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PubMed1986

Paramagnetic macrocyclic complexes as contrast agents for MR imaging: proton nuclear relaxation rate enhancement in aqueous solution and in rat tissues.

Paramagnetic macrocyclic chelates show promise as magnetic resonance (MR) imaging contrast agents due to stability and relaxivity comparable to those of DTPA-type chelates. For the three copper and manganese macrocyclic complexes studied in aqueous solution, T1 and T2 relaxivities ranged from 0.14 to 5.88 mM-1sec-1 at 6.25 MHz. In rats, the intravenous administration of 16 mumol/kg of Mn(cyclam) caused the liver T1 relaxation rate to double at 15 minutes after injection. T1 measurements by pulsed MR imaging and manganese analyses on excised tissue showed that both relaxation rate (1/T1) and manganese content of liver and kidney increase linearly with the dosage of Mn(cyclam). The linear relationship between 1/T1 and manganese content can be considered an "in tissue" relaxivity plot for the agent. The resulting relaxivity is 54 mM-1sec-1 in liver, compared with 3.1 mM-1sec-1 in aqueous solution. Although this work is preliminary, the implication for medical MR imaging applications is that macrocyclic contrast agents can be effective at approximately one-tenth the current typical dose used for gadolinium DTPA.

Animals↗
PubMed1999

Inhibition of P-glycoprotein-mediated transport by a hydrophobic contaminant in commercial gluconate salts.

The substitution of gluconate for Cl- is commonly used to characterize Cl- transport or Cl--dependent transport mechanisms. We evaluated the effects of substituting gluconate for Cl- on the transport of the P-glycoprotein substrate rhodamine 123 (R123). The replacement of Ringer solution containing Cl- (Cl--Ringer) with gluconate-Ringer inhibited R123 efflux, whereas the replacement of Cl- by other anions (sulfate or cyclamate) had no effect. The inhibition of R123 efflux by gluconate-Ringer was absent after chloroform extraction of the sodium gluconate salt. The readdition of the sodium gluconate-chloroform extract to the extracted gluconate-Ringer or to cyclamate-Ringer inhibited R123 efflux, whereas its addition to Cl--Ringer had no effect. These observations indicate that the inhibition of P-glycoprotein-mediated R123 transport by gluconate is due to one or more chloroform-soluble contaminants and that the inhibition is absent in the presence of Cl-. The results are consistent with the fact that P-glycoprotein substrates are hydrophobic. Care should be taken when replacing ions to evaluate membrane transport mechanisms because highly pure commercial preparations may still contain potent contaminants that affect transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Interaction of Cl- and other halogens with Cl- transport systems in rabbit cortical collecting duct.

We have reported that in the rabbit cortical collecting duct (CCD) we can identify electrophysiologically three distinct cell types; the collecting duct (CD) cell and the alpha- and beta-intercalated (IC) cell. To further characterize the Cl- transport properties of each cell type, we examined the interaction between Cl- and other halogens or SCN- in the isolated and perfused CCD by intracellular microelectrode impalement. The rapid depolarization of the basolateral membrane potential (VB) caused by replacement of bath Cl- with each anion revealed that the sequences of apparent halogen selectivity for the basolateral Cl- conductance were similar in all three cell types. The ranking of Cl- > Br- > F- > I- corresponds to the sequence 5 of Eisenman's series, indicating "strong" interaction of the anions with the selectivity site. The basolateral Cl- conductance of these three cell types may share common characteristics, although I- permeability is less in IC cells than in CD cells. Hyperpolarization of the basolateral membrane of the beta-IC cell upon reduction of luminal Cl- reflects alterations in either Cl- entry across the apical membrane, or Cl- exit across the basolateral membrane, or both. Luminal Cl- replacement with each anion showed that the sequence of the hyperpolarization of the basolateral membrane was I- >> cyclamate = SCN- > F- > Br-, suggesting that I-inhibits either apical Cl- entry or basolateral Cl- exit. On the other hand, in the CD cell reduction of the perfusate Cl- by replacement with each anion caused the basolateral membrane to hyperpolarize with a different ranking: cyclamate = F- > I- = SCN- > Br-.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

The metabolism of intense sweeteners.

Three organic acids (saccharin, acesulfame-K and cyclamate) are used or have been used extensively as intense sweeteners. Once absorbed from the gut they are eliminated, largely in the urine, without undergoing metabolism. Early studies using radiolabelled saccharin indicated the existence of limited metabolism, but this was not confirmed by later more extensive studies using highly purified compound. Metabolism could not be induced by a variety of pretreatments. Following an initial report of the presence of traces of cyclohexylamine in the urines of subjects given cyclamate, it was shown that chronic administration of the sweetener caused the induction of extensive metabolism. The metabolism, which showed wide inter- and intra-individual variability was performed the gut microflora. The peptide sweeteners (aspartame and thaumatin) are metabolized to their constituent amino acids in the gastro intestinal tract, prior to absorption. As such they are incorporated into normal intermediary metabolism and their low-calorie applications derive from their intense sweetness.

Animals↗
PubMed1989

Developmental toxicity testing with FETAX: evaluation of five compounds.

The teratogenic potential of five compounds was evaluated with FETAX (Frog Embryo Teratogenesis Assay: Xenopus). Early embryos of Xenopus laevis were exposed for 96 h to 6-aminonicotinamide (6-AN), isoniazid (INH), urethane, nitrilotriacetate (NTA) or sodium cyclamate, in two separate static-renewal tests of each compound. Based on Teratogenic Index values, growth endpoints and the types and severity of the induced malformations, 6-AN, INH and urethane scored as having strong teratogenic potential. NTA and sodium cyclamate had little or no teratogenic potential. The results support continued evaluation of FETAX as a screening assay for chemical teratogens.

Abnormalities, Drug-Induced↗
PubMed1983

Water absorption in the proximal tubule: effect of bicarbonate, chloride gradient, and organic solutes.

Simultaneous in vivo capillary and luminal microperfusion studies were performed in the superficial proximal convoluted tubule of the rat to determine the effect of intraluminal bicarbonate, the imposition of a transepithelial chloride gradient, and the addition of organic solutes to the luminal perfusion solution on the rates of water absorption (Jv). The capillary perfusion solution contained NaCl, NaHCO3, and KCl. Perfusion of both capillary and lumen with the same solution resulted in a Jv of 3.01 +/- 0.24 nl/min/mm. Imposition of a transepithelial chloride gradient (equimolar substitution of NaCl for NaHCO3 in the luminal solution) resulted in a Jv of 3.18 +/- 0.21 nl/min/mm (P = NS). Addition of cyanide to both solutions in the presence of a chloride gradient resulted in a significantly lower Jv of 2.21 +/- 0.19 nl/min/mm. Luminal substitution of Na cyclamate for NaHCO3 resulted in a solution containing no bicarbonate and no chloride gradient. Jv averaged 0.34 +/- 0.08 nl/min/mm. Addition of cyanide to the solution totally inhibited Jv. The addition of D-glucose, L-alanine, or both, to luminal solutions containing bicarbonate or in the presence of a chloride gradient did not significantly affect Jv. Addition of both organic solutes to the NaCl-Na cyclamate luminal solution resulted in a significantly higher Jv of 0.77 +/- 0.14 nl/min/mm. These studies indicate that Jv in the rat superficial proximal tubule is influenced by active sodium transport, by the presence of bicarbonate in the lumen, and/or by the imposition of a transepithelial chloride gradient. The organic solutes D-glucose and L-alanine also influence water absorption, but this effect could only be demonstrated under some experimental conditions.

Animals↗
PubMed1996

Nickel-catalyzed oxidations: from hydrocarbons to DNA.

Nickel(II) complexes of tetradentate ligands such as cyclam and salen are catalysts for olefin epoxidation using PhIO and NaOCl, respectively. In order to understand the lack of enantioselectivity observed with chiral cyclam and salen complexes, studies of DNA and RNA oxidation were carried out in which evidence for diffusible oxidants might be found. A variety of square-planar, tetradentate nickel(II) complexes were observed to mediate guanine-specific modification in the presence of KHSO5 or magnesium monoperphthalate. In particular, the cationic complex, [(2,12-dimethyl-3,7,11,17-tetraazabicyclo [11.3.1]heptadeca-1(17),2,11,13,15-pentaenato)nickel]2+, [NiCR]2+, has been studied as a probe of nucleic acid folding. The extent of guanine reaction depends upon the exposure of N7, a good transition metal binding site, thus implicating nickel-guanine binding during DNA oxidation. If this is the case, related systems should be able to confer enantioselectivity during the use of chiral nickel complexes and achiral substrates for oxidation. Mechanistic studies, including radical quenching and DNA enantioselectivity, are described and their mechanistic implications discussed.

Base Sequence↗
PubMed1979

Metabolic studies with nonnutritive sweeteners cyclooctylsulfamate and 4-methylcyclohexylsulfamate.

The nonnutritive sweeteners cyclooctylsulfamate and 4-methylcyclohexylsulfamate were fed separately to female Wistar albino rats, and the urine was examined for the possible metabolites cyclooctylamine, cyclooctanone, cyclooctanol, 4-methylcyclohexylamine, 4-methylcyclohexanone, and cis- and trans-4-methylcyclohexanols. The average percent conversions to cyclooctylamine, cyclooctanone, and cyclooctanol were 0.127, 0.08, and 0.092, respectively. The average percent conversions to 4-methylcyclohexylamine and 4-methylcyclohexanone were 0.007 and 0.0013, respectively. No cis- or trans-4-methylcyclohexanol metabolites were found. With cyclooctylsulfamate, 42% was recovered unchanged from the urine. Cyclooctyl- and cycloheptylsulfamates were metabolized to a greater extent than cyclopentylsulfamate, which, in turn, was metabolized to a greater extent than cyclohexylsulfamate (cyclamate) and 4-methylcyclohexylsulfamate.

Animals↗
PubMed1995

Apical membrane sodium and chloride entry during osmotic swelling of renal (A6) epithelial cells.

To assess the role of chloride in cell volume and sodium transport regulation, we measured cell height changes (CH), transepithelial chloride and sodium fluxes, and intracellular chloride content during challenge with hyposmotic solutions under open circuit (OC) conditions. CH maximally increased following hyposmotic challenge within approximately 5 minutes. The change in CH was smaller under short circuit (SC) conditions or following replacement of chloride in the mucosal solution by gluconate or cyclamate (Cl(-)-freem). When corrected for the osmotically inactive cell volume (30 +/- 2%), delta CH for controls (OC) were greater than predicted for an ideal osmometer. In contrast, delta CH for Cl(-)-freem or SC conditions were similar to that predicted for an ideal osmometer. Na+ and Cl- mucosa-to-serosa fluxes increased following hyposmotic challenge. Chloride fluxes increased maximally within 5 min, then decreased. In contrast, the Na+ flux increased slowly and reached a steady state after approximately 25 min. Under isosmotic conditions, exposure to Cl(-)-freem solutions led to decreases in the transepithelial conductance, Na+ flux, and CH. Chloride permeabilities in the apical and basolateral membranes were detected using the fluorescent intracellular chloride indicator MQAE. The results indicate that during osmotic swelling, the entry of both sodium and chloride is increased. The time courses of these increases differ, suggesting distinct mechanisms for the osmotic regulation of these apical membrane transport processes.

Animals↗
PubMed1982

Effect of partial cystectomy on the induction of pre-neoplastic lesions in rat bladder initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by bladder carcinogens and promoters.

The effect of partial cystectomy on the occurrence of pre-neoplastic lesions, papillary or nodular hyperplasia (PN hyperplasia), of the bladder in male F344 rats was studied in an experiment in which bladder carcinogens and promoters were given to the rats after initiation with BBN. The bladder carcinogens tested were N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and N-4[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and the bladder promoters were sodium saccharin, sodium cyclamate, and DL-tryptophan. Partial cystectomy significantly decreased the occurrence of PN hyperplasia in rats treated with EHBN and tended to inhibit that in rats given saccharin or tryptophan. Thus partial cystectomy inhibited rather than enhanced the induction of PN hyperplasia.

Animals↗
PubMed1979

Possible mutagenic activity of saccharin.

A mutagenic effect of saccharin in Chinese hamsters, using the in vivo SCE test, was observed when massive overdoses were administered; cyclamate was not mutagenic.

Animals↗
PubMed1990

Taste as a highly discriminative system: a hamster intrapapillar single unit study with 18 compounds.

Seventy-nine single units were recorded with glass micropipettes applied onto taste pores of the anterior portion of the tongue in anesthetized hamsters. The receptive field of each recorded unit was located by iontophoretic stimulation applying either anodal or cathodal current (1-20 microA) to a non-stimulating solution of sodium cyclamate (5 mM). Different kinds of responses to iontophoretic stimulation were described. Eighteen chemical stimuli including sweet and bitter tastants for humans, and amino acids were locally applied to one papilla of the receptive field of 63 of these units. Stimulations were applied in a continuous flow (30 ml/min) in a small chamber. Response criterion was chosen as 2 S.D. above the mean activity recorded during the minute preceding the stimulus arrival. The low amplitude of single unit responses to chemicals is discussed by reference to the recording and stimulating techniques and compared to results of control experiments on whole nerve recordings and psychophysical experiments on human subjects. The importance of a high flow rate during continuous flow stimulation was demonstrated. The possible necessity of mechanical stimulation to facilitate taste responses was outlined. The sensitivity of units to stimuli applied either chemically or iontophoretically was not identical. Contrary to authors expectations, localized sensitivities for a few specific chemicals were disclosed. The response reproducibility to chemical stimulation was 84% (S.D. = 1.6%). chi 2 calculation, correspondence analysis and hierarchical clustering showed small distances between the two profiles representing the same stimulus or the two profiles representing the same unit, but great distances between profiles representing either different stimuli or different units. All stimuli are different from one another. Only 6 pairs of similar units were found among 63 units. Unit clusters could be found only if a few stimuli were considered but they vanished when all 18 stimuli were used in the calculation. The breadth of tuning of units ranged from 0.25 to 0.92 with a mean of 0.68. We show that the peripheral taste system is highly discriminative. Each stimulus evokes a distinct sensory image. At least 8 independent factors are needed to describe the peripheral taste space, setting a lower limit to the number of different peripheral information channels (putative acceptors) involved.

Action Potentials↗
PubMed1987

Inactivation of antiadherence effect of bladder surface glycosaminoglycans as possible mechanism for carcinogenesis.

We have shown that the urinary bladder secretes and binds to its surface a glycosaminoglycan layer whose nonspecific antiadherence effect protects the bladder from infection and perhaps from stone formation. If bladder cancer is caused by agents present in the urine, as is widely believed, this mechanism may also protect against carcinogenesis. We performed the current study to determine whether suspected carcinogens or cocarcinogens in the urine gain access to the transitional cells by impairing or inactivating the surface antiadherence effect. Using an in vivo method to quantitate bacterial adherence to the rabbit bladder, we compared adherence in control and glycosaminoglycan-deficient bladders to adherence in bladders treated with one of several suspected urinary carcinogens. There were statistically significant differences between adherence in control bladders and adherence in bladders treated with the tryptophan metabolites 3-hydroxykynurenine and 3-hydroxyanthranilic acid, sodium cyclamate, and sodium saccharin. These data indicate that perhaps certain suspected urinary bladder carcinogens inactivate the anti-adherence effect of the glycosaminoglycan layer at the bladder surface and thereby penetrate to the transitional cells to exert their tumorigenic effects; or they may serve as cocarcinogens that inactivate the glycosaminoglycan barrier and permit other urinary carcinogens to transform the transitional cells.

3-Hydroxyanthranilic Acid↗
PubMed1984

Preference for sugars and nonnutritive sweeteners in young beagles.

Two-bowl choice tests were used to examined preference of puppies aged two to four months for compounds tasting sweet to humans. Puppies found many, but not all of the compounds highly palatable, and were sensitive to both type and amount of sugar or nonnutritive sweetener contained in a semi-moist dog food recipe. Lactose, fructose, and sucrose were well accepted, whereas maltose elicited indifference or rejection. Sodium cyclamate, but not sodium saccharin, was preferred at some concentrations to 15 percent sucrose sweetened semi-moist food used as the standard. Solutions of lactose, fructose, glucose and galactose were preferred to plain tap water.

Animals↗
PubMedDate not supplied

The use of continuous flow systems for studying the metabolic activity of the hindgut microflora in vitro.

To investigate the involvement of bacterial enzyme activities in the biotransformation of xenobiotic compounds, we have developed a simulation of the rat hindgut microflora in vitro. This mixed bacterial population exhibits many similarities to the native rat flora, and the diversity of bacterial species and the activity of a number of hydrolytic and reductive enzymes (e.g. azoreductase, beta-glucosidase, beta-glucuronidase, nitrate reductase and nitroreductase) are reproduced in the culture at levels similar to those found in the large intestine. The flora have been found to respond to an anutrient (cyclamate) or to host products (bile acids) with changes in enzyme activity, and to metabolize the azo dye Brown HT to metabolites qualitatively similar to those found in the faeces after oral administration to the rat. The experiments demonstrate that the bacterial population of the large intestine of the rat may be successfully cultured in vitro and provides and alternative to animal studies for the investigation of foreign compound metabolism by the flora.

Animals↗
PubMed1992

Fetal mouse salivary glands and applications for determining teratogenic mechanisms in vitro.

Culture systems offer advantages for studying the actions of chemicals on mechanisms of development. Growth, [3H]thymidine incorporation, and 14C-amino acid incorporation were measured to determine culture conditions and the response of glands to three chemicals. Eagle's MEM supported the best growth and the best time for double isotope presence was the second 24 h of culture. Cyclamate had no effect on growth or isotope incorporation but cycloheximide disturbed 14C more than 3H. 5-Azacytidine was toxic but the incorporation of both isotopes exhibited the same pattern.

Animals↗
PubMed1979

Bladder calculi in rats treated with nitrosomethylurea and fed artificial sweeteners.

Female Wistar rats treated once with nitrosomethylurea (NMU) by urinary bladder instillation were given saccharin, cyclamate or calcium carbonate in the diet for life. X-ray examinations were performed every three weeks to detect early formations of urinary bladder calculi, while an intravenous pyelogram and cystography served as a method for detection of neoplastic alterations. No statistical correlation could be established between the occurrence of urinary bladder stones and neoplasma in the various groups.

Animals↗