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PubMed1988

[Differential effects of non-steroidal anti-inflammatory drugs on cathepsins D and E from rat spleen].

The reactivity and specificity of commonly used non-steroidal anti-inflammatory drugs (NSAID) towards two major intracellular aspartic proteinases, cathepsins D and E, were investigated. Of the different drugs tested, indomethacin and flufenamic acid were shown to be potent inhibitors of cathepsin D. Sodium salicylate (SA) and aspirin also inhibited cathepsin D, although the apparent inhibition was observed at the concentrations of 5 mM or above. The inhibitions by these drugs were pH-dependent. The maximal inhibitory potencies of indomethacin and aspirin against cathepsin D activity were observed at pH values below 4.0, whereas that of flufenamic acid was at pH values above 7.0. The Lineweaver-Burk plots showed that the inhibition of cathepsin D by these drugs was of a non-competitive type. On the other hand, all NSAID tested, except for SA, had no inhibitory effect on cathepsin E. SA alone inhibited cathepsin E at concentrations above 50 mM. The inhibition of cathepsin E by SA was of the non-competitive type. Of the three monohydroxy benzoates, the inhibitory potency of the ortho isomer (SA) against cathepsin E was greater than those of the meta and para isomers.

Animals↗

PubMed2002

A study of the conditions of the supercritical fluid extraction in the analysis of selected anti-inflammatory drugs in plasma.

Supercritical fluid extraction (SFE) was employed to analyze selected anti-inflammatory drugs in plasma. Evaluation of selected drugs (ibuprofen, indomethacin, and flufenamic acid) was performed using the HPLC method on columns with the reverse phase C-18 and detection in the UV region of the spectrum. A study of the conditions of SFE carried out for 30 min at 50 degrees C investigated the magnitude of the pressure of carbon dioxide suitable for drug extraction, the selection of the collecting solvent, and the modification of CO2 with an organic solvent. The results of the study made it possible to determine the optimal procedure for SFE of ibuprofen, indomethacin, and flufenamic acid from plasma, which renders their HPLC quantification possible.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action.

The source of NADPH-dependent cytosolic 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity is unknown to date. This important reaction leads e.g. to the reduction of the potent androgen 5alpha-dihydrotestosterone (DHT) into inactive 3beta-androstanediol (3beta-Diol). Four human cytosolic aldo-keto reductases (AKR1C1-AKR1C4) are known to act as non-positional-specific 3alpha-/17beta-/20alpha-HSDs. We now demonstrate that AKR1Cs catalyze the reduction of DHT into both 3alpha- and 3beta-Diol (established by (1)H NMR spectroscopy). The rates of 3alpha- versus 3beta-Diol formation varied significantly among the isoforms, but with each enzyme both activities were equally inhibited by the nonsteroidal anti-inflammatory drug flufenamic acid. In vitro, AKR1Cs also expressed substantial 3alpha[17beta]-hydroxysteroid oxidase activity with 3alpha-Diol as the substrate. However, in contrast to the 3-ketosteroid reductase activity of the enzymes, their hydroxysteroid oxidase activity was potently inhibited by low micromolar concentrations of the opposing cofactor (NADPH). This indicates that in vivo all AKR1Cs will preferentially work as reductases. Human hepatoma (HepG2) cells (which lack 3beta-HSD/Delta(5-4) ketosteroid isomerase mRNA expression, but express AKR1C1-AKR1C3) were able to convert DHT into 3alpha- and 3beta-Diol. This conversion was inhibited by flufenamic acid establishing the in vivo significance of the 3alpha/3beta-HSD activities of the AKR1C enzymes. Molecular docking simulations using available crystal structures of AKR1C1 and AKR1C2 demonstrated how 3alpha/3beta-HSD activities are achieved. The observation that AKR1Cs are a source of 3beta-tetrahydrosteroids is of physiological significance because: (i) the formation of 3beta-Diol (in contrast to 3alpha-Diol) is virtually irreversible, (ii) 3beta-Diol is a pro-apoptotic ligand for estrogen receptor beta, and (iii) 3beta-tetrahydrosteroids act as gamma-aminobutyric acid type A receptor antagonists.

17-Hydroxysteroid Dehydrogenases↗

PubMed1979

Inhibitory effects of non-steroidal anti-inflammatory drugs on human myeloperoxidase.

Myeloperoxidase with an A420/280 ratio of 0,48 was prepared from normal human leucocytes. This partially purified preparation catalysed guaiacol oxidation, iodination of bovine serum albumin and de-iodination of 125I-thyroxine. Non-steroidal anti-inflammatory drugs (naproxen, indomethacin and flufenamic acid) showed a significant inhibitory effect on myeloperoxidase-catalysed iodination at concentrations of 10(-4)M and higher. Guaiacol also inhibited myeloperoxidase-catalysed iodination, and its iodination inhibition curve was nearly identical to that obtained with the anti-inflammatory drugs. At concentrations between 10(-3)M and 10(-7)M the antiinflammatory drugs had very little or no effect on thyroxine de-iodination. Flufenamic acid and indomethacin, however, inhibited de-iodination significantly at a concentration of 10(-2)M. It is postulated that non-steroidal anti-inflammatory drugs may inhibit myeloperoxidase-catalysed protein iodination by acting as oxidizable cofactors which compete with other oxidizable substrates for oxidants formed by the peroxidase-hydrogen peroxide complex. In view of this and because the myeloperoxidase-hydrogen peroxide system may be involved in inflammatory tissue damage, the possibility should be considered that the action of non-steroidal anti-inflammatory drugs is at least partly attributable to a radical scavenging effect or to sequestration of oxidants.

Flufenamic Acid↗

PubMed2000

Drug distribution in human skin using two different in vitro test systems: comparison with in vivo data.

PURPOSE: Two in vitro test systems used to study drug penetration into human skin--the Franz diffusion cell (FD-C) and the Saarbruecken penetration model (SB-M)--were evaluated, and the results were compared with data gained under analogous in vivo conditions. METHODS: Excised human skin was used in all in vitro experiments. Flufenamic acid dissolved in wool alcohols ointment, was chosen as a model drug, and the preparation was applied using 'infinite dose' conditions. To acquire quantitative information about the drug penetration, the skin was segmented into surface parallel sections at the end of each experiment, first by tape stripping the stratum corneum (SC), and second by cutting the deeper skin layers with a cryomicrotome. The flufenamic acid was extracted from each sample and assayed by high performance liquid chromatography (HPLC). For in vivo experiments, only the tape stripping technique was used. RESULTS: a) Drug penetration into the SC: In both in vitro test systems the total drug amounts detected in the SC were found to increase over the different incubation times. Similar conditions were obtained in vivo, but on a lower level. Using Michaelis-Menten kinetics, the m(max) value was calculated for the skin of two donors. The relations of the m(max) values for the FD-C and the SB-M closely correspond (1.26 [donor 1] and 1.29 [donor 2]). A direct linear correlation of the drug amount in the SC and the time data were found for in vivo with both in vitro test systems. b) Drug penetration into the deeper skin layers: The detected drug amounts in the deeper skin layers continuously increased with the incubation time in the SB-M, while in the FD-C, only very small drug amounts were observed after incubation times of 30 and 60 minutes. It was also noticed, that the drug amounts rose steeply at time points 3 and 6 hours. Additional studies showed a remarkable penetration of water into the skin from the basolateral acceptor compartment in the FD-C. This could explain the different drug transport into the deeper skin layers between the two in vitro test systems. CONCLUSIONS: Both in vitro models showed comparable results for the drug penetration into the SC and a robust correlation with in vitro data. Different results were obtained for the deeper skin layers. Whether a correlation between in vitro and in vivo data is also possible here has to be investigated by further experiments.

Administration, Topical↗

PubMed1980

The ligand specificity of the (adenosine 3',5'-monophosphate)-binding site of yeast glyceraldehyde-3-phosphate dehydrogenase. Interaction with adenosine derivatives and pharmacologically-active compounds.

The high-affinity cAMP-binding site of form-II yeast glyceraldehyde-3-phosphate dehydrogenase has a marked specificity for adenosine derivatives, such ligands including N6-substituted adenosine derivatives active as cytokinins n plant systems and adenine nucleotides. Of a wide range of nucleotides and nucleosides examined only adenosine derivatives bind to the cAMP binding site. A variety of antimitotic compounds (including colchicine, colcemid and phenylcarbamate derivatives), adrenergic receptor antagonists (alprenolol and propranolol) and non-steroidal anti-inflammatory agents (notably indomethacin and flufenamic acid) displace cAMP from glyceraldehyde-3-phosphate dehydrogenase. Colchicine, colcemid, N6-furfuryladenosine, indomethacin, flufenamic acid and propranolol inhibit cAMP binding to the enzyme in an apparently competitive fashion. Given the evolutionary conservatism and abundance of glyceraldehyde-3-phosphate dehydrogenase, the affinity of the cAMP-binding site of this enzyme for a variety of structurally-disparate pharmacologically-active compounds compromises simple one-site interpretations of physiological responses to these agents.

Adenosine↗

PubMed1976

Migraine attacks. Alleviation by an inhibitor of prostaglandin synthesis and action.

Twenty-six patients with migraine attacks were treated for 3 to 16 months with flufenamic acid (125 mg four to six times per attack), an inhibitor of prostaglandin synthesis and action. In 25 patients the drug afforded symptomatic relief in 195 of 200 treated attacks. Side effects observed were mild dyspepsia (eight patients) and severe upper gastrointestinal symptoms (two patients). None of the eight patients treated with placebo reported any relief (20 attacks). The "common" antimigraine drugs afforded symptomatic relief in 12 of the patients, partial relief in seven, and no relief in seven. Treatment with flufenamic acid was based on the hypothesis that prostaglandins are involved in migraine attack and that the drug relieves migraine by inhibition of the vasoactivity of prostaglandins.

Adolescent↗

PubMed1996

Chloride channel blockers decrease intracellular pH in cultured renal epithelial LLC-PK1 cells.

The effects of chloride channel blockers upon intracellular pH (pHi) were examined in renal epithelial monolayers of LLC-PK1 cells. A significant intracellular acidification was found with addition of 100 microM 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), niflumic acid, flufenamate and diphenylamine-2-carboxylate (DPC) but not with 4,4'-diisothiocyanatostilbene-2-2'disulphonic acid (DIDS). The effects of these agents upon pHi was dose-dependent with apparent K0.5 values of: 16.7 +/- 0.3 microM, 34.2 +/- 0.9 microM and 740 +/- 13 microM for niflumic acid, flufenamate and DPC respectively. The results indicate that at concentrations commonly used to block channel activity these chloride channel blockers have profound effects upon pHi.

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

PubMed2006

Effect of selected fluorinated drugs in a "ringing" gel on rheological behaviour and skin permeation.

The purpose of the present study was to investigate the influence of different drugs exhibiting different solubility on the viscoelastic properties and on the skin diffusion profile of a ringing gel. In a preliminary rheology study with the placebo gel predominating elastic properties were confirmed and a temperature influence was indicated. Fluconazole, fludrocortisone-acetate, flumethasone-pivalate, flutamide and flufenamic-acid each 1% (w/w) were incorporated into the preparation and oscillatory measurements were performed at temperatures of 25, 28, 32 and 37 degrees C. In all drug containing formulations a high elastic G' value predominated the viscous G'' value. The highest G' value could be obtained with the incorporated flumethasone-pivalate. Additionally in almost all cases the G' values decreased with increasing temperature compared to the placebo gel. Additionally in vitro standard diffusion experiments using Franz-type cells and porcine skin were performed. Following rank order of the cumulative drug release after 48 h was obtained: fluconazole>flufenamic-acid>flumethasone-pivalate>flutamide>fludrocortisone-acetate. Furthermore an excellent chemical stability of all incorporated drugs was confirmed over 10 weeks.

Animals↗

PubMed1982

[Anti-edema activity of a trans-cutaneous non-steroidal anti-inflammatory agent, etofenamate gel, in rats].

Local anti-inflammatory activity of etofenamate gel (5% etofenamate) was investigated in rats. Etofenamate gel (5--50 mg/paw) produced a dose related inhibition in the hind paw edema caused by carrageenin with a topical application to the inflamed paw, and its ED50-value was 33.0 mg/paw. A weak but significant inhibiton was seen with an application of 50 mg/paw to the non-inflamed paw, but not with 10 mg/paw. Anti-edema activity of oral etofenamate (ED50 = 8.49 mg/kg) was comparable to flufenamic acid. Against the hind paw edema caused by a mixture of kaolin and carrageenin, etofenamate gel showed a significant therapeutic activity with repeated application of 10--50 mg/paw to the inflamed paw, but not with 10 mg/paw to the non-inflamed paw. Etofenamate gel (50 mg/paw/day), applied topically to the inflamed hind paw of adjuvant rats, showed a significant therapeutic activity. The potency of oral etofenamate (4--8 mg/kg/day) in adjuvant rats was comparable to flufenamic acid. No gastrointestinal ulcer was produced by a topical application of etofenamate gel (up to 1,000 mg/rat) to the clipped skin, though oral etofenamate (40 mg/kg) produced the ulcer. From these results, it was suggested that etofenamate gel, applied to the skin of rats, showed local anti-edema activity approximately comparable to oral etofenamate, and the ratio of ulcerogenic effective to anti-edema dose of etofenamate gel was larger than that of oral etofenamate.

Administration, Oral↗

PubMed2001

Interrelation of permeation and penetration parameters obtained from in vitro experiments with human skin and skin equivalents.

In a comparative study, two different in vitro cutaneous test systems were examined: (1) The Franz diffusion cell (FD-C), a test system to study drug permeation through the skin and to obtain data like steady state flux and lag time as well as permeability and diffusion coefficients. (2) The Saarbruecken penetration model (SB-M), a test system to investigate drug penetration into different skin layers and after varying incubation times to acquire values about the quasi steady state drug amounts in the stratum corneum (SC). Three drug concentrations (0.9, 0.45 and 0.225%) of a lipophilic model drug preparation, flufenamic acid in wool alcohols ointment, were applied on the skin's surface using 'infinite dose' conditions. Trypsin-isolated SC, heat-separated epidermis, full-thickness skin and reconstructed human skin (RHS) served as skin membranes in the FD-C, while the SB-M experiments were only carried out using full-thickness skin. Increasing steady state flux data and m(ss) values (steady state drug amount in the SC) were detectable after the application of rising drug amounts. Concerning the permeability of the used skin membranes in establishing barrier properties, the following rank order was observed: RHS>SC> or =epidermis>full skin. The flux data of the FD-C experiments for isolated SC, separated epidermis and RHS were linearly related with the m(ss) values of the SB-M investigations, allowing a direct comparison of permeation with penetration parameters. Concerning the drug amount in the SC, previous investigations succeeded in the establishment of an in vivo/in vitro correlation. Based on the results presented here, the prediction of drug amounts present in the SC after different incubation times in vivo is now possible after penetration as well as permeation experiments using the lipophilic model drug preparation, flufenamic acid in wool alcohols ointment.

Epidermis↗

PubMed2003

A novel, voltage-dependent nonselective cation current activated by insulin in guinea pig isolated ventricular myocytes.

Insulin regulates cardiac metabolism and function by targeting metabolic proteins or voltage-gated ion channels. This study provides evidence for a novel, voltage-dependent, nonselective cation channel (NSCC) in the heart. Under voltage clamp at 37 degrees C and with major known conductances blocked, insulin (1 nmol/L to 1 micromol/L) activated an outwardly rectifying current (Iinsulin) in guinea pig ventricular myocytes. Iinsulin could be carried by Cs+, K+, Li+, and Na+ ions but not by NMDG+. It was inhibited by the NSCC blockers gadolinium and SKF96365 but not flufenamic acid. Iinsulin was largely blocked by the insulin receptor tyrosine kinase inhibitor HNMPA-(AM)3 and by the phospholipase C inhibitor U73122 but not by its inactive analogue U73433. Staurosporine, a potent blocker of protein kinase C, did not prevent the activation of Iinsulin. Application of an analogue of diacylglycerol, 1-oleoyl-2-acetyl-sn-glycerol, mimicked the effect of insulin. This activated an outwardly rectifying NSCC that could be carried by Cs+, K+, Li+, or Na+ and that was blocked by gadolinium but not by flufenamic acid or staurosporine. We conclude that the intracellular pathway leading to activation of this novel cardiac NSCC involves phospholipase C, is protein kinase C-independent, and may depend on direct channel activation by diacylglycerol.

Animals↗

PubMed2006

Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.

Transthyretin (TTR) tetramer dissociation, misfolding and misassembly are required for the process of amyloid fibril formation associated with familial amyloid polyneuropathy (FAP). Preferential stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Two NSAIDs, diflunisal and flufenamic acid, and trivalent chromium have this ability. Here, we investigated the feasibility of using these molecules for the treatment of FAP utilizing serum samples from 37 FAP patients with 10 different mutations. We demonstrated that the TTR heterotetramer structures in FAP patients serum are significantly less stable than that in normal subjects, indicating the instability of the variant TTR structure is a fundamental cause of TTR amyloidosis. We also demonstrated that therapeutic serum concentrations of diflunisal (100-200 microM) stabilized serum variant TTR tetramer better than those of flufenamic acid (35-70 microM). Trivalent chromium at levels obtained by oral supplementation did not stabilize TTR in a statistically significant fashion. Importantly, diflunisal increased serum TTR stability in FAP patients beyond the level of normal controls.

Adult↗

PubMed1994

Drug binding properties of glycosylated human serum albumin as measured by fluorescence and circular dichroism.

Binding properties of Sudlow's site-specific drugs to glycosylated human serum albumin (G-HSA) were investigated using fluorescence and circular dichroism (CD). Dansylamide, phenylbutazone and warfarin were used as site I-specific drugs, and dansylproline, ibuprofen and flufenamic acid were used as site II-specific ones. Similar changes in the fluorescence intensity of dansylamide occurred in the presence of both G-HSA and intact human serum albumin (HSA), while the fluorescence enhancement of dansylproline caused by G-HSA was extremely weakened in comparison with that by HSA. These results suggest that the glycosylation of HSA inhibits the binding of the site II-specific drug, dansylproline, to HSA, while it does not influence the binding of the site I specific drug, dansylamide. The induced ellipticities of the complexes of ibuprofen, flufenamic acid and phenyl butazone with G-HSA were diminished in comparison with those with HSA. With the complexes of warfarin, the induced ellipticity was enhanced. These CD results suggest that the glycosylation of HSA induces microenvironmental changes in the binding sites for the above site-specific drugs which influence the drug binding ability of HSA.

Binding Sites↗

PubMed1977

Studies on the effects of pharmacologic doses of cortisone acetate and several nonsteroidal anti-inflammatory compounds on ovo-implantation, early pregnancy, and the deciduomal response in the rat.

Cortisone acetate (10 mg/day), alone or in combination with progesterone (4 mg/day); progesterone (4 mg/day); progesterone (4 mg/day) plus estrone (1 microng/day); indomethacin (0.75 mg/day); phenylbutazone (20 mg/day); flufenamic acid (10 mg/day); and Compound 83161 (tetrazolo less than 1,5-alpha greater than s-triazolo less than 3,4-c greater than quinoxoline) (8 mg/day and 12 mg/day) were each given to intact rats during early pregnancy (days 1 and/or 2 through day 8). Only cortisone acetate treatment caused a true delay in ovo-implantation. Both progesterone treatment beginning on day 1 and cortisone acetate treatment beginning on day 1 or 2 caused an increased postimplantation fetal death rate. Compound 83161, at doses causing signs of general toxicity (12 mg/day), caused a marginal inhibition of implantation. Treatment with indomethacin, phenylbutazone, or flufenamic acid caused some inhibition of the traumatic deciduomal response in spayed rats treated with progesterone, while treatment with cortisone acetate and Compound 83161 did not.

Animals↗

PubMed2006

Gasping activity in vitro: a rhythm dependent on 5-HT2A receptors.

Many rhythmic behaviors are continuously modulated by endogenous peptides and amines, but whether neuromodulation is critical to the expression of a rhythmic behavior often remains unknown, particularly in mammals. Here, we address this issue in the respiratory network that was isolated in spontaneously rhythmic medullary slice preparations from mice. Under control conditions, the respiratory network generates fictive eupneic activity. We hypothesized previously that this activity depends on two types of pacemaker neurons. The bursting properties of one pacemaker rely on the persistent sodium current (INa(p)) and are insensitive to blockade of calcium channels with cadmium (CI-pacemakers), whereas bursting mechanisms of a second pacemaker are sensitive to cadmium (CS-pacemakers) and the calcium-dependent nonspecific cation current blocker flufenamic acid. During hypoxia, fictive eupneic activity is supplanted by the neural correlate of gasping, which is proposed to depend only on CI-pacemakers. Because CI-pacemakers require endogenous activation of 5-HT2A receptors, we tested the hypothesis that 5-HT2A receptor activation is critical for gasping. Here, we demonstrate that fictive gasping and CI-pacemaker bursting were selectively eliminated by the 5-HT2A receptor antagonist piperidine or ketanserin. Neither 5-HT2A antagonist eliminated bursting by CS-pacemakers and ventral respiratory group (VRG) population activity. However, this VRG activity was very different from eupneic activity. In the presence of 5-HT2A antagonists, VRG activity was eliminated by flufenamic acid and could not be reliably restored by adding substance P. These data support the hypothesis that two types of pacemaker bursting mechanisms underlie fictive eupnea, whereas only one burst mechanism is critical for gasping.

Action Potentials↗

PubMed1992

Activation of nonselective cation channels in the basolateral membrane of rat distal colon crypt cells by prostaglandin E2.

Ion channels in the basolateral membrane of colonic crypts were investigated with the patch-clamp technique during stimulation of secretion. Intact crypts were isolated from rat distal colon and the cell potential was recorded by addition of nystatin to the pipette solution. The cell resting potential in the base of the crypt was -74 +/- 1 mV (n = 90). Addition of 100 microM carbachol to the bath resulted in a transient hyperpolarization by 9 mV, which was probably due to the opening of basolateral K+ channels. In contrast, application of prostaglandin E2 (PGE2, 1 nM-1 microM) caused a dose-dependent depolarization in the base of the crypt. With 1 microM PGE2 cells depolarized from -74 +/- 1 to -27 +/- 2 mV (n = 26). Cell potential recordings in the midcrypt showed only a slight and transient depolarization after application of PGE2, whereas cells close to the surface of the crypt had no response. In the base of the crypt the PGE2-induced depolarization could be completely inhibited by addition of 50 microM flufenamic acid, a known blocker of nonselective cation channels. After substitution of all monovalent cations by N-methyl-D-glucamine in the bath, PGE2 had no significant effect on the cell potential. Cell-attached experiments with no nystatin in the patch pipette revealed the activation of ion channels in the basolateral membrane after application of PGE2. After excision of the membrane patch, these channels could be identified as nonselective cation channels. Experiments involving substitution of the bath solution showed that the channel is impermeable for Cl- and scarcely permeable for Ca2+ ions. The permeability sequence for monovalent cations, as calculated from reversal potentials, is NH4+ greater than Na+ = K+ greater than Rb+ = Li+ much greater than TRIS+ = NMDG+. Single channels are completely inhibited by flufenamic acid (50 microM), mefenamic acid (200 microM), as well as by 3',5-dichlorodiphenylamine-2-carboxylate. In conclusion, PGE2 activates nonselective cation channels in the basolateral membrane of cells in the base of colonic crypts. It is suggested that this mechanism initiates the secretion of K+ ions. Na+ influx through the nonselective cation channel will stimulate the Na+/K+ pump and active uptake of K+ at the basolateral side. K+ can leave the cell at the luminal side through K(+)-selective channels.

Animals↗

PubMed1997

Hypotonicity and thrombin activate taurine efflux in BC3H1 and C2C12 myoblasts that is down regulated during differentiation.

The efflux of organic osmolytes such as taurine is an important mechanism by which cells regulate their volume. The effects of hypotonicity and thrombin on taurine efflux were studied in BC3H1 and C2C12 cells, two mouse myoblastic cell lines that can be induced to differentiate with serum deprivation. In proliferating cultures of both cell types preloaded with [3H]taurine, exposure to 27% hypotonicity activated a 10- to 20-fold increase in [3H]taurine efflux (Jtau). This effect was blocked by the C1- channel inhibitors NPPB and flufenamic acid. Thrombin and the thrombin receptor agonist SFLLRN also activated Jtau that was abolished by NPPB and flufenamic acid. Together, hypotonicity and thrombin synergistically activated Jtau. In differentiated myocytes, the effect of thrombin was abolished, while that of hypotonicity was significantly reduced. These results suggest that (i) hypotonicity and thrombin activate taurine-permeable anion channels in BC3H1 and C2C12 cells, and (ii) these anion channels may be involved in cell proliferation.

Animals↗