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PubMed1975

Effect of papain-induced emphysema on permeability of rat lung to drugs.

To investigate the effect of a papain-induced emphysema-like condition on pulmonary absorption of drugs, rats were exposed to either papain aerosol or distilled water aerosol (control) intermittently for 2 wk, and rates of drug absorption from damaged and control lungs were compared. To measure absorption rates, 0.1 ml of drug solution (0.1-10 mM) was administered through a tracheal cannula to anesthetized animals, and after various times lungs were assayed for unabsorbed compound. In absorption experiments with the lipoid-insoluble compounds, mannitol, p-aminohippuric acid, and procaine amide ethobromide, all three drugs were absorbed from the lungs about twice as rapidly in papain-treated rats as in control. In contrast, procaine amide, a relatively lipoid-soluble drug, was absorbed at the same rate in both control and papain-treated animals. The results suggest that papain-induced lung damage increases the porosity of the pulmonary epithelium.

Aerosols↗
PubMed1976

The stone-forming kidney: a study of functional differences between individual kidneys in idiopathic renal lithiasis.

The 24-hour urinary excretion of various electrolytes, as well as the glomerular filtration rate, renal plasma flow and maximal rate of tubular excretion of para-aminohippuric acid was measured in each kidney of 10 patients with idiopathic renal lithiasis. Results in hypercalciuric patients indicate that, in contrast to earlier views, actively stone-forming, normally functioning kidneys are normocalciuric but hypophosphaturic in comparison to their mates with inactive or no stone disease, which are hypercalciuric but normophosphaturic. Therefore, hypophosphaturia rather than hypercalciuria may be an important calculogenic factor in some patients.

Adult↗
PubMed1980

Renal excretion of urea in the salamander, Ambystoma tigrinum.

Renal excretion of urea was assessed in adult and larval Ambystoma tigrinum by comparing simultaneous clearances of urea and inulin. The mean adult urea clearance ratio (CU/CIn) was 0.70 +/- 0.08 indicating net urea absorption. Larvae yielded a mean CU/CIn of 0.92 +/- 0.04. Individual larvae were quite variable however as approximately 30% displayed CU/CIn > 1. There was a significant negative correlation between CU/CIn and fractional water reabsorption. Comparisons of larval kidney urea concentration (KU) and plasma urea concentration (PU) revealed a mean KU/PU of 1.43 +/- 0.15. Treatment with 2,4-dinitrophenol decreased larval CU/CIn to 0.80 +/- 0.05 and KU/PU to 0.91 +/- 0.08. Phloridzin also decreased CU/CIn (0.67 +/- 0.06) however para-aminohippuric acid had no effect. Hypophysectomy combined with cautery of the pituitary stalk resulted in CU/CIn of 1.71 +/- 0.33 as compared to 0.84 +/- 0.08 in shams. These results are consistent with the possibility of net urea secretion at some point in the A. tigrinum nephron, followed by passive reabsorption in the distal segments under the influence of antidiuretic hormone.

Animals↗
PubMed1975

Disappearance of p-aminohippurate and inulin from plasma of newborn and adult rats.

The ability of newborn and adult rats to eliminate p-aminohippuric acid and inulin from plasma was determined. The pattern of development is similar to that observed in vitro using renal cortical slices. The fact that function increases to a peak and then declines over the developmental period while organ weight and histology mature progressively suggests a divergence of functional and antomical maturation. Inulin elimination, unlike PAH, increased over the ages tested, and is apparently more closely related to organ growth.

Age Factors↗
PubMed2004

The legacy of Homer W. Smith: mechanistic insights into renal physiology.

In 1945, Homer W. Smith published an article in the JCI that clearly demonstrated that para-aminohippuric acid is the most suitable agent for the evaluation of renal plasma flow in both humans and dogs; in addition, the paper provided detailed methodology that is still in use today. This paper is but one of many outstanding works performed by Smith and his colleagues that clearly established the clearance technique as a powerful noninvasive approach to gain mechanistic insights into intrarenal function.

Animals↗
PubMed1982

Accumulation of cimetidine by kidney cortex slices.

The mechanisms involved in the excretion of the histamine H2-receptor antagonist cimetidine are as yet incompletely understood. The purpose of this study was to examine the interaction of cimetidine with incubated slices of dog kidney cortex. The results of time and concentration-dependent experiments by using 3H-labeled cimetidine demonstrated that the drug was accumulated without metabolism against a concentration gradient by a saturable process. Inhibition of uptake by cyanide and by incubation under a nitrogen atmosphere indicated energy dependence. Uptake of cimetidine by active cationic transport was likely inasmuch as both cyanine 863 and quinine blocked accumulation. However, a probenecid-sensitive component, accounting for about 20% of steady-state accumulation, also was identified. The lack of inhibitory action of p-aminohippuric acid and the cationic nature of the cimetidine molecule suggest the probenecid-sensitivity was not related to the renal organic anion mechanism. Further, probenecid inhibition was not due to a generalized cellular toxicity because maximally inhibitory concentrations of probenecid did not interfere with uptake of the cation tetraethylammonium.

Animals↗
PubMedDate not supplied

Possible hemodynamic basis to urethane anesthesia-induced reductions in renal clearance.

The hemodynamic basis of reported urethane anesthesia-induced reductions in the clearance of some renally eliminated compounds has been investigated in the laboratory rat. The use of urethane as an anesthetic in pharmacokinetic studies still persists, particularly in experiments of long duration. Using a microsphere technique, the per cent distribution of cardiac output to the kidneys, in both ip urethane- and ip Hypnorm/Hypnovel-anesthetized animals was significantly (p less than 0.01) lower than that observed in ip pentobarbital-anesthetized animals. However, the cardiac index in the Hypnorm/Hypnovel-anesthetized animals was 42% greater (p less than 0.01) than in the pentobarbital-treated animals and 86% greater (p less than 0.01) than in the urethane-treated group. Additionally, the cardiac index in the pentobarbital-anesthetized animals was significantly greater (p less than 0.01) than in the urethane-anesthetized animals. The lower cardiac index and reduced cardiac distribution to the kidneys in the urethane-treated group resulted in significant (p less than 0.01) reductions of approximately 40% in renal blood flow and glomerular filtration rate compared with the animals anesthetized with pentobarbital or Hypnorm/Hypnovel. The transport capacity of the basolateral organic anion secretory mechanism was not compromised by an ip injection of urethane, as demonstrated by p-aminohippuric acid transport studies conducted in isolated renal tubule fragments prepared from anesthetized animals. In conclusion, urethane anesthesia results in significant alterations of renal hemodynamics compared with pentobarbital and Hypnorm/Hypnovel anesthesia in the rat. For primarily renally eliminated compounds, such alterations are likely to influence pharmacokinetic data generated using this anesthetic agent.

Anesthesia↗
PubMed1992

A simple new method for repeated in vivo cerebral cortex flux measurement in rats.

A new application of an indicator dilution technique, using nonradioactive para-aminohippuric acid, is described for superior sagittal sinus blood flow determination in rats. Superior sagittal sinus blood flow, mainly representing cerebral cortex blood flow, amounted to 541 +/- 49 microliters/min in ketamine-anesthetized, but otherwise normal, rats breathing room air. Increasing arterial pCO2 enhanced superior sagittal sinus blood flow (P less than 0.01), providing evidence that this method correctly measures cerebral blood flow. The respiratory quotient was 1.1 and the cerebral cortex metabolic rate of oxygen consumption was +/- 1.45 mumol/min. Cerebral cortex ammonia uptake was not significantly different from zero and of the amino acid fluxes, only alanine differed from zero (P less than 0.05). Flux measurements are crucial in studies of healthy or altered organ metabolism in both experimental animals and postoperative surgical patients. We devised a simple and economical method of repeated cerebral cortex flux measurement in rats that is a potentially valuable tool in metabolic studies of the cerebral cortex.

Animals↗
PubMed1979

Effect of indomethacin on renal function and plasma renin activity in dogs with chronic renovascular hypertension.

The effect of indomethacin on plasma renin activity (PRA) and renal function was examined in conscious dogs with chronic renovascular hypertension before or after volume expansion. PRA did not change following the infusion of indomethacin: PRA was 5.18 +/- 1.46 ng/ml/h during control periods and was 5.01 +/- 0.95 ng/ml/h (p greater than 0.1) after 80 min of infusion of indomethacin. Mean arterial blood pressure (MABP) was 121.6 +/- 7.4 mm Hg during control periods and was 122.0 +/- 4.6 mm Hg (p greater than 0.1) after 80 min of infusion of indomethacin. Infusion of indomethacin into these dogs undergoing diuresis did not change inulin or p-aminohippuric acid clearance. Sodium excretion (UNaV) showed slight but not signifcant decreases with the infusion of indomethacin. UNaV was 109.3 +/- 25.7 muEq/min during control periods and was 69.6 +/- 21.0 muEq/min (0.05 less than p less than 0.1) after 80 min of infusion of indomethacin. The results suggest that renin release, sodium excretion, and blood pressure in the dog with chronic renovascular hypertension in uninfluenced by indomethacin.

Animals↗
PubMed1997

The cytotoxic effect of paraquat to isolated renal proximal tubular segments from rabbits.

Paraquat (PQ) induces lung, liver and kidney damage. Since PQ mainly is eliminated by the kidney, the kidney damage is of particular importance to the outcome of PQ poisoning. The exact toxic mechanism of PQ is still unclear but it is assumed to involve redox cycling and formation of reactive oxygen species. In this study, further investigations on the toxic mechanism and metabolic effects of PQ were performed using isolated renal proximal tubules from rabbits. Proximal tubules were isolated using a combined iron perfusion and collagenase method. Suspended tubules were incubated for varying periods and concentrations of PQ at 25 or 37 degrees C in Krebs-Ringer phosphate buffer or HCO3-/CO2 buffer. The cytotoxic effect of PQ was evaluated by (1) markers of oxidative stress: status of glutathione (GSH/GSSG) and formation of malondialdehyde (MDA); and (2) markers of tubular metabolism: oxygen consumption (QO2), transport of 14C-p-aminohippuric acid (PAH) and 14C-tetraethylammonium (TEA). Using 0.5 and 5 mM PQ, the GSH/GSSG ratio decreased whereas formation of MDA increased indicating oxidative stress. PQ reduced the accumulation of PAH and TEA, the basal QO2 and the ouabain sensitive QO2 indicating inhibition of the Na/K-ATPase. Nystatin-stimulated QO2 was reduced by PQ, excluding inhibition of Na+ entry as a possible cytotoxic mechanism and suggesting mitochondrial injury. This was confirmed by measuring FCCP-uncoupled QO2. Thus high concentrations of PQ appear to disrupt mitochondrial electron chain transfer resulting in reduction of metabolic functions.

Aminohippuric Acids↗
PubMed1977

The immediate function of the kidney after 24-to 72-hr preservation. Hypothermic storage versus mechanical perfusion.

Seventy-two dog kidneys were stored under hypothermia as described by Collins and Sacks between 24 and 72 hr and then transplanted. The immediate function of the kidneys was measured by p-aminohippuric acid and inulin clearances. Twenty-four hr proved to be the maximum safe preservation time with both methods. The immediate function of the kidneys stored under hypothermia could not be improved by the addition of furosemide to the flushing solution. These results were compared with those gained by mechanical perfusion of the organ. Kidney function after 72 hr of hypothermic mechanical perfusion was significantly better than after 24 hr of hypothermic storage.

Animals↗
PubMed1975

Glomerular filtration rate in the first three weeks of life.

Clearances of inulin and para-aminohippuric acid were performed in 22 newborn infants without renal disease. Ages varied from 12 hours to 25 days. The mean values of inulin and PAH clearances during the first four days of life were 10.8 +/- 1.0 ml/min/m2 and 30.8 +/- ml/min/m2, respectively. A twofold increase in glomerular filtration rate was observed during the first 14 days of life. A similar increase in PAH clearance occurred during this period. No correlation was found between gestational age (range: 32 to 39 weeks) and GFR in ten neonates studied during the first four days after birth.

Age Factors↗
PubMed1995

Validation of miniature ultrasonic transit-time flow probes for measurement of renal blood flow in rats.

This study validates the accuracy of miniature ultrasonic transit-time flow probes for measuring renal blood flow (RBF) in the rat. Probes for 1-mm and 2-mm vessels were calibrated ex vivo using excised arteries at varying flow rates and hematocrit (Hct). Correlation between measured and true flow rates for the 2-mm probe were identical (r = 1.0) at both normal and subnormal Hct values. Correlation for the 1-mm probe was high (r = 0.994) at normal Hct, but varied at both high flow rates and subnormal Hct values. In vivo correlation of RBF measurements using the 1-mm probe with the clearance and extraction of p-aminohippuric acid showed a high correlation (r = 0.84; n = 72, P < 0.0001) over a wide range of flow rates (0.5-21 ml/min) and Hct (36-74%). Zero flow levels remained steady, averaging -0.2 +/- 0.2 ml/min during occlusion in the living animal and -0.1 +/- 0.3 ml/min after exsanguination. This study shows that the ultrasonic transit-time flowmeter (1-mm and 2-mm probes) is a reasonably accurate and reliable method with which to measure RBF in the anesthetized, acute-instrumented rat.

Animals↗
PubMedDate not supplied

Contribution of erythrocytes and plasma in threonine and lysine transfer across the portal drained viscera and the liver in pigs. Effect of threonine and lysine dietary supply.

Contributions of erythrocytes and plasma to threonine and lysine transport across the PDV and the liver were determined in growing pigs successively fed a threonine deficient diet and a control well-balanced diet (experiment 1) or a lysine deficient or a well-balanced diet (experiment 2). The animals were surgically prepared for insertion of chronic catheters in the mesenteric vein (MV), the portal vein (PV), a hepatic vein (HV) and the carotid artery (CA). Plasma and whole blood AA concentrations in PV, HV and CA and PV and HV blood flows were determined during 6 hours of para-aminohippuric acid constant infusion. During this period the pigs were continuously fed (1 meal per hour). The contribution of plasma to lysine and threonine transport was higher in pigs fed the well balanced diets. More than 50% of threonine and lysine appearing in the PV and in the HV are transported by the plasma. Our results suggest that erythrocytes are probably little involved in lysine and threonine transfer across the liver and digestive tract of pig continuously fed.

Animals↗
PubMed1981

A study on renal function in the Indian buffalo (Bubalus bubalis).

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in buffalo species (Bubalus bubalis) were estimated using a single injection technique. The total body clearances of inulin and para-aminohippuric acid (PAH) served as estimates of GFR and ERPF, respectively. Inulin and PAH were administered to animals as a single i.v. bolus. The time-concentration curves were determined for each compound. Three mathematical models were applied to the data. The two compartment model gave the best fit to the data. The single compartment model gave slightly higher values, but could be used in clinical and certain research situations to estimate renal functions when it is not practical to take large number of samples.

Animals↗
PubMed1988

Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat.

Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF.

Acetylglucosaminidase↗
PubMed1994

Confocal microscopic analysis of fluorescein compartmentation within crab urinary bladder cells.

Fluorescein (FL), a fluorescent organic anion, is compartmentalized in cells of organic anion-secreting epithelia, e.g., OK cells, teleost proximal tubule, and crab (Cancer borealis) urinary bladder, a proximal tubule analogue. To further examine the processes involved, FL uptake and distribution were studied in C. borealis urinary bladder cells using epifluorescence and laser confocal microscopy combined with video-image analysis. Intracellular FL was about evenly split between diffuse and punctate compartments after in vitro or in vivo loading. Treatments that affected FL transport into cells (incubation with p-aminohippuric acid or glutarate) altered the FL content of both compartments. However, nocodazole, a microtubule inhibitor, did not affect diffuse FL but significantly reduced punctate FL. Finally, confocal analysis indicated that individual sites of punctate FL accumulation moved in the secretory direction at 0.83 micron/min. Nocodazole nearly abolished this movement and significantly reduced transepithelial organic anion secretion. Thus, in crab urinary bladder, a substantial fraction of total cellular FL is sequestered in vesicles, and these vesicles move in the secretory direction, by a microtubule-dependent process.

Animals↗
PubMed1997

Restricted intestinal absorption of some beta-lactam antibiotics by an energy-dependent efflux system in rat intestine.

PURPOSE: The purpose of this study was to examine factors limiting the intestinal absorption of orally inactive beta-lactam antibiotics. METHODS: Permeation behaviors of various beta-lactam antibiotics across rat intestinal segments were evaluated in vitro using diffusion cells. RESULTS: Poorly absorbed beta-lactam antibiotics, like cephaloridine and cefoperazone, commonly exhibit greater serosal-to-mucosal permeation than mucosal-to-serosal permeation, while cephalexin permeation was greater in the mucosal-to-serosal direction. In the absence of D-glucose, secretory-oriented permeation of cephaloridine and cefoperazone disappeared. Addition of sodium azide into an experimental buffer including D-glucose significantly and selectively enhanced mucosal-to-serosal permeation of cephaloridine and cefoperazone. Although benzylpenicillin, ampicillin, and amoxicillin all showed secretory-oriented permeation, the tendency to permeation was greatest with benzylpenicillin and least with amoxicillin. Probenecid stimulated mucosal-to-serosal permeation of cephaloridine, but verapamil and p-aminohippuric acid had no significant effect on it. CONCLUSIONS: It has been suggested that mechanisms which induce secretory-oriented permeation of orally inactive beta-lactam antibiotics are factors limiting intestinal absorption of such antibiotics. This energy-demanding efflux system was distinct from P-glycoprotein-mediated transport. A free alpha-amino group in the molecule is an important factor for reducing an affinity with the efflux system.

Animals↗