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PubMed1996

Simultaneous measurement of metabolic flux in portally-drained viscera, liver, spleen, kidney and hindquarter in the conscious pig.

A method was developed to measure metabolic fluxes simultaneously across the portally-drained viscera (PDV), liver, spleen, kidney and hindquarter (HQ) in the conscious pig (20-25 kg). For this purpose, sampling catheters were implanted in the abdominal artery, portal vein, hepatic vein, splenic vein, renal vein and caval vein. Further, two extra infusion catheters were implanted in the splenic vein and abdominal artery. These allow continuous infusion of para-aminohippuric acid (PAH), providing a method for estimating the plasma flow of the liver, PDV, spleen, kidney and HQ. To minimize the postoperative recovery period of the pigs, great attention was paid to the housing conditions. After a recovery period of seven days, pigs were used for experiments twice a week. During the three weeks experimental period, food intake, body temperature, weight gain, blood gas data and plasma flow were monitored. Mean plasma flow was: liver 52 +/- 6, PDV 40 +/- 5, HQ 20 +/- 2, spleen 4 +/- 1 and kidneys 15 +/- 2 ml/kg body weight/min. These data were characteristic for a pig in a conscious normal resting and unstressed state. The long-term patency rate of the sampling catheters was very high (ranging from 75% to 100%). This was probably due to the prevention of catheter-related infections using a gentamicin (20 mg/ ml), alpha-chymotrypsin (225 U/ml) solution as catheter filling. We conclude that this model enables simultaneously liver, PDV, intestine, spleen, liver, kidney and HQ flux measurement of many metabolic substances in the conscious pig.

Amino Acids, Branched-Chain↗
PubMed1993

Effect of phosphorus restriction on renal response to oral and intravenous protein loads in rats.

Dietary phosphorus restriction ameliorates renal injury in rats. This may be due to changes in renal hemodynamics, including those factors associated with protein-induced hyperfiltration. To test this, we measured inulin clearance (CIn), p-aminohippuric acid clearance (CPAH), mean arterial blood pressure, and renal vascular resistance (RVR) 1 h before and 100 min after either oral gavage of 2 g bovine serum albumin or intravenous infusion of 5% glycine in female Sprague-Dawley rats previously fed for 3-8 wk a 0.5% or a 0.1% phosphorus diet. Baseline CIn, CPAH, blood pressure, and RVR were similar. After albumin gavage, CIn rose 20% (P < 0.01) for the 0.5% phosphorus group but did not change for rats fed the 0.1% phosphorus diet. Other measured parameters, including plasma glucagon and renin activity, were not influenced by dietary phosphorus content. In contrast, during intravenous infusion of glycine, hyperfiltration was induced in phosphorus-restricted rats. Thus dietary phosphorus restriction ablates oral protein but not intravenous amino acid-induced hyperfiltration, suggesting a gut-mediated mechanism for the former. These data highlight the potential importance of dietary phosphorus as a mediator of renal hemodynamics.

Administration, Oral↗
PubMed1976

Enhanced pulmonary absorption of drugs in rats with experimental silicosis.

To investigate the effect of pulmonary silicosis on absorption of drugs from the lung, rats were given an intratracheal injection of 50 mg quartz dust, and rates of drug absorption from silicotic and control lungs were compared at 60 and 120 days after treatment. The pulmonary absorption of procaine amide ethobromide and p-aminohippuric acid was increased by 33-41% in animals with silicosis, whereas absorption of procaine amide in silicotic animals was not significantly different from control. The results suggest that silicosis results in an increased porosity of the pulmonary epithelium.

Aminohippuric Acids↗
PubMed1996

Assessment of the accuracy of quantitative urine collection in mink (Mustela vison) using osmotic pumps for continuous release of p-amino-hippuric acid and inulin.

A method is described to assess the accuracy of quantitative collection of urine in small experimental animals using implanted Alzet osmotic pumps for continuous release of specific urinary markers. The nominal pumping rate (10.00 +/- 0.15 microliters/h; mean +/- SEM) of 10 osmotic pumps was verified (9.96 +/- 0.12 microliters/h) in a 10-day in vitro assay in isotonic saline at 39.0 degrees C. Ten adult female mink (1100 +/- 34 g) had a 2-ml osmotic pump implanted intraperitoneally for 7 days while maintained in metabolic cages on a conventional mink diet. In 5 mink the pumps contained [3H]-labelled p-aminohippuric acid (PAH) only. The remaining 5 animals received a pump containing [3H]-PAH and [14C]-labelled inulin. The experiment was well tolerated by all animals. In fed animals, the amount of urine collected per day was not influenced by the osmotic pumps, whereas 24 h of fasting (water allowed) caused a dramatic fall in urinary volume. In 4 consecutive 24-h collections of urine (n = 10 animals) the recovery of [3H]-PAH was 70.8 +/- 3.6% (range: 52.0-87.2%), and urinary plus faecal water (= total) recovery of [3H]-PAH averaged 77.0 +/- 3.7% (range: 60.3%-94.3%). For [14C]-inulin (n = 5 animals) the urinary and total recoveries were 68.4 +/- 2.2% and 77.2 +/- 2.4%, respectively. In urine the 14C to 3H counts-ratio was almost identical to that of the infusion solution, indicating that metabolic decomposition of the markers was negligible. The results indicate that the daily recovery of suitable urinary markers, released by implanted osmotic pumps, provides a reproducible and valid measure of the accuracy achieved in quantitative collection of urine in mink and probably also in other animal species. Hence, this technique may be useful in future studies on animal nutrition and/or drug disposition.

Aminohippuric Acids↗
PubMed2000

Novel aspects of the transport of organic anions by the malpighian tubules of Drosophila melanogaster.

Para-aminohippuric acid (PAH) is a negatively charged organic ion that can pass across the epithelium of Malpighian tubules. Its mode of transport was studied in Malpighian tubules of Drosophila melanogaster. PAH transport was an active process, with a K(m) of 2. 74 mmol l(-)(1) and a V(max) of 88.8 pmol min(-)(1). Tubules had a low passive permeability to PAH, but PAH transport rates (832 nmol min(-)(1 )mm(2)) and concentrative ability ([PAH](secreted fluid):[PAH](bath)=81.2) were the highest measured to date for insects. Competition experiments indicated that there were two organic anion transporters, one that transports carboxylate compounds, such as PAH and fluorescein, and another that transports sulphonates, such as amaranth and Indigo Carmine. PAH transport appears to be maximal in vivo because the rate of transport by isolated tubules is not increased when these are challenged with cyclic AMP, cyclic GMP, leucokinin I or staurosporine. Basolateral PAH transport was inhibited by ouabain and dependent on the Na(+) gradient. The Malpighian tubules appeared not to possess an organic acid/ &agr; -keto acid exchanger because PAH accumulation was not affected by low concentrations (100 micromol l(-)(1)) of &agr; -keto acids ( &agr; -ketoglutarate, glutarate, citrate and succinate) or the activity of phosphokinase C. PAH transport may be directly coupled to the Na(+) gradient, perhaps via Na(+)/organic acid cotransport. Fluorescence microscopy showed that transport of the carboxylate fluorescein was confined to the principal cells of the main (secretory) segment and all the cells of the lower (reabsorptive) segment. Organic anions were transported across the cytoplasm of the principal cells both by diffusion and in vesicles. The accumulation of punctate fluorescence in the lumen is consistent with exocytosis of the cytoplasmic vesicles. Apical PAH transport was independent of the apical membrane potential and may not occur by an electrodiffusive mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Renal amino acid metabolism during endotoxemia in the rat.

BACKGROUND: The kidney has an important function in the exchange of nitrogenous metabolites. Glutamine is the most important substrate for renal ammoniagenesis and thus plays a crucial role in acid-base homeostasis. Furthermore, the kidney is the main endogenous source for de novo arginine production from citrulline, which in turn is derived from intestinal glutamine metabolism. Sepsis is a condition in which glutamine availability is reduced, whereas the need for arginine biosynthesis may be increased. Limited bioavailability of glutamine may affect arginine synthesis, which may have consequences for nitric oxide (NO) synthesis. Therefore, we studied renal glutamine and arginine metabolism in a rat model of endotoxemia and related this to NO metabolism. MATERIALS AND METHODS: Rats were subject to double hit endotoxemia, and control rats received 0.9% NaCl. Renal blood flow was measured using para-aminohippuric acid. Concentrations of plasma amino acids and nitrate were measured in the aorta and renal vein to calculate net renal uptake or release of amino acids and address NO production. RESULTS: The arterial concentrations of glutamine and ammonia were not changed in endotoxemic rats. Although renal glutamine uptake was reduced, total renal ammonia production was not changed during endotoxemia. The arterial concentration of citrulline and renal citrulline uptake was not altered in endotoxin-treated rats, but renal arginine production was increased. However, no effect was observed on nitric oxide production. CONCLUSIONS: Although the kidney has very important functions in the excretion of waste products and in interorgan metabolism, this study suggests that the kidney has a limited role in glutamine, arginine, and NO metabolism during late endotoxemia in rats.

Amino Acids↗
PubMed2004

Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules.

Human organic anion transporter OAT4 is expressed in the kidney and placenta and mediates high-affinity transport of estrone-3-sulfate (E1S). Because a previous study demonstrated no trans-stimulatory effects by E1S, the mode of organic anion transport via OAT4 remains still unclear. In the present study, we examined the driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4 (S2 OAT4). OAT4-mediated E1S uptake was inhibited by glutarate (GA) (IC50:1.25 mM) and [14C]GA uptake via S2 OAT4 was significantly trans-stimulated by unlabeled GA (5 mM) (P<0.001). [3H]E1S uptake via S2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [14C]GA efflux was significantly trans-stimulated by unlabeled E1S in the medium (P<0.05). In addition, both the uptake and efflux of [14C]p-aminohippuric acid (PAH) and [14C]GA via S2 OAT4 were significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of OAT4 were observed in the apical membrane of proximal tubules along with those of basolateral organic anion/dicarboxylate exchangers such as hOAT1 and hOAT3 in the same tubular population. These results indicate that OAT4 is an apical organic anion/dicarboxylate exchanger and mainly functions as an apical pathway for the reabsorption of some organic anions in renal proximal tubules driven by an outwardly directed dicarboxylate gradient.

Animals↗
PubMed1977

A stop flow analysis of the effects of intrarenal infusion of bradykinin.

The effects of bradykinin (Bk) on renal function were investigated in the in situ dog kidney by means of the stop-flow method. Bradykinin, when injected into the renal artery of the dog, reduced the proximal reabsorption of sodium and water and decreased the secretion of p-aminohippuric acid (PAH). Because filtration was stopped during the experiments, there was no alteration of the peritubular colloid osmotic pressure, and geometric changes of the tubules were minimized. This enabled us to conclude that Bk decreased the transport efficiency of sodium and PAH. The demonstration of the inhibitory effects of Bk on PAH secretion suggests that the inhibition of acid secretion is dependent not only upon the increase in medullary blood flow, but also upon a reduction of the cortical clearance of PAH.

Animals↗
PubMed1976

Effect of paraquat-induced lung damage on permeability of rat lung to drugs.

To investigate the effect of paraquat-induced lung damage on pulmonary absorption of drugs, rats were given a single oral dose of paraquat (250 mg/kg), and rates of drug absorption from damaged and control lungs were compared after various times. To measure absorption rates of drugs, 0.1 ml of 10 mM drug solution was administered through a tracheal cannula to anesthetized animals and, after various times, lungs were assayed for unabsorbed compound. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, and procaine amide. Rates of drug absorption increased 1.4-2.8-fold at 3.5 days after paraquat administration and returned to near control values by the 15th day. The results suggest that paraquat-induced lung damage increases the porosity of the pulmonary epithelium.

Aminohippuric Acids↗
PubMed1975

Inhibition of furosemide-induced renin release by vasoconstrictors.

The effect of i.v. infused (asp1-beta-amid, val5)-angiotensin II (1.0 mug/kg min), octapressin (phe2, lys8-vasopressin) (10.0 mU/kg min) and of the alpha-sympathomimetic amine phenylephrine (40.0 mug/kg min) on the stimulation of renin secretion by furosemide (10.0 mg/kg i.v.) was investigated. The vasoconstrictors abolished the renin release induced by forosemide. Studies on the clearance of p-aminohippuric acid (PAH) (i.e. renal plasma flow) showed that the action of the vasoconstrictors cannot be explained by a decrease in access of furosemide to its intrarenal sites of action. The mechanism of the suppressive action of the vasoconstrictors on renin release is discussed.

Aminohippuric Acids↗
PubMed1976

A study of the Bratton and Marshall hydrolysis procedure utilizing high performance liquid chromatography.

Most analytical methods for conjugated aromatic amines require hydrolysis to free the amine group. The rate of conversion of N-acetyl-p-aminohippuric acid to its deacetylated and deglycinated derivatives is directly related to the hydrolysis reaction time and the concentration of hydrochloric acid used in the reaction. Variations in methodology involving either of these hydrolysis parameters produced artifacts which were not detectable by the standard colorimetric procedures. High performance liquid chromatography offers an improved tool for detecting and quantitating the changes produced during hydrolysis.

Amines↗
PubMed1985

Net absorption of amino acids by portal-drained viscera and hind half of beef cattle fed a high concentrate diet.

Two experiments were conducted to measure the effect of level of feed intake on net amino acid absorption by portal-drained viscera of six beef heifers with catheters in a mesenteric vein, portal vein and iliac artery (Exp. 1) and to evaluate intrajugular infusion of insulin or glucose on amino acid uptake by hind half of four beef steers with catheters in posterior aorta and vena cava (Exp. 2). Experiment 1 was a replicated 3 X 3 Latin square design. Treatments were calculated intakes of 84, 157 or 225 kcal metabolizable energy (ME)/kg.75 live weight. Treatments in Exp. 2 were control (no infusion), insulin infusion (1.4 IU/min for 90 min) and glucose infusion (2.5 mmol/min for 90 min) in that order. Mean live weight of animals +/- SE was 295 +/- 4 kg (Exp. 1) and 345 +/- 15 kg (Exp. 2). The diet used in both experiments was pelleted, 85% concentrate (2.9 Mcal ME/kg dry matter). Blood flow (BF) was measured by dilution of a primed, continuous infusion of para-aminohippuric acid into the mesenteric vein (Exp. 1) or the posterior aorta (Exp. 2). Net uptake or absorption was the product of BF times portal-arterial (Exp. 1) or arteriovenous (Exp. 2) differences in amino acid concentrations in blood. Increased feed intake caused linear (P less than .05) increases in net absorption of several amino acids, including lysine, methionine, leucine and valine (Exp. 1). Feed intake did not affect (P greater than .05) net absorption of glutamate or glutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed2002

Short-term regulation of basolateral organic anion uptake in proximal tubular OK cells: EGF acts via MAPK, PLA(2), and COX1.

The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases,mitogen-activated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [(14)C]PAH was abolished by the phospholipase A(2) inhibitor AACOCF3.[(14)C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA(2). In addition, EGF stimulated the influx of extracellular Ca(2+). However, Ca(2+)-influx was not required for the stimulatory action of EGF on [(14)C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [(14)C]PAH uptake dose-dependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [(14)C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E(2) (PGE(2)) increased basolateral [(14)C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [(14)C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [(14)C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA(2), leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.

Animals↗
PubMed2001

Interaction of 2,3-dimercapto-1-propane sulfonate with the human organic anion transporter hOAT1.

The kidney is the primary target organ in which inorganic mercury (Hg2+) accumulates and expresses its toxic effects. The chelating agent 2,3-dimercapto-1-propanesulfonic acid (DMPS) can rapidly reduce the renal burden of mercury and increase the urinary excretion of mercury. However, the cellular and molecular basis of its efficacy is still unknown. A number of previous studies implicated the "classical organic anion secretory pathway" in the secretion of DMPS and its chelation products. In this study we used the human ortholog of the organic anion transporter (hOAT1) expressed in the Xenopus oocyte expression system to study the interaction of DMPS and its mercury chelates with hOAT1. [3H]PAH was used to show the transport activity of hOAT1 (Km = 3.9 +/-1.3 microM). Uptake of [3H]para-aminohippuric acid (PAH) was inhibited by reduced DMPS (K(i) = 22.4 +/- 8.4 microM). We also investigated the interaction of oxidized DMPS with hOAT1 because it has been shown that at least 80% of DMPS in the blood is oxidized within 30 min. Oxidized DMPS also inhibited uptake of [3H]PAH (K(i) = 66 +/-13.6 microM). In contrast, we found no interaction of the DMPS-Hg chelate with hOAT1. To determine whether DMPS and oxidized DMPS are transported by hOAT1 we examined the effect of inwardly directed gradients these two compounds on efflux of [3H]PAH from HeLa cells transiently transfected with hOAT1. Gradients of both DMPS and oxidized DMPS significantly trans-stimulated efflux of [3H]PAH. These data suggest that hOAT1 can transport DMPS and oxidized DMPS, whereas the DMPS-Hg chelate has no significant affinity for the transporter.

Albumins↗
PubMed1978

The importance of renal prostaglandin synthesis in maintaining renal blood flow and glomerular filtration after renal artery stenosis in the conscious dog.

We studied the effects of inhibiting prostaglandin synthesis on the renal blood flow and glomerular filtration rate of four conscious dogs with chronic unilateral renal artery stenosis. Dogs were prepared by exteriorizing the bladder trigone to allow repeated split renal function studies. Renal artery stenosis was produced with a Goldblatt clamp on one renal artery. Each of ten studies determined the function of each kidney in the conscious dog before and after indomethacin treatment. Administration of indomethacin resulted in a 90 per cent reduction of urinary prostaglandin E excretion, but no functional changes were produced in the kidney with the stenotic artery. These studies indicate that renal prostaglandins are not responsible for maintenance of creatinine and para-aminohippuric acid clearances after renal artery stenosis in the dog. However, the concentration gradient for creatinine between the stenotic and non-stenotic kidney was enhanced by indomethacin.

Animals↗
PubMed1984

Protective effect of organic cation transport inhibitors on cis-diamminedichloroplatinum-induced nephrotoxicity.

Cis-diamminedichloroplatinum (II) (cisplatin) is a frequently used cancer chemotherapeutic agent. Nephrotoxicity is a serious dose-limiting side effect. Many approaches have been studied for protective action against cisplatin-induced nephrotoxicity, but with the exception of diuretics and hydration none are in widespread use. We have used a modified Sperber technique in unanesthetized hens to examine the effect of cisplatin on renal organic cation and anion transport and on renal morphology. The effects of the organic cation transport inhibitors quinine and cyanine on cisplatin-induced toxicity also were evaluated. Administration of cisplatin (3.0 mg/kg i.v.) produced nephrotoxic and lethal effects. Four days after cisplatin administration there was a significant inhibition of renal tubular excretory transport of the organic cation tetraethylammonium and the organic anion p-aminohippuric acid. Acute multifocal tubular necrosis of the proximal tubules was present. Administration of quinine (1.5 mumol/min) and cyanine (0.122 mumol/min) protected against the lethal effects, the inhibition of renal organic cation and anion transport and the renal lesions induced by cisplatin.

Animals↗
PubMed1987

Increased thromboxane B2 excretion in diabetes mellitus.

Thromboxane (TX) A2 is a potent vasoconstrictor as well as a proaggregator of platelets. Augmented TXB2 platelet synthesis and attenuated vascular prostacyclin formation have been demonstrated in diabetes mellitus. We undertook to establish a simple method of extracting urinary TXB2 (UTXB2) and to elucidate the pathophysiologic role of renal TXA2 in diabetes mellitus. One-step extraction of UTXB2 with an octadecylsilyl-silica column was sufficient as pretreatment for TXB2 radioimmunoassay because recovery of UTXB2 was good, the eluate was parallel with the dose-response curve, and the value coincided with that obtained by the conventional method. When platelet TXA2 synthesis was completely suppressed by administration of 100 mg aspirin, urinary TXB2 excretion (UTXB2V) declined to 41% of the initial levels, suggesting that renal TXA2 formation contributes significantly to UTXB2V. UTXB2V was 94.5 +/- 14.0 ng/day or 108.8 +/- 17.3 ng/gm creatinine in controls. Approximately half of the patients with diabetes demonstrated a UTXB2 level higher than the mean + 2 SD level of controls. Although UTXB2V did not show a significant correlation with protein excretion, UTXB2V in patients with diabetes with proteinuria greater than 100 mg/day was augmented (224.4 +/- 30.5 ng/day) compared with that in patients with diabetes without proteinuria greater than 100 mg/day. Furthermore, UTXB2V correlated negatively with the p-aminohippuric acid clearance rate, but not with the creatinine clearance rate. The results suggest that renal TXA2 synthesis may be augmented in diabetic nephropathy and may play a pathophysiologic role in renal hemodynamics as well as in protein excretion.

Adult↗