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PubMed1978

Effects of renal fuels on uptake of PAH and uric acid by separated renal tubules of the rabbit.

A rapid-filtration procedure was used to examine the effects of a wide variety of renal fuels on the uptake of p-aminohippuric acid (PAH) and uric acid (UA) by separated rabbit renal tubules. PAH and UA uptakes in 15 min over a range of substrate concentrations of 0.01-10.2 mM were determined. All tricarboxylic acid cycle intermediates and pyruvate showed biphasic stimulation of PAH and UA uptake. alpha-Ketoglutarate produced a 320 +/- 54% increase in PAH uptake and a 192 +/- 60% increase in UA uptake at 0.16 mM, the concentration at which uptake was maximal, while causing 20 +/- 3 (PAH) and 35 +/- 7% (UA) inhibition at 10.2 mM. Citrate produced a 373 +/- 19% increase in PAH uptake and a 246 +/- 41% increase in UA uptake at 0.64 mM. PAH and UA uptake were also stimulated by acetate, glucose frutose, phosphoenolypyruvate and L-glutamic acid. The data indicate a direct relationship between stimulation of PAH and uric acid transport and stimulation of renal cortical oxidative metabolism.

Aminohippuric Acids↗

PubMed1991

Studies of the pharmacokinetics and metabolism of 4-amino-propiophenone (PAPP) in rats, dogs and cynomolgus monkeys.

The pharmacokinetics and metabolism of 4-aminopropiophenone (PAPP), a cyanide antidote, have been studied in rats, dogs and cynomolgus monkeys using 14C-PAPP. Radiolabelled material was rapidly excreted in all three species, mainly in urine. In rats, PAPP was metabolized by N-acetylation, while in dogs, ring and aliphatic hydroxylation occurred. In monkeys, both N-acetylation and oxidation took place. In the latter pathway, PAPP was oxidized to p-aminobenzoic acid which underwent amino acid-conjugation to p-aminohippuric acid. In rat blood in vitro, the PAPP metabolites, p-aminobenzoic, p-aminohippuric and N-acetyl-p-aminobenzoic acid were only weak methaemoglobin producers.

Animals↗

PubMed1989

Effects of renal clearance on plasma concentrations of homovanillic acid. Methodologic cautions.

Recently, there has been considerable interest in plasma concentrations of homovanillic acid (HVA) in various psychiatric disorders. Homovanillic acid is a weak organic acid, and its excretion probably resembles that of other organic acids (eg, p-aminohippuric acid) that are actively secreted by the kidney. Alterations in renal plasma flow can affect clearance of organic acids, resulting in changes in plasma concentrations. In our study, concentrations of plasma HVA and urinary HVA (from 24-hour urine collections) were measured in 20 prepubescent boys who received 3 weeks of placebo, dextroamphetamine sulfate, and fenfluramine hydrochloride in a randomized, double-blind, counterbalanced study of the treatment of attention-deficit disorder. Plasma HVA concentrations were significantly lower during fenfluramine treatment than during amphetamine treatment. This difference, however, seemed to be caused by alterations in renal clearance of HVA rather than changes in production. Whole-body production of HVA, as indexed by total urinary HVA excretion, was unaffected by the different treatments, while renal clearance of HVA did differ significantly between amphetamine and fenfluramine treatment. It seems that alterations in renal clearance can affect plasma HVA concentrations, which should be taken into account when plasma HVA is studied.

Child↗

PubMed1999

Metabolic kinetics of p-aminobenzoic acid in rabbits.

The metabolic kinetics of p-aminobenzoic acid (PABA) in rabbits was studied. PABA is predominantly metabolized by acetylation and glycine conjugation to form p-acetamidobenzoic acid (PAABA), p-aminohippuric acid (PAHA), and p-acetamidohippuric acid (PAAHA). After PABA IV administration (20 mg/kg) to rapid (n=16) and slow (n=8) acetylation rabbits, PABA was eliminated rapidly. The half-lives of PABA were 7.01+/-0.32 min in rapid acetylation rabbits and 7.08+/-0.78 min in slow acetylation rabbits. Significant differences were obtained in formation of PAABA and PAHA formed from PABA in both acetylation phenotype rabbits. The formation fraction of PAABA, formed by acetylation of PABA, was 0.8029+/-0.0267 in rapid acetylators and 0.2385+/-0.0428 in slow acetylators (p<0.001). PAHA formed from PABA was 0.0462+/-0.0102 in rapid acetylators and 0. 6652+/-0.0562 in slow acetylators (p<0.001). Only 0.0156+/-0.0030 of PABA could be detected as PAAHA in rapid acetylation rabbits which was obtained by acetylation of PAHA. After individual IV injection of PAHA, PAAHA, and PAABA to both phenotypes of rabbits, PAABA and PAAHA were eliminated in their unchanged forms whereas PAHA was further acetylated to form PAAHA. The formation fraction of PAAHA formed from the acetylation of PAHA was 0.4408+/-0.0570 in rapid acetylators and 0.0539+/-0.0084 in slow acetylators (p=0.002). From the results obtained, metabolic pathways of PABA show significant differences in both acetylation phenotypes of rabbits. Acetylation is the major metabolic route of PABA in rapid acetylation rabbits, while glycine conjugation is more predominant in slow acetylation rabbits.

4-Aminobenzoic Acid↗

PubMed1985

The renal handling of terephthalic acid.

By use of the Sperber in vivo chicken preparation method (1948, Ann. R. Agric. Coll. Swed. 15, 317-349), infusion of radiolabeled terephthalic acid ([14C]TPA) into the renal portal circulation revealed a first-pass excretion of the unchanged compound into the urine. This model was utilized further to characterize the excretory transport of [14C]TPA and provide information on the structural specificity in the secretion of dicarboxylic acids. At an infusion rate of 0.4 nmol/min. 60% of the [14C]TPA which reached the kidney was directly excreted. An infusion rate of 3 or 6 mumol/min resulted in complete removal of [14C]TPA by the kidney. These results indicate that TPA is both actively secreted and actively reabsorbed when infused at 0.4 nmol/min and that active reabsorption is saturated with the infusion of TPA at higher concentrations. The secretory process was saturated with the infusion of TPA at 40 mumol/mn. The excretory transport of TPA was inhibited by the infusion of probenecid, salicylate, and m-hydroxybenzoic acid, indicating that these organic acids share the same organic anion excretory transport process. m-Hydroxybenzoic acid did not alter the simultaneously measured excretory transport of p-aminohippuric acid (PAH), suggesting that there are different systems involved in the secretion of TPA and PAH. The structural specificity for renal secretion of dicarboxylic acids was revealed by the use of o-phthalic acid and m-phthalic acid as possible inhibitors of TPA secretion. m-Phthalate, but not o-phthalate, inhibited TPA excretory transport, indicating that there is some specificity in the renal secretion of carboxy-substituted benzoic acids. TPA was actively accumulated by rat and human cadaver renal cortical slices.

Animals↗

PubMed1996

Determination of p-aminobenzoic acid and its metabolites in rabbit plasma by high-performance liquid chromatography with fluorescence detection.

A simple, accurate and sensitive high-performance liquid chromatographic method with fluorescence detection was used for measuring plasma concentrations of p-aminobenzoic acid (PABA) and its three metabolites: p-acetaminobenzoic acid (PAABA), p-aminohippuric acid (PAHA) and p-acetaminohippuric acid (PAAHA). A Cosmosil MS-C18 column (250 x 4.6 mm, 5 microns) was used under temperature control at 40 degrees C. The mobile phase was H2O-CH3CN-CH3COOH (100:3:1, pH 4.0) with a flow-rate of 1.5 ml/min. The excitation and emission wavelengths for fluorescence detection were set at 270 and 350 nm, respectively. Plasma samples (200 microliters) were acidified by the addition of 150 microliters of 1 m HClO4 solution containing salicylic acid (SA) as the internal standard. After centrifugation, 30 microliters of the supernatant were injected onto the column. Using this method, PABA and its three metabolites could be determined within 25 min. Within the investigated concentration ranges of PABA (0.1-50 micrograms/ml), PAABA (0.2-50 micrograms/ml), PAHA (0.1-50 micrograms/ml) and PAAHA (0.5-50 micrograms /ml), good linearity (r > 0.99) for the standard curves was obtained. The validation of this method showed coefficient of variance (C.V.) that was well below 15% for all compounds. After intravenous (i.v.) administration of PABA (20 mg/kg) to rabbits (n = 7), PABA followed a one-compartment open model elimination with a half-life of 10.90 +/- 1.03 min. The mean half lives for PAABA, PAHA and PAAHA were 24.61 +/- 6.42, 12.81 +/- 6.04 and 11.27 +/- 2.77 min, respectively.

4-Aminobenzoic Acid↗

PubMed2003

Increased renal vascular sensitivity to angiotensin II in hypertension is due to decreased response to prostaglandins.

OBJECTIVES: An enhanced sensitivity to angiotensin II in the renal circulation has been demonstrated in the pre-hypertensive phase both in the spontaneously hypertensive rat and in man. To further characterize this abnormality and the role of prostanoids, renal haemodynamics in normotensive young men with a positive (PFH) or a negative (NFH) family history of hypertension were studied. METHODS: Renal vascular reactivity was assessed during infusion of angiotensin II with and without inhibition of prostaglandin synthesis. Normotensive men with PFH (n = 13) and with NFH (n = 10) with a mean age of 38 years were given on two different occasions: (i). angiotensin II infusion i.v. (0.1, 0.5 and 1.0 ng/kg per min) and (ii). angiotensin II infusion after inhibition of prostaglandin synthesis with indomethacin (150 mg daily three consecutive days). Glomerular filtration rate (GFR) and renal plasma flow were measured with renal clearances of chromium edetic acid and para-aminohippuric acid. RESULTS: Before angiotensin II challenge, the groups did not differ with respect to blood pressure, body mass index, plasma renin activity, GFR, renal blood flow (RBF) or urinary sodium excretion. There was no significant difference in systolic or diastolic blood pressure response to angiotensin II between the two groups. In PFH, the lowest angiotensin II dose caused a significant decrease in RBF and increase in renal vascular resistance (RVR) from baseline (P < 0.01 for both). In NFH, only the highest angiotensin II dose produced a significant decrease in RBF and increase in RVR (P < 0.01 for both). During inhibition of prostaglandin synthesis, all three angiotensin II doses caused a significant decrease in RBF (P < 0.02) and increase in RVR (P < 0.02) also in NFH. The renal haemodynamic difference between PFH and NFH was thus eliminated. CONCLUSIONS: These findings indicate that young human subjects with a positive family history of hypertension have a defective vasodilator prostaglandin system, which is responsible for increased renal vascular sensitivity to angiotensin II. Enhanced renal vasoconstriction may be an early event leading to the generation of primary hypertension.

Adult↗

PubMed1993

Effects of adenosine on renal function and central hemodynamics after coronary artery bypass surgery.

In the early postoperative period after coronary artery bypass surgery, arterial hypertension commonly occurs which requires intravenous vasodilator therapy. Purine adenosine is a potent vasodilator and when exogenously administered it decreases systemic arterial blood pressure effectively. We evaluated the effects of adenosine on central hemodynamics and renal function when used to control postoperative hypertension after coronary artery bypass grafting (CABG). Two separate series of experiments were performed postoperatively in the Intensive Care Unit (ICU). In the first study (n = 10), postoperative hypertension was controlled in the rewarming phase, with sodium nitroprusside (SNP, 1.7 +/- 0.4 micrograms.kg-1 x min-1) or adenosine (147.2 +/- 38.9 micrograms.kg-1 x min-1) to keep mean arterial systolic pressure at approximately 80 mm Hg. In the second study on a separate group of patients (n = 9), low doses of adenosine (0, 30, 60, 90, and 0 micrograms.kg-1 x min-1) were infused when the patients were normotensive and rewarmed. Central hemodynamics, urine flow (UF), renal blood flow (RBF), glomerular filtration rate (GFR), and ECG were evaluated during periods of 30 min for each drug in the first study and during each dose of adenosine in the second study. RBF and GFR were determined using standard urinary clearance methods for 51Cr-ethylenediaminetetraacetic acid and p-aminohippuric acid. In the first study, adenosine infusion, compared to SNP, decreased (A - V)O2, increased central filling pressures and heart rate, and caused a more pronounced ST segment depression. During adenosine administration RBF (-44%), GFR (-52%), and UF (-76%) decreased, while renal vascular resistance and filtration fraction (FF) were unaltered compared to data obtained during SNP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1975

[Kidney function and arterial acid-base status during continuous stimulation of the carotid chemoreceptors in vagotomized cats].

In spontaneously breathing, chloralose narcotized and bilaterally vagotomized cats under mannite saline diuresis, the isolated carotid sinus were perfused for 1 hr with arterial and then for 1 hr with venous blood, and subsequently again with arterial blood for 1 hr. Either measure d or calculated were the parameters of arterial acid-base status, the arterial systemic bl-od pressure, the p-aminohippuric acid (PAH), inulin (IN), and osmolar clearance, the filtration fraction, the tubular reabsorption of oxmotically free water, the urinary time volume, and fractional excretions of the kidneys. Stimulation of the carotic chemoreceptors increased respiration, slightly enhanced the CPAH, and caused a minor fall of CIN with little altered filtration fraction. The renal resistance increased. The absolute and fractional excretions of urine, sodium, potassium, and of osmotically active particles rose significantly. Tubular reabsorption of osmotically free water showed a singificant increase. Urinary osmolarity remained constant in general. The changes of water and electrolyte excretion did not correlate with those of renal hemodynamics. The results argue against natriuresis being caused on chemoreceptor stimulation by increased filtrate volume of the whole kidney, or by decreased osmolarity of the renal medulla. The results are discussed with regard to the renal function in arterial oxygen deficiency.

Acid-Base Equilibrium↗

PubMed1988

Renal handling of drugs in renal failure. I: Differential effects of uranyl nitrate- and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats.

Two etiologically different models of experimental acute renal failure were induced in rats by administration of either glycerol or uranyl nitrate. Both compounds caused a substantial decrease in the glomerular filtration rate (GFR) and the net tubular secretion of tetraethylammonium bromide (TEAB) and para-aminohippuric acid (PAH). The degree of renal impairment induced by uranyl nitrate and glycerol appeared to be dose related. Deprivation of drinking water 24 hr before the administration of glycerol potentiated the renal damage. In uranyl nitrate-induced renal failure, the decline of the net tubular secretion for TEAB and PAH was not proportional to the decrease in GFR; the secretion process deteriorated faster than the GFR. For example, when 0.5 mg/kg uranyl nitrate was administered, GFR fell to approximately 65% of normal, whereas the net tubular secretion was decreased to 30% of normal. These results suggest that the tubular transport was preferentially affected by uranyl nitrate. In contrast, in glycerol-induced renal failure, the decline of TEAB secretion fell in a parallel fashion with the GFR, suggesting that the glomeruli and the proximal tubules were equally damaged by glycerol. However, in this latter model, the decline of PAH secretion did not parallel the decrease in GFR, contradicting the proposal that glycerol affects equally the glomeruli and the proximal tubules. This discrepancy may be due to the selective competitive inhibition of PAH secretion by the accumulation of naturally occurring organic acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed2001

Uptake mechanism of valproic acid in human placental choriocarcinoma cell line (BeWo).

Valproic acid is an anticonvulsant widely used for the treatment of epilepsy. However, valproic acid is known to show fetal toxicity, including teratogenicity. In the present study, to elucidate the mechanisms of valproic acid transport across the blood-placental barrier, we carried out transcellular transport and uptake experiments with human placental choriocarcinoma epithelial cells (BeWo cells) in culture. The permeability coefficient of [3H]valproic acid in BeWo cells for the apical-to-basolateral flux was greater than that for the opposite flux, suggesting a higher unidirectional transport in the fetal direction. The uptake of [3H]valproic acid from the apical side was temperature-dependent and enhanced under acidic pH. In the presence of 50 microM carbonyl cyanide p-trifluoromethoxylhydrazone, the uptake of [3H]valproic acid was significantly reduced. A metabolic inhibitor, 10 mM sodium azide, also significantly reduced the uptake of [3H]valproic acid. Therefore, valproic acid is actively transported in a pH-dependent manner on the brush-border membrane of BeWo cells. Kinetic analysis of valproic acid uptake revealed the involvement of a non-saturable component and a saturable component. The Michaelis constant for the saturable transport (K(t)) was smaller under acidic pH, suggesting a proton-linked active transport mechanism for valproic acid in BeWo cells. In the inhibitory experiments, some short-chain fatty acids, such as acetic acid, lactic acid, propanoic acid and butyric acid, and medium-chain fatty acids, such as hexanoic acid and octanoic acid, inhibited the uptake of [3H]valproic acid. The uptake of [3H]valproic acid was also significantly decreased in the presence of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, salicylic acid and furosemide, which are well-known inhibitors of the anion exchange system. Moreover, p-aminohippuric acid significantly reduced the uptake of [3H]valproic acid. These results suggest that an active transport mechanism for valproic acid exists on the brush-border membrane of placental trophoblast cells and operates in a proton-linked manner.

3-O-Methylglucose↗

PubMed1987

[Physico-chemical mechanisms of organic acid transport in the apical membrane cells of the proximal kidney tubules in rats. I. Kinetic transport parameters and effect of the lipid phasic state on transport].

The kinetics of the transport of 3H-para-aminohippuric acid (PAH) and the influence of the temperature on the initial rate of transport were studied on the vesicles of a purified fraction of the apical membrane isolated from cells of kidney proximal tubules. The PAH transport is accomplished owing to the facilitate diffusion mechanism. The apparent Michaelis constant at 36 degrees C was equal to 7.0 + 1.0 mM, the maximum rate was 15 nmol/min on 1 mg of protein, the inhibition constant for the PAH transport by probenecid being 0.5 mM. At 22 degrees C the apparent Michaelis constant was drastically increased. When the temperature dependence of the initial rate of PAH transport into vesicles was replotted in the form of the Arrhenius plot, there was a turning-point of the line at 28-30 degrees C. The same turning-point is shown on the Arrhenius plot for temperature dependence of alkaline phosphatase activity (a marker enzyme for the apical membrane). The electron paramagnetic resonance spectra analysis of 5-doxylstearate-labeled apical membrane preparation reveals a thermotropic transition near 21-29 degrees C. It is concluded that the function of the carrier and the activity of alkaline phosphatase depend on the phasic state of membrane lipids; the normal function of membrane proteins is possible under the liquid-crystalline state of the lipid bilayer.

Aminohippuric Acids↗

PubMed1988

[Physicochemical mechanisms of organic acid transport in the apical membrane vesicles of the cells of proximal kidney tubules in rats. II. Kinetic parameters of transport and phase state of the lipid bilayer in mutant Campbell strain rats].

The kinetics of 14C-para-aminohippuric acid (PAH) transport in the vesicles and the influence of the temperature on the initial rate of this transport were studied using a purified fraction of the apical membrane isolated from the kidney cortex of the Campbell strain rats with an autosomic recessive gene. The transport was brought about owing to the facilitate diffusion mechanism. At 36 degrees C the apparent Michaelis constant was equal to 29 mM, the maximum rate--62 nmol/min on 1 mg of protein, the inhibition constant for the PAH-transport by probenecid--1.5 mM. The temperature dependence of the initial rate of PAH-transport in vesicles and that of the rate of substrate splitting by alkaline phosphatase show the break point on the Arrhenius plot at 36 degrees C-38 degrees C. The analysis of electron magnetic resonance reveals the thermotropic transition at temperatures near 30 degrees-35 degrees C. Therefore the affinity of the carrier to its substrates in vesicles of the Campbell strain rats is strongly reduced and the lipid layer is more viscous than in the normal rats. We decide therefore that the mutation taking place in the Campbell strain leads to pleotropic membrane reconstructions in different organs (eye, kidney). The discovery of such a mutation is of considerable biological interest and promotes bases for development of the membrane biochemical genetics.

Aminohippuric Acids↗

PubMed1978

Effect of thyroxine on permeability of the neonatal rat lung to drugs.

The effect of thyroxine (1-2 microgram/g i.p. on days 1-4 after birth) on development of adult-type permeability characteristics in the lung was investigated in rats 6-18 days of age. In both treated and control rats, the lipid-soluble drug procaine amide was absorbed at similar rates in all age groups. In contrast, in thyroxine-treated animals, pulmonary absorption rates for the lipid-insoluble compounds mannitol and p-aminohippuric acid declined to adult levels at age 6-12 days, 6 days earlier than in controls. Thyroxine treatment thus accelerates development of adult permeability characteristics in the pulmonary epithelium.

Aminohippuric Acids↗

PubMed1981

Effect of cortisone on permeability of the neonatal rat lung to drugs.

The effect of cortisone (5 mg/animal i.p. on day 5 after birth) on the development of adult-type permeability characteristics in the lung was investigated in rats 6-18 days of age. In both treated and control rats, the lipid-soluble drug procainamide was absorbed at similar rates in all age groups. In contrast, in cortisone-treated animals, pulmonary absorption rates for the lipid-insoluble compounds mannitol and p-aminohippuric acid declined to adult levels at the age of 6 days, which was 12 days earlier than in controls. Cortisone treatment thus accelerates development of adult permeability characteristics in the pulmonary epithelium.

Aging↗

PubMed1994

Affinity identification of organic anion transporters in brush-border membrane vesicles from rat kidney.

The inhibitory properties of bromoacetyl-p-aminohippuric acid as the affinity probe of the organic anion transport system were studied. Bromoacetylated p-aminohippurate was shown to be able to inhibit irreversibly the p-aminohippurate (PAH) uptake in brush-border membrane vesicles. The inhibition depends on both the time of treatment and the affinity probe concentration. The treatment of brush-border membrane with 1 mM bromoacetyl-p-aminohippurate for 1.5 h results in 100% irreversible inhibition of PAH transport but no changes were observed in the activity of alkaline phosphatase, gamma-glutamyltranspeptidase or maltase. The affinity labelling of the organic anion transporters was performed with bromoacetyl-p-amino[3H]hippuric acid. It was shown, by means of SDS-polyacrylamide gel electrophoresis, that the probe bound covalently to the brush-border membrane proteins with molecular masses of 28 kDa, 63 kDa, 98 kDa, and > 150 kDa. The data obtained with SITS and probenecid as the organic anion transport inhibitors indicate that brush-border membrane proteins of 28 kDa, 63 kDa, 98 kDa may correspond to the organic anion transport system.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed2006

Absorption of folate by Caco-2 cells is not affected by high glucose concentration.

The aim of this work was to investigate the effect of high glucose exposure on the absorption of folate by Caco-2 cells. We verified that apical high glucose did not affect the apical uptake of [(3)H]folate. Both different concentrations of glucose (10-45 mM) and different exposure times (10 min-24 h) were tested. Furthermore, apical high glucose (30 mM) did not affect the intracellular steady-state levels of [(3)H]folate, and simultaneous apical and basolateral high glucose (30 mM) did not change the apical-to-basolateral apparent permeability (P(app)) to [(3)H]folate. Both the apical uptake and the steady-state intracellular levels of [(3)H]folate were strongly reduced by 5-methyltetrahydrofolate, methotrexate, SITS (4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) and indomethacin, but were not affected or only hardly affected by p-aminohippuric acid and fumitremorgin C. Moreover, DIDS and indomethacin significantly reduced (by 50-60%) the apical-to-basolateral P(app) to [(3)H]folate, but [(3)H]folate present in the cells at the end of the experiment was higher in the case of indomethacin. Fumitremorgin C had no effect. The effect of the drugs tested was not changed or only hardly changed by high glucose. In conclusion, absorption of [(3)H]folate is not modulated by either apical or basolateral high glucose exposure in Caco-2 cells. Moreover, our results suggest that the apical uptake of [(3)H]folate by Caco-2 cells involves the Reduced Folate Transporter (but not the Organic Anion Transporter), and that Multidrug Resistance Protein and/or Organic Anion Transporter (but not Breast Cancer Resistance Protein) may mediate apical efflux of [(3)H]folate.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1996

Renal effects of angiotensin I-receptor blockade and angiotensin convertase inhibition in man.

1. The objective was to compare two means of inhibition of the renin-angiotensin system [angiotensin-converting enzyme inhibition and selective antagonism of angiotensin II subtype 1 (AT1) receptor] on renal function in 10 healthy normotensive volunteers on a normal sodium diet. Since mechanisms of action may differ between both drugs, a synergistic action was further studied by combining the two drugs. 2. The design was a double-blind randomized acute administration of either placebo or a single oral dose of enalapril, 20 mg, followed in each case by administration of the AT1 selective antagonist losartan potassium, 50 mg orally. 3. The methods included measurements of hormones (plasma renin activity, plasma aldosterone), blood pressure and renal function from 45 to 135 min after administration of placebo or enalapril, and from 45 to 135 min after losartan and placebo or losartan and enalapril. Renal function was studied using clearance of sodium, lithium, uric acid, inulin and para-aminohippuric acid. To examine further the determinants of glomerular filtration at the microcirculation level, fractional clearance of neutral dextran was determined and sieving curves were applied on a hydrodynamic model of ultrafiltration. 4. Losartan did not change plasma renin activity, blood pressure or glomerular filtration rate, but increased significantly renal plasma flow and urinary excretion of sodium and uric acid. Enalapril increased plasma renin activity and renal plasma flow, and decreased blood pressure without natriuretic, lithiuretic or uricosuric effects. The renal vasodilatation was potentiated when losartan and enalapril were combined, despite a further rise in plasma renin. In contrast to enalapril, losartan either alone or in combination with enalapril significantly depressed fractional clearances of dextran of small radii (34-42 A). These changes in fractional clearances of dextran were presumably related to the rise in glomerular plasma flow since the other major determinants of filtration, i.e. transcapillary glomerular pressure gradient, ultrafiltration coefficient and membrane property, were computed as unchanged by either losartan, enalapril or a combination of both. 5. In conclusion, these findings suggest that in normal sodium-repleted man the renal, hormonal and blood pressure effects of AT1 antagonism and angiotensin-converting enzyme inhibition are not strictly similar and could be synergistic.

Adult↗