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PubMed1996

Inhibition by fenamates of calcium influx and proliferation of human lymphocytes.

1. Flufenamic and tolfenamic acids have recently been shown to inhibit receptor-mediated calcium influx in human neutrophils. The present work was designed to study the effects of these two nonsteroidal anti-inflammatory drugs on human peripheral blood lymphocyte activation. 2. Peripheral blood mononuclear cells (PBMNCs; containing 90% lymphocytes) were stimulated by mitogen concanavalin A (Con A) or by a combination of an inhibitor of microsomal Ca(2+)-adenosine triphosphatase thapsigargin (TG) and phorbol myristate acetate (PMA). The effects of the two fenamates on cell proliferation were compared with respective changes in calcium metabolism. 3. Flufenamic and tolfenamic acids (10-100 microM) inhibited both Con A and TG + PMA-induced [3H]-thymidine incorporation in a dose-dependent manner. At the same concentration range, the two fenamates inhibited the increase in intracellular free calcium concentration induced by Con A or TG + PMA. This effect was due to inhibition of calcium influx whereas calcium release from intracellular stores remained unaltered. 4. The inhibition of divalent cation influx was confirmed by showing that fenamates inhibited TG + PMA-induced Mn2+ influx. 5. The inhibitory effects of fenamates on PBMNC proliferation and Ca2+ influx were qualitatively similar with those of SK&F 96365, an earlier known inhibitor of receptor-mediated calcium entry. Ketoprofen, a chemically different prostaglandin synthetase inhibitor did not show similar suppressive effects on PBMNCs. 6. The data suggest that flufenamic and tolfenamic acids suppress proliferation of human peripheral blood lymphocytes by a mechanism which involves inhibition of Ca2+ influx and is not related to inhibition of prostanoid synthesis.

Analysis of Variance↗
PubMed1995

Pharmacological control of human polymorphonuclear leukocyte degranulation by fenamates and inhibitors of receptor-mediated calcium entry and protein kinase C.

The present work was designed to study the mechanism of inhibitory action of flufenamic and tolfenamic acids on the degranulation response of human polymorphonuclear leukocytes (PMNs). We have recently shown that fenamates inhibit PMN degranulation as well as other PMN functions at micromolar drug concentrations. However, the mechanism of their action remains unknown. To clarify this mechanism, the degranulation response was induced by agents known to activate different steps in the activation cascade in PMNs: the receptor-mediated activator fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine); a calcium ionophore (A23187); an inhibitor of calcium-ATPase (thapsigargin); and an activator of protein kinase C (phorbol myristate acetate, PMA). For comparison, SK&F 96365 (an inhibitor of receptor-mediated calcium entry), Ro 31-8220 (an inhibitor of protein kinase C) and ketoprofen (another cyclooxygenase inhibitor) were used. Flufenamic and tolfenamic acids inhibited A23187- and fMLP-induced degranulation in a dose-dependent manner. The thapsigargin-triggered response was reduced only slightly and that induced by PMA remained unaltered. The pattern of the inhibitory action of fenamates differed from those of Ro 31-8220 and ketoprofen. The action of fenamates resembled that of the inhibitor of receptor-mediated calcium entry, SK&F 96365, especially when A23187, fMLP or PMA were used to stimulate the cells. This prompted us to measure the effects of flufenamic and tolfenamic acids on receptor-mediated calcium entry. The two fenamates inhibited the fMLP-induced increase in intracellular free calcium in fura-2 loaded PMNs in the presence but not in the absence of extracellular calcium. The results suggest that the suppressive actions of fenamates on PMN degranulation are neither related to the activity of cyclooxygenase nor PMA-activated protein kinase C. In contrast, fenamates resemble the antagonist of receptor-mediated calcium entry, SK&F 96365, in their antagonistic action on PMN degranulation.

Calcium↗
PubMed1994

Modulation of three types of K+ currents in canine coronary artery smooth muscle cells by NS-004, or 1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone.

The effects of the cardioprotective, vasorelaxant agent NS-004 [1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone] on K+ currents of freshly isolated canine coronary artery smooth muscle cells were examined using the suction pipette method. The Ca(++)-sensitive K+ current (IK, Ca) was isolated by using a holding potential of 0 mV and 5 mM ATP in the internal perfusate. The voltage-dependent delayed rectifier K+ current (IK, DR) was recorded at potentials below 20 mV in internal solution containing 5 mM ATP. The ATP-sensitive K+ current (IK, ATP) was induced by removing ATP in the pipette solution and was measured at potentials negative to -30 mV where IK, Ca and IK, DR were absent. External application of NS-004 activated IK, Ca, which, at 80 mV, was increased from 0.28 +/- 0.03 to 1.1 +/- 0.2, to 3.2 +/- 1.0, to 5.6 +/- 1.6 and to 8.5 +/- 1.6 nA, respectively, by 12.5, 25, 50 and 100 microM NS-004. Structurally related flufenamic, niflumic and mefenamic acids, at 100 microM, also enhanced IK, Ca. The order of potency for IK, Ca activation was NS-004 >> flufenamic = niflumic > mefenamic. In contrast, NS-004 blocked IK, DR, beginning at 2 microM with 50% inhibition at 22 microM. NS-004 also inhibited IK, ATP with a Ki value of 2.4 microM and a Hill coefficient of 1.3 in 0 mM intracellular ATP. These results demonstrate that NS-004 is a more potent activator of IK, Ca than the fenamates and that it is also a relatively potent blocker of IK, DR and IK, ATP in canine coronary artery smooth muscle cells.

Animals↗
PubMed1996

Functional differences between rabbit and human Na(+)-dicarboxylate cotransporters, NaDC-1 and hNaDC-1.

The rabbit and human Na(+)-dicarboxylate cotransporters, NaDC-1 and hNaDC-1, were expressed in Xenopus oocytes, and the transport of succinate, citrate, and glutarate was compared. Both transporters had similar affinities for succinate and glutarate, with Michaelis-Menten constant (K(m)) values of approximately 0.5- 0.8 mM (succinate) and 6-7 mM (glutarate), verifying that they are low-affinity sodium-dependent dicarboxylate transporters. The two transporters differed in their handling of citrate. At pH 7.5, the K(m) value for citrate was 0.9 mM in the rabbit NaDC-1 and 7 mM in the human hNaDC-1. However, the human transporter was more sensitive to pH than the rabbit. At pH 5.5, the K(m) value for citrate decreased to 1.2 mM in hNaDC-1 and decreased to 0.3 mM in the rabbit transporter. Both transporters had Hill coefficients between 1.6 and 2.1, suggesting that multiple sodium ions are coupled to the transport of divalent anions. However, the human transporter, hNaDC-1, had a lower apparent affinity for sodium (KNa, 78 mM) than the rabbit transporter (KNa, 41 mM). In addition, the human hNaDC-1 was relatively insensitive to inhibition by lithium, furosemide, and flufenamate compared with the rabbit NaDC-1. The differences between the human and rabbit transporters may account for observed differences in renal handling of citrate between species.

Animals↗
PubMed1996

Anion secretion induced by capacitative Ca2+ entry through apical and basolateral membranes of cultured equine sweat gland epithelium.

1. Anion secretion induced by capacitative Ca2+ entry through apical and basolateral membranes of cultured equine sweat gland epithelium was studied using the short-circuit current (Isc) technique. 2. Thapsigargin induced an increase in Isc that could be inhibited when external Ca2+ was chelated by EGTA. 3. The inhibition of the thapsigargin-induced Isc could be reversed by re-addition of Ca2+ to apical or basolateral solutions. The magnitude of the reactivated Isc depended predominantly on basolateral Ca2+ concentration. 4. The magnitude of the reactivated Isc upon basolateral Ca2+ addition increased with the thapsigargin concentration, indicating its dependence on the emptied state of the Ca2+ store induced by thapsigargin. 5. The thapsigargin-induced Isc, as well as the Ca(2+)-dependent reactivation of Isc in EGTA-treated epithelia, was inhibitable by apical, but not basolateral, addition of flufenamate, and by basolateral addition of La3+. Other Ca2+ channel blockers, verapamil and nifedipine, had no effect when applied to either membrane. 6. The results suggest that thapsigargin-induced anion secretion by the equine sweat gland epithelial cells is crucially dependent upon the Ca2+ influx occurring primarily through the basolateral membrane, and that apical and basolateral membranes may possess different pathways for Ca2+ entry.

Animals↗
PubMed1998

Fenamates protect neurons against ischemic and excitotoxic injury in chick embryo retina.

Three fenamates (flufenamate, meclofenamate and mefenamate) were examined for their protective effect on neurons under ischemic (glucose/oxygen deprivation) or excitotoxic conditions, using the isolated retina of chick embryo as a model. Retinal damage was evaluated by histology and lactate dehydrogenase assay. Whole-cell recording was used to examine the direct effect of the fenamates on glutamate receptor-mediated currents. The fenamates protected the retina against the ischemic or excitotoxic insult. Part of the neuroprotection by the fenamates derived from inhibition of N-methyl-D-aspartate receptor-mediated currents. However, kainate receptor-mediated currents were not blocked by the fenamates, which nonetheless reduced kainate receptor-mediated retinal damage. Our results raise the possibility that fenamates may serve as lead structures in the development of novel therapeutic agents against brain ischemia.

Animals↗
PubMed1994

Effects of non-steroidal anti-inflammatory drugs on polymorphonuclear leukocyte functions in vitro: focus on fenamates.

Prostanoid-independent anti-rheumatic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are a matter of debate. The aim of the present study was to compare the effects of chemically different NSAIDs (diclofenac, indomethacin, ketoprofen, paracetamol, piroxicam and four fenamates: flufenamic, meclofenamic, mefenamic and tolfenamic acids) on human polymorphonuclear leukocyte (PMN) functions, i.e. calcium ionophore A23187-triggered degranulation, leukotriene B4 (LTB4) release, platelet-activating factor (PAF) production and migration towards LTB4. The four fenamates caused a dose-dependent inhibition of each of the PMN functions tested. Flufenamic, meclofenamic and tolfenamic acids were about equipotent to inhibit PMN degranulation (IC50S 21-32 microM) and LTB4 release (IC50s 21-25 microM) whereas mefenamic acid achieved similar effects at somewhat higher drug concentrations. Tolfenamic and meclofenamic acids were the most potent fenamates to inhibit PAF synthesis (IC50s 37 and 51 microM) as well as migration towards LTB4 (IC50s 61 and 92 microM). Out of the other NSAIDs, diclofenac (which is chemically related to fenamates) suppressed degranulation as well as LTB4 and PAF production. Indomethacin inhibited LTB4 and PAF synthesis whereas ketoprofen reduced degranulation. The inhibitory effects of the non-fenamate NSAIDs occurred only at drug concentrations far higher than those achieved clinically. Paracetamol and piroxicam (up to 300 microM) did not influence the PMN functions tested. We conclude that NSAIDs with a fenamate structure differ from other NSAIDs by inhibiting PMN functions induced either by receptor-mediated stimulus (LTB4) or calcium ionophore (A23187) at micromolar drug concentrations.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Interactions of benzylpenicillin and non-steroidal anti-inflammatory drugs with the sodium-dependent dicarboxylate transporter NaDC-3.

Sodium-dependent dicarboxylate transporters located in the basolateral membrane (NaDC-3) of renal proximal tubule cells maintain the driving force for exchange of organic anions and drugs against alpha-ketoglutarate via organic anion transporters OAT1 and OAT3. So far, information on direct interaction of drugs with the cloned NaDC-3 was missing. Here we tested the interaction of non-steroidal anti-inflammatory drugs (NSAIDs) and benzylpenicillin with NaDC-3 cloned from winter flounder (fNaDC-3) and human (hNaDC-3) kidneys. Flufenamate and benzylpenicillin inhibited [14C]succinate uptake in oocytes expressing fNaDC-3. Flufenamate elicited Na(+)-dependent currents in oocytes expressing fNaDC-3 with a reversal potential around -60 mV. Raising extracellular K+ concentration depolarized fNaDC3-expressing oocytes more in the presence of flufenamate than in its absence, an effect not seen with water-injected control oocytes. These findings suggest that flufenamate via interaction with fNaDC-3 increased the K+ conductance. Acetylsalicylate, indomethacin, and salicylate showed small potential-dependent inward currents in fNaDC-3 but not in hNaDC-3 expressing oocytes. Benzylpenicillin induced voltage-dependent inward currents which were Na(+)-dependent in oocytes expressing fNaDC-3. The currents were, however, much smaller than those induced by succinate, reflecting probably a low fit of the monovalent benzylpenicillin to the dicarboxylate binding site. The data show hitherto unknown effects of monovalent anionic drugs on a transporter for divalent di- and tricarboxylates.

Animals↗
PubMed2002

Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs.

It has been recently described that some non-steroidal anti-inflammatory drugs (NSAIDs) are able to induce the shedding of L-selectin in neutrophils, an adhesion molecule that plays an essential role in the inflammatory response. We have found that, according to this capability, NSAIDs could be grouped into three categories. A high releaser group (flufenamic, meclofenamic, and mefenamic acids, diclofenac and aceclofenac), a group of moderate releasers (aspirin, indomethacin, nimesulide, flurbiprofen, and ketoprofen), and a non-releaser group (phenylbutazone and the oxicams, piroxicam and meloxicam). Only NSAIDs from the high releaser group shared diphenylamine in their chemical structure. The amine group of this chemical agent proved to be essential for the anti-L-selectin activity of diphenylamine-based NSAIDs. The presence of a carboxylic acid group in the diphenylamine (N-phenylanthranilic acid) highly increased its ability to reduce the L-selectin surface expression in neutrophils. Diphenylamine and N-phenylanthranilic acid neither affected COX activity in platelets nor modified the activation state of neutrophils. Diphenylamine-related compounds, which include the diphenylamine-based NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration, which correlated with the differential ability of such compounds to trigger L-selectin shedding (r = 0.97, p < 0.01). Diphenylamine-related compounds failed to down-regulate L-selectin in a tumor necrosis factor-alpha-converting enzyme (TACE)-deficient murine monocytic cell line. Our data indicate that diphenylamine seems to be the structural core of NSAIDs accounting for their down-regulatory activity of L-selectin leukocyte expression. Diphenylamine and its related compounds exert this action on L-selectin through a prostaglandin-independent, TACE-dependent mechanism that seems to be linked to the capability of these agents to uncouple the mitochondrial oxidative phosphorylation.

ADAM Proteins↗
PubMed2003

Sodium influx and accumulation in Arabidopsis.

Arabidopsis is frequently used as a genetic model in plant salt tolerance studies, however, its physiological responses to salinity remain poorly characterized. This study presents a characterization of initial Na+ entry and the effects of Ca2+ on plant growth and net Na+ accumulation in saline conditions. Unidirectional Na+ influx was measured carefully using very short influx times in roots of 12-d-old seedlings. Influx showed three components with distinct sensitivities to Ca2+, diethylpyrocarbonate, and osmotic pretreatment. Pharmacological agents and known mutants were used to test the contribution of different transport pathways to Na+ uptake. Influx was stimulated by 4-aminobutyric acid and glutamic acid; was inhibited by flufenamate, quinine, and cGMP; and was insensitive to modulators of K+ and Ca2+ channels. Influx did not differ from wild type in akt1 and hkt1 insertional mutants. These data suggested that influx was mediated by several different types of nonselective cation channels. Na+ accumulation in plants grown in 50 mM NaCl was strongly reduced by increasing Ca2+ activity (from 0.05-3.0 mM), and plant survival was improved. However, plant biomass was not affected by shoot Na+ concentration, suggesting that in Arabidopsis Na+ toxicity is not dependent on shoot Na+ accumulation. These data suggest that Arabidopsis is a good model for investigation of Na+ transport, but may be of limited utility as a model for the study of Na+ toxicity.

Arabidopsis↗
PubMed1975

Effect of anti-inflammatory drugs on the membrane potential of vascular endothelial cells in vitro.

1 Cells of the aortic endothelium isolated from the guinea-pig and bathed at 37 degrees C with a calcium-free superfusion fluid had membrane potentials of minus 41 plus or minus 7 mV (mean plus or minus s.e mean). 2 Depolarization was produced by addition of potassium (50-200 mM) or certain other monovalent metal cations to the superfusion fluid. Depolarization was rapidly reversed on return to the original superfusate. 3 Several divalent metal cations, notably calcium (16 mM), caused depolarization which was only slowly and incompletely reversed on return to the original calcium-free superfusate. 4 Repolarization after exposure to calcium was accelerated and made more complete by addition of indomethacin (0.25 mM) to the superfusate, 5 The trivalent cations of lanthanum, aluminium or iron (0.1 mM) inhibited the depolarizing effect of calcium (16 mM). 6 Exposure to histamine (100 mug/ml) or heating to 45 degrees C for 1 h caused depolarization in the presence but not in the absence of calcium. Subsequent removal of histamine or cooling again to 37 degrees C in the continued presence of calcium permitted only slow and partial repolarization. However, repolarization was more rapid and complete in the presence of indomethacin (0.25 mM). 7 Heating to 45 degrees C for 5 h in the presence of calcium caused progressive and almost complete depolarization. Lanthanum, cinchocaine, indomethacin, flufenamic, meclofenamic and salicylic acids, phenylbutazone and aminopyrine each reduced the depolarization, but hydrocortisone, chloroquine, benzindamine, isoprenaline and aminophylline did not.

Animals↗
PubMed1981

[Pharmacologic studies on Ro 12-0068, a new non-steroidal anti-inflammatory drug (author's transl)].

The pharmacological profile of Ro 12-0068 as a new anti-inflammatory agent has been established in 9 different animal models and was compared with the profiles of 10 reference drugs. In adjuvant arthritis, scald-related edema and bradykinin-induced capillary permeability tests, the inhibitory potency of Ro 12-0068 was greater than findings in the case of diclofenac sodium which was the most potent agent available, while Ro 12-0068 exerted a stronger inhibitory effect on granuloma formation than did indomethacin. Anti-inflammatory potency of Ro 12-0068 in other models was equivalent to that of piroxicam. Ro 12-0068 was categorized as a potent anti-inflammatory agent and was grouped with diclofenac sodium, indomethacin and piroxicam, as compared to rather weak agents such as naproxen, carprofen, phenylbutazone, flufenamic, mefenamic, and acetylsalicylic acids. In fasting rats, ulcerogenicity of Ro 12-0068 in the gastric glandular and duodenal portions was weaker than that of indomethacin, appeared to be less than that of piroxicam and was equivalent to that of diclofenac sodium. Induction of fecal occult bleeding in dogs was markedly greater in case of indomethacin and piroxicam than with Ro 12-0068, within few days after oral treatment. Ro 12-0068 and piroxicam had much the same inhibitory effect on prostaglandin synthesis of inflammatory tissues and exudates from gastro-intestinal tissues. Nevertheless, therapeutic indices of Ro 12-0068 in rats were larger than those of piroxicam, in all models, and those of indomethacin in most cases. These results strongly suggest that Ro 12-0068 is a potent anti-inflammatory agent and that the occurrences of related gastro-intestinal disturbances are fewer.

Analgesics↗
PubMed1982

Inhibition of anion transport in the red blood cell by anionic amphiphilic compounds. I. Determination of the flufenamate-binding site by proteolytic dissection of the band 3 protein.

Flufenamate, non-steroidal anti-inflammatory drug, is a powerful inhibitor of anion transport in the human erythrocyte (I50 = 6 . 10(-7) M). The concentration dependence of the binding to ghosts reveals two saturable components. [14C]Flufenamate binds with high affinity (Kd1 = 1.2 . 10(-7) M) to 8.5 . 10(5) sites per cell (the same value as the number of band 3 protein per cell); it also binds, with lower affinity (Kd2 = 10(-4) M) to a second set of sites (4.6 . 10(7) per cell). Pretreatment of cells with 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), a specific inhibitor of anion transport, prevents [14C]flufenamate binding only to high affinity sites. These results suggest that high affinity sites are located on the band 3 protein involved in anion transport. Extracellular chymotrypsin and pronase at low concentration cleave the 95 kDa band 3 into 60 kDa and 35 kDa fragments without affecting either anion transport of [14C]flufenamate binding. Splitting by trypsin at the inner membrane surface of the 60 kDa chymotryptic fragment into 17 kDa transmembrane fragment and 40 kDa water-soluble fragment does not affect [14C]flufenamate binding. In contrast degradation at the outer membrane surface of the 35 kDa fragment by high concentration of pronase or papain decreases both anion transport capacity and number of high affinity binding sites for [14C]flufenamate. Thus it appears that 35 kDa peptide is necessary is necessary for both anion transport and binding of the inhibitors and that the binding site is located in the membrane-associated domain of the band 3 protein.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1982

Evidence for a mediator role of thromboxane A2 in the myotropic action of leukotriene B4 (LTB4) on the guinea-pig lung.

The mechanism of action of LTB4 has been investigated on the guinea-pig lung parenchymal strip. Mepacrine (20 microgram/ml), an inhibitor of phospholipase A2, abolished the action of LTB4 on parenchymal strips. Eicosatetraynoic acid (10 microgram/ml) and BW755C (40 microgram/ml) which are inhibitors of cyclooxygenase and lipoxygenase pathways, produced a marked inhibition of the lung strip contraction to LTB4. Similarly, aspirin (30 micrograms/ml) and flufenamate (1 microgram/ml) showed a strong inhibition of the contraction of parenchymal strips to LTB4; these results suggested that cyclooxygenase products mediate the action of LTB4. The response to LTB4 was unaffected by 15-hydroperoxyeicosatatraenoic acid (15-HPETE; 1 microgram/ml) while L8027 (25 ng/ml) reduced the contraction by 50%, suggesting that thromboxane A2 rather than prostacyclin was involved. Since parenchymal strips do not appear to be very sensitive to PGF2 alpha, PGE2 and the endoperoxides, and since effluents from LTB4-treated lungs produced contractions of lung strip and rabbit aorta which were reduced after 5 min. at 25 degrees, thromboxane A2 was postulated to mediate the lung effect of LTB4. The release of thromboxane B2 (TxB2) from lungs stimulated with LTB4 was confirmed by gas-chromatography-mass spectrometric (GC-MS) analyses.

Animals↗
PubMed1987

Evidence for cAMP as a mediator of gonadotropin secretion from female pituitaries.

Sodium flufenamate, which inhibited gonadotropin-releasing hormone (GnRH)-stimulated increases in adenosine 3',5'-cyclic monophosphate (cAMP), was used to evaluate the potential role of cAMP as a mediator of GnRH-stimulated gonadotropin secretion. Quartered pituitaries from diestrous II female rats were perifused at 37 degrees C, and sequential effluent fractions were collected every 10 min. Administration of GnRH resulted in a characteristic biphasic response for both luteinizing hormone (LH) and follicle-stimulating hormone (FSH), whereas 5 microM cycloheximide inhibited the secondary augmented responses (phase II) of both hormones. Infusions of 0.1 mM flufenamate inhibited GnRH-stimulated gonadotropin secretion in a manner similar to that of cycloheximide, whereas the administration of 5 mM dibutyryl cAMP in combination with GnRH and flufenamate resulted in the restoration of LH and FSH secretion. The dibutyryl cAMP-restored response appeared to be protein synthesis dependent and specific for cAMP. These results suggest that although the cyclic nucleotide is not involved in the acute release of LH and FSH, it does appear to play a pivotal but indirect role in phase II release of the hormones, by effects involving the stimulation of de novo protein synthesis.

Adenosine Monophosphate↗
PubMed1980

Antagonism by fenamates of prostaglandin action in guinea-pig and human alimentary muscle.

1 Low concentrations of meclofenamate, flufenamate or mefenamate had little effect on contractions in response to acetylcholine in any tissue studied. 2 Sodium meclofenamate potently antagonized contractions of guinea-pig ileum longitudinal muscle to prostaglandin E2 (PGE2), PGF2 alpha or PGD2. 3 In guinea-pig colonic longitudinal muscle, contractions to PGE2 were reduced by sodium meclofenamate, but contractions of the longitudinal or circular muscle to PGF2 alpha or PGD2 were less effectively inhibited. 4 In human gastrointestinal longitudinal muscle, sodium meclofenamate or flufenamate potently inhibited contractions to PGF2 alpha, but not to PGE2. 5 Sodium mefenamate or mefenamic acid, even in high concentrations, had little effect on contractions to PGF2 alpha, but tended to inhibit PGE2-induced contractions of human gastrointestinal longitudinal muscle. 6 The therapeutic advantages of prostaglandin synthesis inhibitors which also antagonize responses to certain prostaglandins are discussed.

Animals↗
PubMed1982

Laxative-like effects of nonsteroidal anti-inflammatory drugs on intestinal fluid movement and membrane integrity.

Certain nonsteroidal anti-inflammatory drugs (NSAID) of the fenamate chemical class are known to cause diarrhea in clinical use. Paradoxically, this action is shared by prostaglandins, against whose syntheses are inhibited by NSAID. This study was done to investigate the laxative potential of 5 NSAID (meclofenamate, flufenamate, mefenamate, indomethacin and aspirin). The ability to produce a laxative response was assessed by determining effects on fluid absorption in vitro in hamster everted sacs and by the enteropooling assay in hamster small intestine. In addition, the lytic action of these drugs on the erythrocyte membrane was determined to arrive at a possible mechanism of action. All of the NSAID, except aspirin, produced dose-related inhibition of fluid transport, similar to prostaglandin E1 and E2. The order of inhibition was flufenamate greater than meclofenamate greater than mefenamate greater than indomethacin. Like results were obtained when enteropooling was measured in vivo. Flufenamate and meclofenamate produced lumenal fluid accumulation comparable to two laxatives, dioctyl sodium sulfosuccinate and ricinoleic acid. Finally, the effects of these NSAID on fluid movement paralleled their lytic action on the erythrocyte membrane model, suggesting that NSAID may produce diarrhea in a manner similar to certain laxatives, by increasing mucosal permeability through membrane damage.

Alprostadil↗
PubMed1994

Effects of inhibitors on anion exchangers in rabbit renal brush border membrane vesicles.

Cl-formate, Cl-oxalate, and SO4-CO3 exchange participate in Cl and organic anion transport across the brush border membrane of the rabbit proximal tubule. To determine the functional similarity of these transporters to each other and to band 3, we characterized, in isolated membrane vesicles, the inhibition of these transporters by compounds known to inhibit erythrocyte band 3. 4,4'-Dinitro-2,2'-disulfonic stilbene (DNDS), diphenylamine-2-carboxylate (DPC), flufenamate, and 4-aceto-4'-isothiocyano-2,2'-disulfonic stilbene (SITS) were effective inhibitors of Cl-oxalate and SO4-CO3 exchange, suggesting at least some common structural motifs between these exchangers and band 3. Cl-formate exchange was relatively insensitive to DNDS and DPC but sensitive to flufenamate (IC50 = 43 microM). Sensitivity to DNDS but not 4-amino-4'-amino-2,2'-disulfonic stilbene, a feature of band 3, was seen only for the SO4-CO3 exchanger. None of the exchangers had significant affinity for dipyridamole, furosemide, or probenecid. Finally, the presence of DPC or flufenamate increased the IC50 for reversible inhibition by DNDS, consistent with at least a partial overlap between the disulfonic stilbene and diphenylamine carboxylate binding sites of the Cl-oxalate exchanger. We next examined the effect of irreversible SITS binding. The Cl-oxalate exchanger was inhibited 90%, consistent with its high affinity for reversible inhibition by stilbenes. SITS pretreatment caused 50% inhibition of the Cl-formate exchanger, consistent with the reduced affinity of this exchanger for reversible binding of stilbenes. Despite the high sensitivity of the SO4-CO3 exchanger to reversible inhibition by stilbenes, SITS pretreatment caused < 20% irreversible inhibition of this exchanger. Finally, we characterized the stilbene inhibition of the Cl-oxalate exchanger in more detail. The presence of oxalate increased the IC50 for reversible inhibition by DNDS or SITS, implying that oxalate can directly compete at the reversible stilbene binding site of the Cl-oxalate exchanger. However, oxalate could not protect against covalent inactivation of the Cl-oxalate exchanger by SITS, indicating the presence of a separate site for irreversible binding of disulfonic stilbenes. These results suggest a dissociation between the sensitivities of proximal tubule anion exchangers to reversible and irreversible inhibition by disulfonic stilbenes. In contrast to band 3, the Cl-oxalate exchanger must possess separate sites for reversible and irreversible interaction with stilbenes, with only the former overlapping the substrate binding site.

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