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PubMedDate not supplied

Isolated lung chemotherapeutic infusions for treatment of pulmonary metastases: a pilot study.

A pilot study was designed to determine the feasibility of combining minimally invasive surgery techniques and cardiac surgical catheter technology to deliver high-dose unilateral pulmonary chemotherapy. Single lung ventilation general anesthesia was combined with catheter-based left pulmonary artery (PA) control in 4 mongrel dogs. p-Aminohippuric acid (PAH) was used to quantify leakage of pulmonary arterial infusate. Surgical exposure was progressively less invasive. Dissection of cranial and caudal pulmonary veins followed methods used in minimally invasive pulmonary lobectomy. All animals survived the experimental procedure. The Heart-Port Endoplege catheter controlled the canine PA. A volume (50 cm(3)) of infusate much smaller than the calculated pulmonary vascular volume caused less vascular overdistention and diffused throughout the pulmonary vascular bed within 3-5 min as verified by fluoroscopy. 75% of the tracer remained in the lung at the completion of the 30-min dwell time. The pulmonary circulation can be isolated by minimally invasive operative and catheter technology so that the pulmonary parenchyma can be exposed to a high concentration of a compound for at least 30 min in the canine model.

Animals↗
PubMed2002

Pitfalls of single-sample determination of renal clearance.

BACKGROUND: Single-sample techniques are widely used for determination of renal clearance by elimination kinetics of radiolabelled marker substances. Frequently, however, formulae for transforming single-time measurement values into estimates of kinetic function, such as renal clearance, are being established exclusively by data reduction methods and are devoid of any physiological meaning. METHODS: Using 11 subjects with normal or impaired renal function, we compared one such method using (99m)Tc-labelled mercaptoacetyltriglycine ((99m)Tc-MAG(3)) for single-sample determination of tubular extraction rates with a more elaborate computer-based system identification technique. This latter method yields measures for glomerular filtration rate as well as effective renal plasma flow based on elimination kinetics of sinistrin and p-aminohippuric acid. RESULTS: When applying the single-sample technique, two of the 11 estimated values for tubular extraction rate were negative, indicating an erroneous analysis of kinetic behaviour. This single-sample method failure was not caused by the marker, but rather by the specific mathematical procedure used for the evaluation. Importantly, evaluation of the same experimental data with a conventional two-sample technique would eliminate the principal mathematical defect and produce physiologically reasonable results, without requiring additional effort. CONCLUSIONS: Our study does not criticize the (99m)Tc-MAG(3) technique per se. Rather, these findings indicate that usage of single-sample techniques for determination of inherently kinetic phenomena may produce incorrect results. Therefore, despite their obvious practical advantages, such simplified methods should be performed with great caution.

Adult↗
PubMed2005

Intestinal renal metabolism of L-citrulline and L-arginine following enteral or parenteral infusion of L-alanyl-L-[2,15N]glutamine or L-[2,15N]glutamine in mice.

Previously, we observed increased plasma arginine (ARG) concentrations after glutamine (GLN)-enriched diets, in combination with clinical benefits. GLN delivers nitrogen for ARG synthesis, and the present study was designed to quantify the interorgan relationship of exogenous L-GLN or GLN dipeptide, by enteral or parenteral route, contributing to intestinal citrulline (CIT) and renal de novo ARG synthesis in mice. To study this, we used a multicatheterized mouse model with Swiss mice (n = 43) in the postabsorptive state. Stable isotopes were infused into the jugular vein or into the duodenum {per group either free L-[2,(15)N]GLN or dipeptide L-ALA-L-[2,(15)N]GLN, all with L-[ureido-(13)C-(2)H(2)]CIT and L-[guanidino-(15)N(2)-(2)H(2)]ARG} to establish renal and intestinal ARG and CIT metabolism. Blood flow was measured using (14)C-para-aminohippuric acid. Net intestinal CIT release, renal uptake of CIT, and net renal ARG efflux was found, as assessed by arteriovenous flux measurements. Quantitatively, more de novo L-[2,(15)N]CIT was produced when free L-[2,(15)N]GLN was given than when L-ALA-L-[2,(15)N]GLN was given, whereas renal de novo L-[2,(15)N]ARG was similar in all groups. In conclusion, the intestinal-renal axis is hereby proven in mice in that L-[2,(15)N]GLN or dipeptide were both converted into de novo renal L-[2,(15)N]ARG; however, not all was derived from intestinal L-[2,(15)N]CIT production. In this model, the feeding route and form of GLN did not influence de novo renal ARG production derived from GLN.

Algorithms↗
PubMed1987

Renal effects of endotoxin in the male rat.

A new model of acute reduction in renal function induced by a 2-h infusion of endotoxin (Escherichia coli 026:B6 lipopolysaccharide, 5 mg X kg-1 X h-1) was developed in the anesthetized male rat. In the absence of significant glomerular fibrin deposition, inulin clearance (glomerular filtration rate, GFR) was reduced from 8.50 +/- 0.34 to 4.01 +/- 0.45 ml X kg-1 X min-1 (P less than 0.0005), and p-aminohippuric acid clearance was reduced from 23.7 +/- 0.8 to 15.0 +/- 1.8 ml X kg-1 X min-1 (P less than 0.0005), indicating a hemodynamic basis for the reduction in GFR. The lack of morphological tubular injury and a decreased fractional Na excretion (from 2.63 +/- 0.27 to 0.54 +/- 0.09%, P less than 0.00005) exclude a significant contribution of tubular mechanisms to the reduction in GFR. Administration of theophylline, a competitive adenosine receptor antagonist, concurrently with or immediately after the endotoxin infusion, restored inulin and PAH clearances and fractional Na excretion toward normal. Moreover, the renal effects of endotoxin were mimicked by intravenous administration of N6-(L-phenylisopropyl)-adenosine (L-PIA), an adenosine receptor agonist, and the effects of L-PIA in turn were also antagonized by theophylline. These data suggest that adenosine plays a significant role in mediating the hemodynamic derangements of this model.

Animals↗
PubMed1984

Long-term effects of captopril on renal function in hypertensive patients.

The effect of captopril up to 450 mg/day on blood pressure and renal function were investigated during sustained treatment of 10 patients whose severe hypertension had not responded to previous therapy. All the patients were kept on diuretics and most of them on beta-blockers, too. A control determination of glomerular filtration rate (GFR) and para-aminohippuric acid clearance (CPAH) was performed during the prior treatment. The effect of the addition (or substitution) of captopril were assessed after an average of 25 days (short-term) and 26 weeks (long-term). Short-term treatment produced a 15.5% decrease in mean blood pressure and interindividually variable effects on renal function. On average GFR was somewhat lower and CPAH slightly higher than the control values (not significant). This pattern is quite similar to the effects of most other antihypertensive drugs. On long-term therapy GFR rose by a mean of 9% (NS) and CPAH by 17% (p less than 0.02). However, in a patient who developed a captopril-induced nephrotic syndrome, GFR dropped to 56% and CPAH to 50% of the control values. In another patient a transient rise in serum creatinine accompanied a severe drug reaction.

Adult↗
PubMed1996

Renal function and organic anion and cation transport during dehydration and/or food restriction in chickens.

The effect of dehydration in the presence or absence of continued food intake on renal function was evaluated in chickens. In addition, renal transport of organic anions and cations under these conditions was assessed in vitro by uptake of 14C-para-aminohippuric acid and 14C-tetraethylammonium bromide by renal slices. Water restriction with continued food intake resulted in increases in serum osmolality and serum concentrations of sodium, uric acid, calcium and total protein. If food was restricted in addition to water, only serum osmolality and sodium concentration were significantly increased after 48 hours. Dehydration with continued access to food resulted in marked decreases in extracellular fluid volume, glomerular filtration rate and effective renal plasma flow. If food was restricted during dehydration, the decrease in effective renal plasma flow was attenuated despite reductions in glomerular filtration rate and extracellular fluid comparable to that seen in dehydrated birds allowed free access to food. Transport of organic anions was significantly increased after 24 and 48 hours of water restriction, regardless of whether food was withheld. Enhanced transport of organic anions in the presence of decreased glomerular filtration rate and effective renal plasma flow during dehydration may promote precipitation of urates and nephrosis in chickens.

Animals↗
PubMed1995

Nitric oxide mediates redistribution of intrarenal blood flow during bacteremia.

The normal or hyperdynamic circulatory response during the early phases of the systemic septic response is associated with renal microvascular constriction and can result in renal dysfunction. Intrarenal redistribution of blood flow from the outer cortex to the medulla appears to account for decreased glomerular filtration in spite of normal or elevated renal blood flow, but the mechanisms of this response are not well described. Nitric oxide is recognized as an important regulator of regional blood flow during both normal and pathologic conditions including sepsis, and we hypothesized that alterations in nitric oxide contribute to redistribution of renal blood flow during sepsis. The current study used laser Doppler fluximetry and clearance of p-aminohippuric acid (effective renal plasma flow, ERPF) to study intrarenal distribution of blood flow during basal conditions and during normodynamic Escherichia coli bacteremia, with and without inhibition of nitric oxide. Inhibition of nitric oxide in normal animals resulted in a decrease in ERPF (-19%) with a decrease in cortical flux (-39%) without alteration of medullary flux. Bacteremia resulted in a decrease in cortical flow (-17%), an increase in medullary flow (36%), and a modest reduction (-9%) in ERPF. Inhibition of nitric oxide synthase during bacteremia worsened cortical flow (-43%), reversed the increase in medullary flux (-42%), and further impaired ERPF (-28%). These data suggest that nitric oxide regulates renovascular tone during normal conditions and bacteremia, and indicate that it is a prime mediator of intrarenal redistribution of blood flow during sepsis.

Animals↗
PubMed1997

Chronic renal blood flow measurement in dogs by transit-time ultrasound flowmetry.

To test the validity of transit-time ultrasound flowmetry for chronic measurement of renal blood flow in dogs, we compared this method with the renal clearance of para-aminohippuric acid (CPAH) (corrected for hematocrit), and with direct volumetric measurements. When flow-probes were implanted without silastic sheeting to stabilize the implant, there was significant disparity between the (within-dog) mean levels of renal blood flow estimated by flow-probe and CPAH. In contrast, when the flow-probe implants were stabilized with silicone sheeting, there was close agreement in each dog between the flow rates measured by the two methods. When flow-probes were calibrated volumetrically in situ, there was a close linear relationship between flow derived from the flow-probe and that measured volumetrically (r = 0.98 +/- 0.02). We conclude that valid, chronic measurement of renal blood flow in dogs can be achieved using transit-time ultrasound flowmetry, provided the implant is stabilized with silicone sheeting.

Animals↗
PubMed2002

Rapid microplate method for PAH estimation.

Evaluation of renal hemodynamics requires estimation of effective renal plasma flow, which is commonly measured by the renal clearance of p-aminohippuric acid (PAH). There are many existing methods for PAH assay that are complicated, expensive, or time consuming. We describe a rapid, precise, and accurate microplate-based assay of PAH using p-dimethylaminocinnamaldehyde, which produces a red color on reaction with PAH, and compare it with a reference HPLC method. Renal PAH clearances were measured in 10 volunteers, and clearances were calculated by using the new and HPLC methods. There was excellent agreement between the HPLC and the microplate method of PAH assay. The average ratio of microplate to HPLC method was nearly 1.0, and the limits of agreement (2 SD) for plasma, urine, and clearances were 17.2, 19.3, and 25.5%, respectively. Intraday coefficient of variation for urine and plasma was <7%; interday coefficient of variation was <6% for urine and plasma samples. The microplate method is a reliable alternative to a reference HPLC method and can be performed for a fraction of the cost, time, and reagents.

Chromatography, High Pressure Liquid↗
PubMed1982

Impaired renal function gout: its association with hypertensive vascular disease and intrinsic renal disease.

Inulin clearance was measured in 624 patients with gout, and para-aminohippuric acid (PAH) clearance in 359; Group I consisted of 397 patients with uncomplicated gout; Group II, 191 patients with hypertension and/or ischemic heart disease; and Group III, 36 patients with chronic renal disease. Mean inulin clearance was normal in Group I, slightly depressed in Group II and more markedly decreased in Group III. There was some reduction in PAH clearance in all groups, but not in the very young patients with no complications. A disproportionate reduction in PAH clearance was noted in Groups II and III, particularly in the older patients with longer duration of gout. Uncomplicated gout, except in rare cases of fulminating gout, does not lead to decreased renal hemodynamics. An increased incidence of tophi correlates with decreased renal function, but incidence of renal calculi does not. Renal insufficiency when seen in patients with gout usually correlates with coexistence of hypertension, ischemic heart disease, or primary preexistent renal insufficiency.

Adolescent↗
PubMed1975

Induction of transport of organic anions in Malpighian tubules of Rhodnius.

1. The ability of Rhodnius Malpighian tubules to transport organic anions such as p-aminohippuric acid (PAH) and amaranth depends on the physiological state of the insect. Unfed insects progressively lose this ability, but the transport mechanisms rapidly become activated after a blood meal. 2. This induction occurs in adults as well as larval instars and is not prevented by decapitation. 3. No increase in rates of excretion of organic anions follows a meal of Ringer's solution or a single injection of 0-1 mumoles of PAH into the haemolymph. 4. Accelerated PAH excretion is induced in insects fed (a) blood plasma alone or a suspension of red blood cells in saline, (b) solutions of serum albumin or casein, and (c) whole or diluted milk. 5. These results show that the ingestion of a protein-rich meal is sufficient to induce an accelerated transport of organic anions such as PAH and they suggest that this induction is not controlled by a hormone released in response to abdominal distension but depends instead on the continued presence in the haemolymph of some product of digestion of the meal.

Age Factors↗
PubMed1998

Exposure to ochratoxin A impairs organic anion transport in proximal-tubule-derived opossum kidney cells.

Ochratoxin A (OTA) is a widespread mycotoxin, which is nephrotoxic and carcinogenic. Because a decline in net-secretion of para-aminohippuric acid (PAH) was observed after chronic OTA exposition in vivo, we investigated the effect of OTA on proximal-tubule-derived opossum kidney (OK) cells. OTA up to 10(-5) mol/liter had no acute effect on PAH transport when bovine serum albumin (BSA) was present. By contrast, 72-hr incubation of OK cells led to a decrease of PAH transport with half-maximal inhibition at 6 . 10(-7) mol/liter for transepithelial secretion and 6 . 10(-8) mol/liter for basolateral uptake of PAH. Incubation of OK cells with 10(-6) mol/liter OTA for 72 hr reduced the affinity of PAH uptake, and decreased the maximum secretion rate to one-fifth of control values. Apical uptake of amino acids and basolateral uptake of glutarate were not affected. In addition, no signs of general toxic action could be observed. Specific basolateral binding affinity of PAH was reduced to 50% of control. Furthermore, incubation with OTA led to a decrease of PAH efflux across the apical membrane, although efflux across the basolateral membrane and the amount remaining in the cells increased as compared to control. By contrast to control cells, uptake of PAH in OTA-treated cells was not stimulated after preloading with glutarate. Our data show, that 1) long-term incubation with free OTA in the nanomolar range reduces the activity of the organic anion transporter, 2) without influencing general cell function. 3) OTA seems to act preferentially on organic anion transport, by affecting the exchange of organic anions and dicarboxylates. 4) Thereby, OTA reduces its own secretion. 5) The excretion of other xenobiotics and drugs may be also impaired, whereby OTA can exert an indirect toxic action.

Animals↗
PubMed1988

Complexing activity and excretion of 2,3-dimercapto-1-propane sulfonate in rat kidney.

The renal handling of the heavy metal complexing agent, 2,3-dimercapto-1-propane sulfonate (DMPS), was examined in the isolated perfused rat kidney (IPRK). Net tubular secretion of DMPS was saturable and blocked by p-aminohippuric acid (PAH) and probenecid (PRB), indicating involvement of carrier-mediated transport in the excretion of DMPS. DMPS was oxidized to a disulfide form (DMPSS) in perfusate and reduced to a sulfhydryl form (DMPSH) in kidney. In kidneys isolated from rats pretreated with HgCl2, DMPS produced a dose-dependent decrease in retention of inorganic mercury, an increase in urinary excretion of mercury, and an increase in the amount of mercury transferred from kidney into venous perfusate. At a maximally effective dose, 40% of the renal mercury content was excreted in urine during 30 min of perfusion. Urinary excretion of mercury induced by DMPS was completely blocked by concentrations of PRB that blocked tubular secretion of DMPS and decreased uptake of DMPS in kidney. Thus tubular secretion of DMPS and reduction of DMPSS to DMPSH are important in the renal handling of DMPS and may contribute to the activity of DMPS as a complexing agent for renal mercury.

Animals↗
PubMed1975

The effect of norethandrolone on organic ion transport by rat renal cortical slices.

Norethandrolone (NE) and other androgenic steroids have been shown to be renotropic in various species and have also been reported to have salutary effects in patients with diminished renal function. Renal cortical slices prepared from rats pretreated with NE showed an increased capability to concentrate p-aminohippuric acid (PAH). Pretreatment with NE failed to stimulate the transport of the organic base tetraethylammonium and the organic acid benzylpenicillin. Stimulation of PAH transport was observed after eight daily subcutaneous injections of NE. No stimulation was observed with shorter pretreatment intervals. When NE was given subcutaneously for 14 days at doses of 2.6 or 20 mg kg-1 day-1, significant stimulation of PAH transport was seen at all three dose levels but no dose-effect relationship was apparent. Stimulation of PAH transport was seen in female rats as well as castrated and intact males. In addition to its general anabolic properties, NE induces the synthesis of hepatic microsomal drug-metabolizing enzymes. For comparative purposes, therefore, the effect of pregnenolone-16 alpha-carbonitrile (PCN) was also investigated. This agent is a potent inducer of drug metabolism but is neither anabolic nor renotropic. When rats were pretreated with an inducing dose of PCN (75 mg kg-1 day-1 for 3 days), there was no significant stimulation of PAH transport. It would seem, then, that the stimulatory effect of NE on PAH transport is more closely associated with its generalized anabolic effect than with its ability to induce hepatic microsomal enzymes.

Aminohippuric Acids↗
PubMed2000

Regulation of the renal basolateral transport system for organic anions by calcium channel blockers.

Calcium channel blockers have been reported to exert multiple effects on renal tubular function. Therefore, the effects of the calcium channel blockers nifedipine and verapamil on the cellular uptake of tritiated para -aminohippuric acid (PAH) into microdissected non-perfused rabbit kidney S2 proximal tubule segments were investigated to study a possible influence of calcium channel blockers on renal PAH transport. Since the tubules were entirely collapsed, the accumulated radioactivity overwhelmingly reflects the transport across the basolateral membrane. Tubular PAH accumulation was increased by 1 and 10 microm verapamil, and by 1 microm nifedipine, but it was unaffected by lower or higher concentrations of these calcium channel blockers. The increase in PAH accumulation caused by 1 microm nifedipine or 10 microm verapamil was independent from changes in intracellular Ca(2+) and inhibited by staurosporine (1 and 10 n m) a potent inhibitor of protein kinase C (PKC). Our results indicate that the calcium channel blockers nifedipine and verapamil increase the transport of organic anions across the basolateral membrane of proximal tubules, probably by an activation of PKC. Furthermore, the increased tubular PAH transport may disturb the estimation of the renal PAH-clearance.

Adenosine Triphosphate↗
PubMed1989

Operational modes of the organic anion exchanger in canine renal brush-border membrane vesicles.

This study delineates the various operational modes catalyzed by the organic anion exchanger present in the canine renal brush-border membrane. The experiments examined the carrier-mediated effects of various organic and inorganic anions on the transport of either p-[3H]aminohippuric acid ([3H]PAH) or 36Cl-. [3H]PAH countertransport was significantly stimulated by PAH, urate, Cl-, Br-, HCO3-, and by a pH gradient. This pH stimulation remained in the absence of HCO3- (i.e., under N2), implying PAH-OH- exchange. Furosemide, bumetanide, penicillin, and probenecid inhibited countertransport of [3H]PAH. Likewise, the above anions produced cis inhibition of [3H]PAH transport. The cis and trans effects of SO4(-2) and formate were minimal. 36Cl- countertransport was stimulated by PAH, Cl-, Br-, HCO3-, formate, and by a pH gradient that was effective even in the absence of HCO3- (i.e., under N2), implying Cl- -OH- exchange. Cl- -OH- and Cl- -Cl- exchange was inhibited by PAH. In each instance, the trans-stimulation of 36Cl- efflux was insensitive to maneuvers that created an inside-positive membrane potential, demonstrating electroneutral mediated exchange. We conclude that the organic anion transporter can operate in three distinct exchange modes: organic-organic, organic-inorganic, and inorganic-inorganic.

Animals↗
PubMed1995

Drawbacks of the constant-infusion technique for measurement of renal function.

We investigated the validity of the steady-state constant infusion method (CIM), in which quantitative urinary recovery and constant plasma concentrations of the solute infused are required. Successive 3-h clearances of inulin and p-aminohippuric acid (PAH) were determined for 27 h in 25 patients with renal disease. Results were compared with the standard method of bladder clearance (StM) and with a modified CIM (ModCIM). The 24-h urinary recovery was incomplete for both inulin and PAH. Mean 24-h ModCIM inulin clearance overestimated StM by 4.5 ml.min-1 x 1.73 m-2 (range 0-9, P < 0.001) independent of the extent of renal impairment and pointed to slow distribution and/or extrarenal clearance of inulin. For PAH, the difference between ModCIM and StM clearance was related to the average PAH clearance by ModCIM and StM (r = 0.78). Furthermore, neither plasma inulin nor PAH became completely constant, because of the circadian rhythm in renal function. In conclusion, the conditions of the steady-state CIM technique are not fulfilled, and the method is not suitable for accurate measurement of inulin and PAH clearance, especially when the clearance is low.

Adolescent↗
PubMed2002

Comparison of bidirectional cephalexin transport across MDCK and caco-2 cell monolayers: interactions with peptide transporters.

PURPOSE: Bidirectional transport studies were conducted to determine whether Madin-Darby canine kidney (MDCK) cell monolayers could be used as an alternative to the traditional Caco-2 assay as a fast-growing in vitro model of peptide transport. METHODS: Transport of cephalexin and glycylsarcosine across MDCK and Caco-2 cell monolayers was quantified using LC-LC/MS. Glycylsarcosine, p-aminohippuric acid (PAH), and tetraethylammonium chloride (TEA) were tested as inhibitors of cephalexin transport. RESULTS: The ratio of apparent cephalexin permeabilities (apical to basolateral/basolateral to apical) obtained from MDCK monolayers was almost 5-fold greater than that obtained from Caco-2 monolayers. The opposite trend was observed for glycylsarcosine. When MDCK monolayers were used, glycylsarcosine reduced the cephalexin/apparent permeability ratio almost 90%. PAH and TEA did not inhibit cephalexin transport across MDCK or Caco-2 cell monolayers. CONCLUSION: MDCK cell monolayers may be a promising, fast-growing alternative to Caco-2 cells for identifying peptide transporter substrates. However, differences in the apical-to-basolateral transport of cephalexin and glycylsarcosine suggest that the basolateral transport mechanisms for these compounds are different in the two cell lines. Additionally, because the activity of the peptide transporter in MDCK cells was low, scaling factors may be required when using this cell line to predict in vivo drug absorption.

Animals↗