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At least 343 records · Page 19Linked to original sources
PubMed2003

Pharmacological sensitivity of ATP release triggered by photoliberation of inositol-1,4,5-trisphosphate and zero extracellular calcium in brain endothelial cells.

Recently, ATP has gained much interest as an extracellular messenger involved in the communication of calcium signals between cells. The mechanism of ATP release is, however, still a matter of debate. In the present study we investigated the possible contribution of connexin hemichannels or ion channels in the release of ATP in GP8, a rat brain endothelial cell line. Release of ATP was triggered by photoactivation of InsP(3) or by reducing the extracellular calcium concentration. Both trigger protocols induced ATP release significantly above baseline. InsP(3)-triggered ATP release was completely blocked by alpha-glycyrrhetinic acid (alpha-GA), the connexin mimetic peptides gap 26 and 27, and the trivalent ions gadolinium and lanthanum. ATP release triggered by zero calcium was, in addition to these substances, also blocked by flufenamic acid (FFA), niflumic acid, and NPPB. Gap 27 selectively blocked zero calcium-triggered ATP release in connexin-43 transfected HeLa cells, while having no effect in wild-type and connexin-32 transfected cells. Of all the agents used, only alpha-GA, FFA and NPPB significantly reduced gap junctional coupling. In conclusion, InsP(3) and zero calcium-triggered ATP release show major similarities but also some differences in their sensitivity to the agents applied. It is suggested that both stimuli trigger ATP release through the same mechanism, which is connexin-dependent, permeable in both directions, potently blocked by connexin mimetic peptides, and consistent with the opening of connexin hemichannels.

Adenosine Triphosphate↗
PubMed1995

The Ca(2+)-induced leak current in Xenopus oocytes is indeed mediated through a Cl- channel.

Defolliculated oocytes of Xenopus laevis responded to removal of external divalent cations with large depolarizations and, when voltage clamped, with huge currents. Single channel analysis revealed a Cl- channel with a slope conductance of about 90 pS at positive membrane potentials with at least four substates. Single channel amplitudes and mean channel currents had a reversal potential of approximately -15 mV as predicted by the Nernst equation for a channel perfectly selective for Cl-. Readdition of Ca2+ immediately inactivated the channel and restored the former membrane potential or clamp current. The inward currents were mediated by a Ca2+ inactivated Cl- channel (CaIC). The inhibitory potency of Ca2+ was a function of the external Ca2+ concentration with a half maximal blocker concentration of about 20 microM. These channels were inhibited by the Cl- channel blockers flufenamic acid, niflumic acid and diphenylamine-2-carboxylate (DPC). In contrast, 4,4'-acetamido-4'-isothiocyanatostilbene-2, 2'-disulfonicacid (SITS), another Cl- channel blocker, led to activation of this Cl- channel. Like other Cl- channels, the CaIC was activated by cytosolic cAMP. Extracellular ATP inhibited the channel while ADP was without any effect. Injection of phorbol 12-myristate 13-acetate (PMA), a protein kinase C activating phorbol ester, stimulated the Cl- current. Cytochalasin D, an actin filament disrupting compound, reversibly decreased the clamp current demonstrating an influence of the cytoskeleton. The results indicate that removal of divalent cations activates Cl- channels in Xenopus oocytes which share several features with Cl- channels of the CLC family. The former so-called leak current of oocytes under divalent cation-free conditions is nothing else than an activation of Cl- channels.

1-Methyl-3-isobutylxanthine↗
PubMed1977

[Pharmacology and toxicology of etofenamate. 1st Communication (author's transl)].

1. The reliable antiphlogistic action of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate active principle of Rheumon Gel) in various experimental inflammatory models in animals is demonstrated following oral and cutaneous administration. 2. The proven inhibition of inflammatory edema by chronic administration of Rheumon gel evidences the percutaneous absorption of the active principle through the intact skin. 3. The effect of Rheumon gel sets in independently of whether the gel is applied to normal or to pathologically inflamed tissue areas. 4. Gastrointestinal mucous tolerance is better for etofenamate than for flufenamic acid, phenylbutazone and other anti-inflammatory drugs.

Animals↗
PubMed1975

Radioimmunoassay of main urinary metabolite of prostaglandin F2alpha.

Radioimmunoassay of 5alpha, 7alpha-dihydroxy-11-keto-tetranorprosta-1,16-dioic acid, main urinary metabolite of prostaglandin F2alpha (PGF2alpha), was performed using an antiserum produced in the rabbit. The antibody in 100 mu1 of 1,600-fold diluted antiserum binds with 60 picograms of metabolite. The main urinary metabolite level fell when flufenamic acid, a prostaglandin synthetase inhibitor, was given to rats. In contrast, it was significantly elevated when PGF2alpha was administered.

Animals↗
PubMed1991

Salicylate inhibits human placental sulphate transport in vitro.

The effect of salicylate on sulphate transport by the human placenta has been studied using isolated brush-border membrane vesicles and placental tissue slices. Sulphate uptake by isolated vesicles was inhibited in a dose dependent fashion (K1 approximately 3 mM) by salicylate. It appears that this drug blocks sulphate accumulation in a non-competitive manner. Sulphate efflux from preloaded vesicles was also found to be markedly reduced by salicylate in a non-competitive fashion. Consistent with the vesicle studies salicylate inhibited sulphate transport by placental tissue slices. The results suggest that salicylate ingestion could compromise feto-placental sulphate homeostasis. In addition we have found that the aspirin-like drug, flufenamic acid, inhibits sulphate transport by isolated microvillus membrane vesicles.

Biological Transport↗
PubMed1976

Corpus luteum function in the ewe: effect of PGF2alpha and prostaglandin synthetase inhibitors.

A series of experiments were conducted to evaluate the effects of mode and frequency of administration and estrous cycle stage on the response of the cycling ewe to PGF2alpha. The effects of dexamethasone, arachadonic acid and prostaglandin synthetase inhibitors on estrous cycle length and plasma progesterone levels were also determined. Intramuscular administration of 5 or 10 mg of PGF2alpha, on days 8 and 9 after estrus (5 ewes/group), significantly (p less than .01) shortened the mean length of the estrous cycle and the interval from the end of treatment to estrus. Mean plasma progesterone levels, 24 hours after initial injection, were significantly (p less than .01) lowered. When administered on day 8 only, these doses were considerably less effective in shortening estrous cycle length or lowering plasma progesterone levels. Intravaginal administration of PGF2alpha, by polyurethane tampon, was also largely ineffective. Treatment of ewes with 10 mg of PGF2alpha, by polyurethanetampon, was also largely ineffective. Treatment of ewes with 10 mg of PGF2alpha i.m., on days 3 and 4 of the estrous cycle, resulted in a return to estrus in 2 days in 25% of the treated animals. Plasma progesterone levels of PGF2alpha-treated ewes were significantly lower than controls on the second, third and fourth days after the start of dosing. It would appear that PGF2alpha exerts a retarding effect on developing CL functionality. The prostaglandin synthetase inhibitors, aspirin, flufenamic acid and 1-p-chlorobenzylidene-2-methyl-5-methoxy-3-indenylacetic acid, were administered orally or parenterally for 16 days beginning on day 8 of the estrous cycle. These compounds failed to prolong estrous cycle length. Parenteral administration of dexamethasone did not result in PGF2alpha release in the cycling ewe, at least not in quantities sufficient to induce luteolytis. The prostaglandin precursor, arachadonic acid, also was not luteolytic when given parenterally to cycling ewes.

Acetates↗
PubMed1995

Calcium entry in rabbit corneal epithelial cells: evidence for a nonvoltage dependent pathway.

We performed experiments to elucidate the calcium influx pathways in freshly dispersed rabbit corneal epithelial cells. Three possible pathways were considered: voltage-gated Ca++ channels, Na+/Ca++ exchange, and nonvoltage-dependent Ca(++)-permeable channels. Whole cell inward currents carrying either Ca++ or Ba++ were not detected using voltage clamp techniques. We also used imaging technology and the Ca(++)-sensitive ratiometric dye fura 2 to measure changes in intracellular Ca++ concentration ([Ca]i). Bath perfusion with NaCl Ringer's solution containing the calcium channel agonist Bay-K-8644 (1 microM), or Ni++ (40 microM), a blocker of many voltage-dependent calcium channels, did not affect [Ca++]i. Membrane depolarization with a KCl Ringer's bath solution resulted in a decrease in [Ca++]i. These results are inconsistent with the presence of voltage gated Ca++ channels. Nonvoltage gated Ca++ entry, on the other hand, would be reduced by membrane depolarization and enhanced by membrane hyperpolarization. Agents which hyperpolarize via stimulation of K+ current, such as flufenamic acid, resulted in an increase in ratio intensity. The cells were found to be permeable to Mn++ and bath perfusion with 5 mM Ni++ decreased [Ca++]i suggesting that the Ca++ conductance was blocked. These results are most consistent with a nonvoltage gated Ca++ influx pathway. Finally, replacing extracellular Na+ with Li+ resulted in an increase in [Ca++]i if the cells were first Na(+)-loaded using the Na+ ionophore monensin and ouabain, a Na(+)-K(+)-ATPase inhibitor. These results suggest that Na+/Ca++ exchange may also regulate [Ca++]i in this cell type.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

Antimonial-induced increase in intracellular Ca2+ through non-selective cation channels in the host and the parasite is responsible for apoptosis of intracellular Leishmania donovani amastigotes.

The capability of the obligate intracellular parasites like Leishmania donovani to survive within the host cell parasitophorous vacuoles as nonmotile amastigotes determines disease pathogenesis, but the mechanism of elimination of the parasites from these vacuoles are not well understood. By using the anti-leishmanial drug potassium antimony tartrate, we demonstrate that, upon drug exposure, intracellular L. donovani amastigotes undergo apoptotic death characterized by nuclear DNA fragmentation and externalization of phosphatidylserine. Changes upstream of DNA fragmentation included generation of reactive oxygen species like superoxide, nitric oxide, and hydrogen peroxide that were primarily concentrated in the parasitophorous vacuoles. In the presence of antioxidants like N-acetylcysteine or Mn(III) tetrakis(4-benzoic acid)porphyrin chloride, an inhibitor of inducible nitric-oxide synthase, a diminution of reactive oxygen species generation and improvement of amastigote survival were observed, suggesting a close link between drug-induced oxidative stress and amastigote death. Changes downstream to reactive oxygen species increase involved elevation of intracellular Ca2+ concentrations in both the parasite and the host that was preventable by antioxidants. Flufenamic acid, a non-selective cation channel blocker, decreased the elevation of Ca2+ in both the cell types and reduced amastigote death, thus establishing a central role of Ca2+ in intracellular parasite clearance. This influx of Ca2+ was preceded by a fall in the amastigote mitochondrial membrane potential. Therefore, this study projects the importance of flufenamic acid-sensitive non-selective cation channels as important modulators of antimonial efficacy and lends credence to the suggestion that, within the host cell, apoptosis is the preferred mode of death for the parasites.

Animals↗
PubMed1995

Nonselective cation channel activation during wound healing in the corneal endothelium.

Rabbit corneas were injured by mechanical or thermal trauma. At several time points after wounding, corneal endothelial cells were isolated and their ion channels examined using standard and amphotericin perforated-patch whole cell patch-clamp configurations. Within 15-24 h after mechanical or thermal trauma, a nonselective cation current was observed in 79% of the cells examined that was not present in unwounded or sham-wounded corneas. By 73 h postwounding, the current was present in only 10% of the cells examined. The wound healing-induced current is outwardly rectifying, activates at depolarized voltages, shows no sign of inactivation, and is inhibited by flufenamic acid, quinidine, and acetate. In addition to this new current, it was observed that endothelial cells from freeze-wounded corneas no longer expressed the transient K+ current seen in control, sham, and mechanically wounded corneas. Corneal endothelial superfusion experiments found no significant difference in swelling rates between control and flufenamic acid-superfused wounded corneas, indicating that the wound healing-induced channel is not involved in the stromal hydration maintenance function of the corneal endothelium.

Animals↗
PubMed1973

Evaluation of cryogenine on rat paw thermal oedema and rat isolated uterus.

1. Significant inhibition of oedema formation caused by thermal injury was observed for calcium carbaspirin, phenylbutazone, hydrocortisone, cryogenine and indomethacin when given daily beginning 2 days prior to thermal exposure and afterwards. Several anti-inflammatory drugs, including cryogenine, failed to reduce thermal oedema significantly when given as single doses 1 h prior to the thermal injury.2. Kinetic experiments on the rat isolated uterus demonstrated that cryogenine, chlorpromazine, and flufenamic acid were, in part, competitive inhibitors of synthetic bradykinin, while indomethacin and tetrabenazine showed only non-competitive antagonism.

Alkaloids↗
PubMed1986

Colitis caused by non-steroidal anti-inflammatory drugs.

Four cases of acute proctocolitis associated with non-steroidal anti-inflammatory drug therapy are presented. The drugs implicated were flufenamic acid, mefenamic acid, naproxen and ibuprofen. After resolution of symptoms and signs of proctocolitis three of the four patients were subsequently rechallenged with the implicated drug: in each there was a rapid relapse.

Aged↗
PubMed1976

Control of bleb fibrosis after glaucoma surgery by anti-inflammatory agents.

The methods used to identify and evaluate anti-inflammatory agents, and the effects of a triple drug regimen, consisting of oral prednisone and flufenamic acid and topical l-adrenaline in controlling bleb inflammation and fibrosis around drainage implants in patients with terminal glaucoma are described. The benefits of anti-inflammatory agents in other surgical glaucoma procedures are suggested.

Anti-Inflammatory Agents↗
PubMed1985

Synthesis and anti-inflammatory and analgesic activities of 3-methyl-N-phenyl-1H-pyrazol-5-ylcarboxamides.

The anti-inflammatory and analgesic activities of a series of 3-methyl-N-phenyl-1H-pyrazol-5-ylcarboxamides were investigated and compared with flufenamic acid. The compounds were synthesized by condensation of diketopiperazines 2 with the appropriate aniline. The pharmacological tests showed that some compounds have good anti-inflammatory activity in rat paw edema induced by carrageenin and low toxicity.

Animals↗
PubMed1999

Expression of an mNSC1 in mammalian cells.

We have cloned a cDNA inducing a cation-permeable current (mNSC1) from pancreatic beta-cells, which shows niflumate-sensitive current in Xenopus oocytes. To elucidate the expression in mammalian cells, mNSC1 was expressed in CHO cells. The reversal potential by mNSC1 was shifted toward positive which was significantly reversed by flufenamic acid. Single-channel analysis showed a characteristic of a Ca-activated nonselective cation channel. Therefore, we may conclude that mNSC1 expresses a fenamates-sensitive cation channel, inducing membrane depolarization in a mammalian cell.

Animals↗
PubMed2004

Analysis of slow hyperpolarizing potentials in frog taste cells induced by glossopharyngeal nerve stimulation.

Electrical stimulation of the frog glossopharyngeal (GP) nerve evoked slow hyperpolarizing potentials (HPs) in taste cells. This study aimed to clarify whether slow HPs were postsynaptically induced in taste cells. The slow HPs were recorded intracellularly with a microelectrode. When Ca2+ concentration in the blood plasma was decreased to approximately 0.5 mM, the amplitude of slow HPs reduced and their latency lengthened. When the Ca2+ concentration was increased to approximately 20 mM, the amplitude of slow HPs increased and their latency shortened. Addition of Cd2+ to the plasma greatly reduced the amplitude of slow HPs and lengthened their latency. These data suggest that the slow HPs are dependent on presynaptic activities in the GP nerve terminals in the taste disk. Of various antagonists injected intravenously for blocking receptors of neurotransmitter biogenic amines and peptides, only antagonists for substance P blocked the slow HPs at 2-4 mg/kg body wt. Application of substance P of 2 mg/kg to the plasma induced hyperpolarizing responses in taste cells, whose amplitude was the same as that of the slow HPs induced by GP nerve stimulation. Application of a nonselective cation channel antagonist, flufenamic acid, to the plasma blocked the slow HPs. These results suggest that the slow HPs are generated by closing the nonselective cation channels in the postsynaptic membrane of taste cells following possible release of substance P from the GP nerve terminals in the taste disk.

Action Potentials↗
PubMed1997

Characterization of Ca(2+)- and voltage-dependent nonselective cation channels in human HepG2 cells.

Nonselective cation channels have been identified and linked to important cell functions in rat hepatocytes. In this study, we characterized inward rectifying nonselective cation channels in detail by the patch clamp technique in human HepG2 cells. Channel properties were studied with high resistance borosilicate pipettes in cell-attached and inside-out configurations. With Ringer's solution and KCl as pipette solutions, the conductances were 19.7 +/- 2.1 and 22.2 +/- 0.0 picosiemens (pS), and reversal potentials were 30.9 +/- 3.5 and 31.3 +/- 4.6 mV, respectively. The channel was permeable to Ba2+, and the sequence of permeability ratios was Na+ > K+ > Cs+ > Ba2+. In the cell-attached configuration, the channel had a higher opening probability at depolarizing potential than at hyperpolarizing. In the inside-out patches with symmetric Ringer's solution, the current voltage curve was linear with conductance of 19.8 +/- 0.9 pS. Reversal potential shifted from -0.2 +/- 1.0 mV to 23.2 +/- 1.0 mV when the bath solution was replaced by dilute Ringer's solution. In the inside-out configuration, the gating was Ca(2+)-dependent, and the opening probability increased with increasing intracellular calcium concentration ([Ca2+]i). An outward rectifying channel appeared when [Ca2+]i was less than 1 mumol/L. The nonselective channel was reversibly blocked by 10 mumol/L internal flufenamic acid. We conclude that Ca(2+)- and voltage-dependent nonselective cation channels are present in human HepG2 cells. The channels might be involved in the regulation of Ca2+ influx and are associated with activation of other ion channels.

Animals↗
PubMed2005

Pharmacological properties of homomeric and heteromeric pannexin hemichannels expressed in Xenopus oocytes.

Several new findings have emphasized the role of neuron-specific gap junction proteins (connexins) and electrical synapses in processing sensory information and in synchronizing the activity of neuronal networks. We have recently shown that pannexins constitute an additional family of proteins that can form gap junction channels in a heterologous expression system and are also widely expressed in distinct neuronal populations in the brain, where they may represent a novel class of electrical synapses. In this study, we have exploited the hemichannel-forming properties of pannexins to investigate their sensitivity to well-known connexin blockers. By combining biochemical and electrophysiological approaches, we report here further evidence for the interaction of pannexin1 (Px1) with Px2 and demonstrate that the pharmacological sensitivity of heteromeric Px1/Px2 is similar to that of homomeric Px1 channels. In contrast to most connexins, both Px1 and Px1/Px2 hemichannels were not gated by external Ca2+. In addition, they exhibited a remarkable sensitivity to blockade by carbenoxolone (with an IC50 of approximately 5 microm), whereas flufenamic acid exerted only a modest inhibitory effect. The opposite was true in the case of connexin46 (Cx46), thus indicating that gap junction blockers are able to selectively modulate pannexin and connexin channels.

Animals↗
PubMed1993

Nonselective cation channels in cells of the crypt-base of rat distal colon.

Cells in the base of isolated intact crypts of rat distal colon were investigated with the slow whole-cell patch-clamp technique with nystatin in the patch pipette. Addition of either prostaglandin E2 or forskolin to the bath depolarized the cell from -74 mV to -27 mV. This depolarization was reversed when bath Na+ was replaced by N-methyl-D-glucamine (NMDG+), or when flufenamic acid (50 microM) was added to the bath. In cell-attached and cell-excised patches of the basolateral membrane nonselective cation channels (gamma = 38 pS, 35 degrees C) were recorded. It is concluded that nonselective cation channels are activated by PGE2 and forskolin. The channels could be involved in cell proliferation.

Animals↗