/cm2 per h in MDCK-C7 cells when temperature was decreased from 37 degrees C to 4 degrees C. In both cell clones, the dipeptides carnosine and glycylsarcosine but not the amino acids glycine or phenylalanine had an inhibitory effect on OTA transport. In both cell clones, transepithelial transport of OTA was dependent on the apical pH (pK(a) of OTA = 7.1). In an environment mimicking the transepithelial in vivo pH gradient to some extent with more acidic pH on the apical side than on the basolateral side, transport was 4-fold higher in both cell clones as compared to conditions when pH was 7.4 in both bath solutions. In the absence of a pH gradient, transport rates were similar to that at 4 degrees C. Apical uptake of [3H]OTA was inhibited by carnosine and by glycylsarcosine and the uptake of [3H]carnosine was inhibited by OTA. Our results indicate that OTA is transported across the apical membrane of MDCK cells by both non-ionic diffusion and by a H+-dipeptide cotransporter. Thus, reabsorption of OTA in the collecting duct contributes to the observed long half life of OTA in the mammalian body.

Animals↗
PubMed1996

Renal function during intravenous infusion of urological irrigating fluids in the sheep.

BACKGROUND: Oliguria or anuria is an important sign of the transurethral resection syndrome, but the mechanism is not clear. METHODS: We gave an intravenous infusion of 40 ml/kg of glycine 1.5%, sorbitol 2%-mannitol 1%, and isotonic saline (control) in 6 conscious ewes and studied if irrigating fluids cause acute disturbances of kidney function. RESULTS: Both the electrolyte-free solutions induced an increase in urine flow and persistent hypo-osmolality. The renal clearances of p-aminohippuric acid and inulin as well as the unilateral renal blood flow, which was measured via ultrasonic flow probes, increased in response to infusion of glycine but not to sorbitol-mannitol. After the infusions, the renal clearances decreased transiently to below baseline levels. Hypertonic saline was given after half of the infusions of electrolyte-free irrigating fluid. This treatment redistributed water from the cells to the extracellular fluid, but had no effect on renal function. CONCLUSIONS: We conclude that 2500 ml of electrolyte-free irrigating fluid had no detrimental effects on kidney function in sheep. The changes we observed were essentially the same as after infusion of isotonic saline.

Animals↗
PubMed1986

Early indices of warm ischemic damage in autotransplanted canine kidneys preserved by simple hypothermic storage.

After measurement of normal renal function, dog kidneys (n = 52) were subjected to 3, 15, or 30 min of normothermic warm ischemia (WI). After 24 hr of preservation by simple hypothermic storage (SHS) in a modified Collins solution, autotransplant was done and renal function was again measured beginning at 1 hr. Compared with preharvest values, kidneys with minimal (3 min) WI had significantly decreased clearances of creatinine (Cr) and para-aminohippuric acid (PAH), PAH extraction, absolute and fractional Na reabsorption, Na excretion, and urinary Na concentration; no change in urine flow rate or K excretion; and significantly increased fractional excretion of Na, K, and H2O. Compared with minimal WI, 30-min WI produced further significant decreases in clearances of Cr, PAH, and PAH extraction; and further increases in fractional excretion of Na, K, and H2O. Urine flow was also decreased by about half and urine Na concentration rose significantly. Several parameters were very significantly correlated with the length of WI, but the most reliable index was the fractional reabsorption of Na. When several functional parameters were used together, kidneys with significant (30 min) WI prior to preservation could be identified with a high degree of statistical reliability.

Animals↗
PubMed1983

Renal disposition of moxalactam in experimental animals as revealed by stop-flow analysis.

The mechanisms of moxalactam excretion were studied by stop-flow analysis in dogs, monkeys, and rabbits. In dogs, the amount of moxalactam excreted in the urine was almost equal to that estimated by glomerular filtration. There was no specific moxalactam peak corresponding to the p-aminohippuric acid (PAH) peak in the stop-flow patterns of the dogs. The PAH peak disappeared with administration of probenecid, but the moxalactam stop-flow pattern showed no change. In monkeys, no specific moxalactam peak corresponding to the PAH peak could be detected. In the stop-flow pattern of the rabbit, the peak moxalactam concentration corresponded with that of PAH and disappeared with probenecid. These results suggest that in dogs and monkeys renal excretion of moxalactam takes place mostly through glomerular filtration. In rabbits, however, there is a small renal tubular secretory component added to the primary element, glomerular filtration. These observations point to differences in the mechanisms of moxalactam excretion in different animal species.

Animals↗
PubMed1987

The newborn rabbit: a model for studying hypoxemia-induced renal changes.

The newborn rabbit was used as an experimental model for studying renal changes during normocapnic hypoxemia. Renal extraction of p-aminohippuric acid (PAH), as assessed in 15 normoxemic and 8 hypoxemic rabbits amounted to 54.6 +/- 3.7 and 45.7 +/- 4.6%, respectively (NS). Changes in glomerular filtration rate (GFR), and renal blood flow (RBF) as assessed by inulin and PAH clearances, respectively, were determined during normoxemia and subsequent hypoxemia in 8 additional anesthetized and mechanically ventilated newborn rabbits. Normocapnic hypoxemia (PaO2 = 38.6 +/- 2.1 mm Hg) induced a significant fall in GFR from 2.10 +/- 0.21 to 1.51 +/- 0.18 ml/kg/min (p less than 0.01), in filtration fraction (p less than 0.01) and U/P inulin ratio (p less than 0.01). RBF, renal vascular resistance and urine flow rate did not change significantly. In comparison with other immature animal species the newborn rabbit appears a valuable and inexpensive model for the study of acute hypoxemia-induced renal changes.

Animals↗
PubMed1975

alpha-Adrenergic (norepinephrine) effect on antidiuretic hormone activity.

The mechanism by which norepinephrine (NE) inhibits the antidiuretic activity of anti-diuretic hormone (ADH) was studied in anesthetized normal and ADH-deficient rats. NE infusion increased aortic blood pressure and resulted in increased urine volume and sodium and potassium excretion without changes in creatinine excretion. p-Aminohippuric acid excretion did not change in normals and rose (from 34 +/- 9 to 51 +/- 11, P less than 0.025) in ADH-deficient rats. Urine osmolality fell in normals (from 363 +/- 29 to 298 +/- 42, P less than 0.05) but not in ADH deficients (from 332 +/- 29 to 363 +/- 26, p less than 0.1). ADH-deficient rats given 50 muU per kg-min of ADH intravenously responded with antidiuresis, including hyperosmolality (from a range of 225 to 240 to a range of 332 to 333, P less than 0.025). When NE was infused at 0.5 mug per kg-min, no inhibition of hyperosmolality was noted but natriuresis and augmented volume excretion occurred. At 1.5 mug per kg-min, NE completely reversed the hyperosmolality induced with ADH. The results suggest that NE-induced pressure diuresis reduces osmolality only when ADH is present in the system and so by competitive inhibition of ADH action on the renal tubule.

Aminohippuric Acids↗
PubMed1975

Pressure-dependent PAH and creatinine transport from the brain ventricles.

The brain ventricular system of the adult dog was perfused with an artificial cerebrospinal fluid (CSF) containing inulin, creatinine and radioactively labeled p-aminohippuric acid (PAH) and mannitol. Inflow and outflow rates and concentrations of test molecules were measured at different intraventricular pressures, allowing calculation of their steady-state rates of removal from the ventricles. Clearance of inulin, a measure of CSF bulk absorption varied nearly with intraventricular pressure (- 15 to +12 cm H2O relative to the external auditory meatus). The efflux coefficient (Ko; representing clearance of a molecule by means other than bulk absorption) for mannitol was independent of intraventricular pressure. Ko's for PAH and creatinine were pressure dependent. PAH and creatinine efflux may be related to the amount of fourth ventricular choroid plexus surface exposed to the perfusion fluid. Ko's for creatinine and PAH (46 plus or minus 4 mul/min; 34 plus or minus 4mul/min, respectively) were significantly greater than mannitol (16 plus or minus 8 mul/min) at comparable intraventricular pressures, suggesting that both creatinine and PAH leave the CSF by an active process in addition to passive diffusion.

Aminohippuric Acids↗
PubMed1988

Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood.

We have evaluated the long-term prognosis in an unselected group of adult patients either uni-nephrectomized in childhood because of hydronephrosis or born with unilateral renal agenesis. Thirty-six patients aged 7-47 years were followed for 7-40 years. In 23 control subjects aged 20-47 years the glomerular filtration rate (GFR) and the p-aminohippuric acid clearance (CPAH) did not change significantly with age. In patients with a single kidney the size of that kidney was larger and GFR and CPAH were higher than single kidney values in control subjects. However, in patients with a single kidney since childhood the GFR and the CPAH declined slowly but significantly during the follow-up period. Significant microalbuminuria occurred in 47% of the patients with a single kidney and was more frequent with a longer follow-up period. No patient had renal insufficiency or a marked increase in arterial blood pressure. We conclude that in patients with a single kidney since childhood the long-term prognosis is good, but the late decrease in GFR and increase in albumin excretion may indicate a moderate risk for premature renal damage.

Adaptation, Physiological↗
PubMed1987

Glomerular filtration, renal blood flow, and solute excretion in conscious aging rats.

Measurement of daily food and water intakes and of renal water and solute excretion in 10-, 20-, and 30-mo-old female rats revealed that they ate the same amounts of food and excreted the same amounts of glucose, sodium, and potassium irrespective of age but that in the 30-mo-old rats phosphate, calcium, and magnesium excretion rose. The glomerular filtration rate and p-aminohippuric acid clearance measured in conscious animals following moderate volume expansion did not differ with age, when expressed per 100 g body wt, but decreased markedly in the 30-mo-old rats when compared with kidney weight. This was related to the senile hypertrophy of the kidneys in the 30-mo-old group, which was reflected by increases in glomerular volume and length of the proximal tubules and by enlargement of the medulla, with the number of nephrons remaining constant with age. There was no evidence of glomerulosclerosis or kidney disease, and proteinuria remained at a low level in all three age groups. These results suggest that the diminished renal filtration rate observed in both conscious and anesthetized senescent rats is due to a reduced supply of blood per gram of kidney tissue and not to loss of nephrons.

Aging↗
PubMed1998

Basolateral uptake of inorganic mercury in the kidney.

Renal disposition of administered inorganic mercury was studied in rats that had undergone an acute bilateral ureteral ligation shortly before being injected with a nontoxic 0.5-micromol/kg iv dose of inorganic mercury with or without 2.0 micromol/kg glutathione (GSH) or cysteine. Ureteral ligation and induction of "stop-flow" conditions were carried out to decrease glomerular filtration rate to negligible levels prior to the administration of inorganic mercury. The disposition of mercury was studied in the kidneys, liver, and blood 1 h after treatment. In rats given only mercuric chloride, the renal burden of mercury was approximately 20-25% of the administered dose of mercury, which is approximately 50% of the renal burden of mercury detected on average in normal rats. Coadministration of inorganic mercury with GSH or cysteine caused a significant increase in the renal uptake of mercury 1 h after treatment. The enhanced uptake of mercury in the kidneys was due to increased uptake of mercury in the renal cortex and outer stripe of the outer medulla. Pretreatment with para-aminohippuric acid caused significant reductions in the renal concentration and burden of inorganic mercury in all the rats administered inorganic mercury, regardless of whether the inorganic mercury was coadministered with GSH or cysteine. Overall, the findings from the present study provide additional evidence that there is basolateral uptake of inorganic mercury in the kidneys and that the primary mechanism involved in this basolateral uptake is dependent on the activity of the organic anion transporter. More importantly, the present findings also show that GSH and cysteine enhance the basolateral uptake of mercuric ions in the kidney when they are coadministered with inorganic mercury (presumably in the form of mercuric conjugates). On the basis of the present findings, one is led to believe that mercuric conjugates of GSH and cysteine are taken up at the basolateral membrane following exposure to inorganic forms of mercury.

Animals↗