Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Probenecid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,603 records · Page 89Linked to original sources
PubMed1992

The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity.

Administration of 2,3,5-(triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] to rats causes severe renal proximal tubular necrosis. Although the cellular target(s) for 2,3,5-(triGSyl)HQ is not known, substantial evidence implicates mitochondria as the primary cellular target for aliphatic S-conjugates. To determine whether mitochondria are targets for 2,3,5-(triGSyl)HQ, the in vivo and in vitro effects of this conjugate on rat renal mitochondria (RRM) were investigated. In vitro exposure of RRM to 2,3,5-(triGSyl)HQ inhibited site I-supported respiration to a much greater extent than site II-supported respiration. Inhibition of mitochondrial function, as manifested by decreases in the respiratory control ratios, were a consequence of significant elevations in state 4 respiration. Inhibition of constitutive gamma-GT activity with AT-125 had no effect on the ability of 2,3,5-(triGSyl)HQ to decrease mitochondrial function. The effects of 2,3,5-(triGSyl)HQ on mitochondrial function in vivo were subsequently assessed. Shortly (0.5-2.0 hr) following administration of 2,3,5-(triGSyl)HQ (20 mumol/kg, iv) to rats, a significant elevation of state 4 respiration was observed. Thereafter (4-16 hr) state 4 respiration returned to control values and state 3 respiration became significantly depressed. A total collapse in RRM function occurred by 24 hr. The effects of 2,3,5-(triGSyl)HQ on state 4 respiration preceded significant elevations in blood urea nitrogen, which occurred at 8 hr. However, pretreatment of animals with probenecid, an inhibitor of organic anion transport, caused a significant decrease in the 2,3,5-(triGSyl)HQ-mediated elevations in state 4 respiration at 1 hr, without preventing the subsequent development of renal necrosis. In contrast, AT-125, which protected animals from 2,3,5-(triGSyl)HQ-mediated nephrotoxicity, had no effect on the early (1 hr) elevations in state 4 respiration but did prevent the later (8 hr) decreases in state 3 respiration. The data suggest that the early elevation in state 4 respiration observed in vivo is unlikely to contribute to 2,3,5-(triGSyl)HQ-mediated nephrotoxicity. The relationship between the decrease in state 3 respiration seen at later time points and the subsequent development of toxicity require further study before a cause and effect relationship can be determined.

Animals↗
PubMed1992

Nephrotoxicity of the 1:1 acrolein-glutathione adduct in the rat.

Previous metabolic studies in rats have suggested in vivo formation of the acrolein-glutathione (acrolein-GSH) adduct following administration of the highly reactive alpha, beta-unsaturated aldehyde acrolein. Early studies by several investigators demonstrated that similar compounds such as alpha, beta-unsaturated aldehyde-cysteine adducts have toxic (carcinostatic) activity against Ehrlich ascites tumor cells implanted in mice. The current studies investigated the in vivo toxicity associated with the acrolein-GSH adduct in the male Sprague-Dawley rat. The 1:1 acrolein-GSH adduct was synthesized and characterized by physical-chemical methods. Rats given the acrolein-GSH adduct intravenously at 0.5 or 1 mmol/kg developed nephrotoxicity characterized by glucosuria, proteinuria, elevation in serum urea nitrogen, and gross and histologic changes of the kidney. The toxicity was not affected by pretreatment of rats with pyrazole, an alcohol dehydrogenase inhibitor; disulfiram, an inhibitor of aldehyde dehydrogenases; or probenecid, a renal organic anion transport inhibitor. Administration of a similar but nonaldehydic glutathione conjugate, S-n-propylglutathione, did not result in nephrotoxicity in the rat. The nephrotoxicity induced by the acrolein-GSH adduct was inhibited by acivicin, a gamma-glutamyl-transpeptidase inhibitor. These results indicate that the acrolein-GSH adduct requires processing through the first step of the renal mercapturic acid synthesis pathway to be activated to a toxic species.

Acrolein↗
PubMed1993

Effect of ageing on monoamine turnover in the prefrontal cortex of rats.

Turnover of dopamine (DA), serotonin (5-hydroxytryptamine) (5-HT), noradrenaline (NA) and their metabolites has been measured in control and aged rats. In addition, tyrosine hydroxylase (TH) activity has been studied. After pargyline treatment, the turnover rates of DA, NA, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), 5-HT and 5-hydroxy-3-indolacetic acid (5-HIAA) and TH activity increased in aged rats with respect to controls. At the same time the DA and 3-MT turnover increase are consistent with the hypothesis that enhanced release of DA may participate in some degenerative processes in ageing. After probenecid treatment, the turnover of homovanillic acid (HVA) was lower in aged rats than in controls. However, DOPAC turnover was higher in the aged rats. The DOPAC increase seems to indicate a reinforcement of this pathway in aged rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

Cyclic AMP formation and release by cultured bone cells stimulated with prostaglandin E2.

PGE2 produced a marked and dose-related increase in cAMP content of cultured bone cells and in the release of cAMP into the incubation medium. The amount of cAMP released from the cells by PGE2 was proportional to the cellular concentration, and was dependent upon the time of incubation with PGE2. The cAMP levels released into the media increased slowly at a linear rate during a 60 min treatment with PGE2. This release was blocked by theophylline, probenecid, ouabain and dinitrophenol, suggesting that the release of cAMP was not a simple diffusive process and required energy. SC-19220 reduced the formation of cAMP more than the release, suggesting that the formation and the release may arise from separate events. Inability of D600 to inhibit PGE2-induced release of cAMP indicates that the release does not require calcium.

Animals↗
PubMed1984

Regulation of urinary thromboxane B2 in man: influence of urinary flow rate and tubular transport.

Thromboxane B2 (TxB) is excreted in human urine, but the mechanism of renal excretion and the quantitative relationship of urinary TxB to the active parent compound, thromboxane A2, of renal or extrarenal origin is not established. To determine the effects of vasoactive hormones, uricosuric agents and urinary flow rate on TxB excretion, urinary TxB was measured by radioimmunoassay and mass spectrometry, and renal metabolism of blood TxB was determined by radiochromatography of urine after i.v. [3H]-TxB infusions. Basal TxB was 6.7 +/- 1.1 ng/h during an oral water load, and TxB fell with s.g. antidiuretic hormone (to 3.4 +/- 0.4 ng/h, P less than 0.01) and with fluid restriction (to 2.6 +/- 0.5 ng/hr, P = 0.001) in parallel with urinary volume. Urinary excretion of unmetabolized [3H]-TxB also fell (by 56%) with fluid restriction, implicating altered metabolism rather than synthesis as the mechanism of the urinary flow effect. Angiotensin II infusions slightly reduced both TxB and urine volume, consistent with a flow effect. In contrast, probenecid did not alter urine volume, but increased urinary uric acid (by 244%), TxB (from 5.6 +/- 0.9 to 11.1 +/- 2.9 ng/h) and urinary excretion of blood [3H]-TxB (by 243%) by similar amounts (all P less than 0.05), suggesting that TxB is actively reabsorbed in the proximal tubule, similarly to uric acid. Thus, urinary excretion of TxB of renal and extrarenal origin is regulated by proximal and distal tubule factors.

Adult↗
PubMed1979

Prostaglandin E1 inhibits acute cell dehydration thirst.

Intraperitoneally injected PGE1 (100 micrograms/Kg) inhibits specifically the drinking induced by both IP and IV 2 M NaCl (6 ml/Kg) and compound 48/80 (100 micrograms/Kg, IP). Probenecid (150 mg/Kg, IP) which is not a dipsogen, has no effect on the PGE1 induced inhibition of acute cell dehydration thirst. It is concluded the PGE1 acts upon the peripheral mast cells, inhibiting their secretion and thus affecting the water intake associated with the activation of these cells either by hypertonicity or specific stimulants of amine release. These results raise the possibility that endogenous prostaglandins might be involved in the modulation of some of the signals which convey to the brain information on the tonicity of the body fluids.

Animals↗
PubMed1982

Measurement of metabolites of dopamine and 5-hydroxytryptamine in cerebroventricular perfusates of unanesthetized, freely-moving rats: selective effects of drugs.

A method was developed for measuring endogenous acid metabolites of dopamine (dihydroxyphenylacetic acid, DOPAC; homovanillic acid, HVA) and of 5-hydroxytryptamine (5-hydroxyindoleacetic acid, 5HIAA) in serial samples of cerebroventricular perfusates from unanesthetized, freely-moving rats by the use of high performance liquid chromatography with electrochemical detection. Systemic administration of probenecid increased while pargyline reduced the efflux of all of the acid metabolites. Intraperitoneal injection of L-tryptophan increased the perfusate content of 5HIAA, decreased HVA and was without effect on DOPAC. Injections of haloperidol increased the efflux of DOPAC and HVA but did not alter the efflux of 5HIAA. Administration of apomorphine decreased the concentration of all three compounds. These drug-induced changes are generally consistent with those reported to occur in brain tissues. The results indicate that this method can be employed to monitor the activity of dopamine and 5-hydroxytryptamine neurons in unanesthetized, freely-moving rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Regional characteristics of stress-induced increases in brain noradrenaline release in rats.

Male Wistar rats were exposed to immobilization stress for various periods (1 to 5 hr) with or without an IP injection of probenecid at 400 mg/kg. The regional characteristics of stress-induced increases in noradrenaline (NA) release in the rat brain related to the time-course of stress were demonstrated by measuring levels of the major metabolite of NA, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4). Increases in MHPG-SO4 levels occurred mainly within the first hr of stress in the hypothalamus, amygdala and thalamus, while the peak elevations of the metabolite levels were delayed in the hippocampus, cerebral cortex, pons + medulla oblongata and basal ganglia. According to the accumulation of MHPG-SO4 during each 1-hr period of stress, regional characteristics of NA release were classified into the following four types based upon regions where the most marked increase in MHPG-SO4 levels occurs mainly: (1) within the first hr of stress (the hypothalamus, amygdala and thalamus), (2) during the first and second hr (the hippocampus and cerebral cortex), (3) during the third hr (the basal ganglia) and (4) to the same extent from the first to the fourth hr of stress (the pons + medulla oblongata). These results suggest that noradrenergic neurons in different brain regions respond differentially to stress and reflect their own characteristic patterns depending upon nature and time-course of the stressor.

Animals↗
PubMedDate not supplied

Inhibition of Fura-2 sequestration and secretion with organic anion transport blockers.

Fura-2 is widely used to measure the concentration of cytosolic free calcium, but in many cells the dye does not remain localized within the cytoplasmic matrix. In these cells, Fura-2 is sequestered within intracellular organelles, secreted into the extracellular medium, or both. We have found that, in mouse peritoneal macrophages, J774 cells, PC12 cells, and N2A cells, Fura-2 sequestration and secretion are mediated by organic anion transport systems and are blocked by the inhibitors probenecid and sulfinpyrazone. Under appropriate conditions these agents have little affect on calcium transients, and may facilitate the use of Fura-2 in a variety of cell types.

Animals↗
PubMed1993

Monitoring of intracellular free calcium in perfused rat liver.

Fluorescent calcium indicators have been widely used to assess cytoplasmic calcium concentration in cells. To examine the role of calcium ions on different physiological functions (e.g. in case of liver; bile secretion, glucose metabolism, etc.) there is a need for whole organ studies. We have developed a technique to estimate intracellular free calcium changes in perfused rat liver. Krebs-Henseleit perfused livers were loaded with 7 microM or 35 microM Indo-1/AM. An area 3 mm in diameter and approximately 300 microns in depth was illuminated at 340 nm. Fluorescence was monitored with photomultiplier tubes at 3 wavelengths (400 nm for Ca-bound dye, 504 nm for free dye and 464 nm for NADH). The viability of liver preparations was assessed by measurement of the concentrations of lactate dehydrogenase and alanine aminotransferase in the effluent. Loading of the livers with 7 microM Indo-1/AM via the portal vein resulted in a 5-fold increase of fluorescence at 400 nm. However the dye 'leaked' out of the liver with a half-time of 18 min. Probenecid (a specific anion carrier blocker) inhibited loss of dye in a dose dependent fashion (2.5-10 mM). Transient calcium elevations were observed in response to vasopressin (5-50 nM) at physiological levels, ethanol (0.3-0.8 M) and the calcium ionophore, ionomycin. Certain limitations were apparent with this approach: (1) it was necessary to use an anion carrier blocker to maintain a relatively steady dye concentration; (2) endogenous NADH fluorescence interfered with the calcium signal; and (3) absolute values of calcium concentration could not be determined.

Animals↗
PubMed1988

Renal handling of amino acid 99mtechnetium chelates.

Four amino acids--alanine, 2,3-diaminopropionic acid, cystine, and cystein--and also one diamine, ethylenediamine, were chelated with 99m-technetium (99mTc), and their renal excretion patterns were studied in rabbits in the presence and absence of two renal tubular transport inhibitors, probenecid and 2,4-dinitrophenol. From the depression of renal excretion for the first three amino acid chelates, in the presence of the inhibitors, a renal tubular excretory pathway of elimination was suggested for these compounds. The renal excretions of 99mTc-cystein and 99mTc-ethylenediamine however, remained undepressed under similar experimental conditions. An explanation of these observations was forwarded from the possible chemical structures of these chelates.

2,4-Dinitrophenol↗
PubMed1990

Technetium-99m amino acid chelates: correlation of their physico-chemical and physiological parameters. Part I.

Ten alpha-aminocarboxylic acids were chelated with 99mTc and purified by sephadex gel chromatography. Their hepatobiliary and renal excretion patterns were determined in rats. It was observed that lipophilicity of these chelates is the only determinant in governing their hepatobiliary excretion, whereas their renal excretion is dependent on some other factors in addition to lipophilicity. Depression of renal excretion in presence of probenecid indicated an interaction of renal tubular transport enzymes with these chelates, which was explained from their hexacoordinated dioxotechnetium (V) chelate structure (II).

Amino Acids↗
PubMed1985

Repeated determination of cerebrospinal fluid amine metabolites by automated direct sampling from an implanted cannula in freely moving rats.

A method is described for the automatic sampling of CSF from conscious freely moving rats and the simultaneous determination of 5-HIAA and HVA by high-pressure liquid chromatography with electrochemical detection (HPLC-EC). Timed samples (30 microliters) were taken directly from a chronically implanted cannula in the cisterna magna of adult female rats by the HPLC autoinjector. The low volume of sample permitted withdrawal of repeated samples without cross-contamination. The cannula could be used the day after implantation and remained patent for at least two weeks. Treatment with probenecid (200 mg/kg i.p.) caused an increase of both metabolites in the CSF. Pargyline (50 mg/kg i.p.) affected both the 5-HT and dopaminergic systems, reducing their metabolite levels. alpha-Methyl-p-tyrosine (200 mg/kg i.p.) acted selectively on the catecholaminergic system lowering HVA levels. The method accurately measured amine metabolite changes in the CSF due to pharmacological manipulations.

Animals↗
PubMed1988

Intraventricular microdialysis: a new method for determining monoamine metabolite concentrations in the cerebrospinal fluid of freely moving rats.

A new method is described to estimate the cerebrospinal fluid (CSF) concentrations of monoamine metabolites (dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA] in the lateral ventricle of freely moving rats by use of in vivo microdialysis. Both the baseline concentrations of these metabolites and the rate of dopamine (DA) turnover (estimated by the accumulation of total DA metabolites after 200 mg/kg probenecid) were within the range reported when other methods were used to sample CSF. A series of preliminary studies were conducted to demonstrate that this method can be used to repeatedly sample CSF, and to show that the method is sensitive to local changes in dopaminergic activity induced by lesions, drugs or grafts. (1) Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra produced a significant decrease in the CSF concentrations of DOPAC and HVA ipsilateral to the lesion, relative to the contralateral side or to concentrations in animals without lesions. (2) When left and right lateral ventricles were sampled simultaneously in animals with a unilateral 6-OHDA lesion, haloperidol induced an increase in DOPAC and HVA concentrations in CSF on both sides of the brain. Interestingly, the haloperidol-induced increase in CSF concentrations of DA metabolites was greater adjacent to the intact striatum of rats with unilateral 6-OHDA lesions than in animals with no lesion. (3) Finally, in animals with adrenal medulla tissue grafted into the lateral ventricle there was an increase in the CSF concentration of DOPAC compared to pregraft values or to those of animals with control grafts.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

REM sleep eye movement activity and CSF concentrations of 5-hydroxyindoleacetic acid in psychiatric patients.

The relationship between rapid-eye-movement (REM) sleep tonic and phasic activity measures and the pre- and postprobenecid cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was examined in a sample of 14 unmedicated psychiatric patients. The average duration of an eye movement burst and the average number of eye movements within a burst were found to be inversely related to the probenecid corrected accumulation of 5-HIAA in the CSF. These results are interpreted as indicating an association between REM burst eye movement activity and serotonin turnover in psychiatric subjects.

Adult↗
PubMed1995

Nitric oxide donors induce extrusion of cyclic GMP from isolated human blood platelets by a mechanism which may be modulated by prostaglandins.

In the presence of 3-isobutyl-methylxanthine (IBMX), induction of cyclic 3',5'-guanosine monophosphate (GMP) production in human washed platelets (HWP) by nitric oxide donors (NOD) is followed by its accumulation in the surrounding medium in a time- and concentration-dependent manner. Thirty minutes incubation of HWP with 3-morpholino-sydonimine (SIN-1, 10 microM) at 37 degrees C resulted in a 4.6-fold increase of cyclic GMP in platelets, whereas in the extracellular medium the increase was 17.6-fold. Similar results were obtained when other NOD such as S-nitroso-N-acetylpenicyllamine (SNAP) and 3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine (GEA 3184) and the selective phosphodiesterase inhibitor, zaprinast (M&B 22948, 10 microM), were used. Probenecid (1-300 microM), an inhibitor of organic anion transport, or ouabain (1-300 microM), an inhibitor of Na+/K+ adenine triphosphate (ATP)-ase had no effect on cyclic GMP production or extrusion after stimulation with SIN-1. Significantly prostaglandin A1 (PGA1) and prostaglandin D2 (PGD2) inhibited the efflux of cyclic GMP from platelets induced by SNAP (10 microM) in a concentration-dependent fashion, with an IC50 of 63 +/- 16 and 143 +/- 17 microM, respectively. These studies suggest that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cyclic GMP levels in platelets with potential physiological and therapeutic consequences.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Cerebrospinal fluid cholecystokinin, bombesin and somatostatin in schizophrenia and normals.

Cerebrospinal fluid from 31 normals and two groups of phenomenologically similar schizophrenics (n = 72) were collected by identical methods. Radioimmunoassay of CSF was carried out for somatostatin, bombesin, and cholecystokinin. One group of schizophrenics had increased baseline somatostatin and cholecystokinin, and decreased bombesin. No CSF gradient effect was found for the peptides nor were their levels affected by probenecid or pimozide treatment. An inverse correlation was found between bombesin and psychosis rating. Intercorrelation between the peptides and HVA, 5-HIAA, and MHPG were not significant.

Adolescent↗
PubMedDate not supplied

The mechanisms of target cell injury by nephrotoxins.

Hexachlorobutadiene-N-acetylcysteine (HCBD-NAC), adriamycin and 2-bromoethanamine hydrobromide are three renal toxins that have shown in vivo a highly selective target cell toxicity--to the proximal tubules, the glomerular epithelial cells and the medullary interstitial cells, respectively. To study some aspects of the mechanisms of this selective toxicity, the three types of target cell were isolated from the kidneys of Wistar rats, and cultures of the cells or tissue fragments were exposed to various concentrations of the three toxins. Using fluorescence microscopy combined with enzyme and histochemical probes, the selective target-cell toxicity of the three compounds already established in vivo was demonstrated also in vitro. Moreover, the in vitro toxic effect of HCBD-NAC was ameliorated by probenecid, as is the case in vivo. Several functional characteristics specific to each of the target cells, such as the selective uptake of a toxin, the presence of lipid droplets and the level of peroxidative enzyme activity, have been identified as probable factors in the occurrence of the target cell necrosis.

Acetylcysteine↗