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At least 757 records · Page 42Linked to original sources
PubMed1997

Angiotensin II increases the cytosolic calcium activity in rat podocytes in culture.

In the glomerulus, angiotensin II (Ang II) reduces the ultrafiltration coefficient and enhances the filtration of macromolecules. During glomerular injury, inhibition of the renin-angiotensin system by angiotensin-converting-enzyme inhibitors reduces proteinuria and retards the progression to end-stage renal insufficiency. The mechanisms by which Ang II modulates glomerular function are still a matter of investigation. To study whether Ang II may regulate the cytosolic calcium activity ([Ca2+]i) in podocytes, these cells were propagated in short-term culture and the effect of Ang II was examined with the Fura-2 microfluorescence technique in single podocytes. The cellular identity of cultured podocytes was proven by the expression of WT-1 and pp44, specific antibodies against podocytes in vivo. Ang II led to a concentration-dependent, reversible and slow increase of [Ca2+]i with an EC50 of 3 nmol/liter Ang II (N = 229). Ten nmol/liter Ang II increased [Ca2+]i from 41 +/- 9 to 260 +/- 34 nmol/liter (N = 210). In a solution with an extracellular reduced Ca2+ concentration of 10 micromol/liter, Ang II-mediated [Ca2+]i increase was significantly reduced by 60 +/- 20% (N = 12), indicating that the [Ca2+]i increase was due to a Ca2+ influx from the extracellular space and a release of Ca2+ from intracellular stores. Flufenamate, an inhibitor of non-selective ion channels, significantly inhibited Ang II-mediated increase of [Ca2+]i (IC50 = 20 micromol/liter, N = 29), whereas the L-type Ca2+ channel blocker nicardipine even in high concentrations of > 1 micromol/liter had only a small inhibitory effect. The AT1 receptor antagonist losartan inhibited Ang II-mediated [Ca2+]i increase with an IC50 of about 0.3 nmol/liter (N = 35). The data suggest that Ang II increases [Ca2+]i in podocytes by an influx of Ca2+ through non-selective channels and by a release of Ca2+ from intracellular stores. The effect of Ang II is mediated via an AT1 receptor.

Angiotensin II↗
PubMed2000

Multiple action sites of flufenamate on ion transport across the rat distal colon.

The antisecretory effects of flufenamate in the rat distal colon were investigated with the Ussing-chamber and the patch-clamp method as well as by measurements of the intracellular Ca(2+) concentration using fura-2-loaded isolated crypts. Flufenamate (5.10(-4) mol l(-1)) suppressed the short-circuit current (Isc) induced by carbachol (5.10(-5) mol l(-1)), forskolin (5.10(-6) mol l(-1)) and the Isc induced by the membrane-permeable analogue of cyclic AMP, CPT - cyclic AMP (10(-4) mol l(-1)). Indomethacin (10(-6) - 10(-4) mol l(-1)) did not mimic the effect of flufenamate, indicating that the antisecretory effect of flufenamate is not related to the inhibition of the cyclo-oxygenase. When the basolateral membrane was depolarized by a high K(+) concentration and a Cl(-) current was induced by a mucosally directed Cl(-) gradient, the forskolin-stimulated Cl(-) current was blocked by flufenamate, indicating an inhibition of the cyclic AMP-stimulated apical Cl(-) conductance. When the apical membrane was permeabilized by the ionophore, nystatin, flufenamate decreased the basolateral K(+) conductance and inhibited the Na(+) - K(+)-ATPase. Patch-clamp experiments revealed a variable effect of flufenamate on membrane currents. In seven out of 11 crypt cells the drug induced an increase of the K(+) current, whereas in the remaining four cells an inhibition was observed. Experiments with fura-2-loaded isolated crypts indicated that flufenamate increased the basal as well as the carbachol-stimulated intracellular Ca(2+) concentration. These results demonstrate that flufenamate possesses multiple action sites in the rat colon: The apical Cl(-) conductance, basolateral K(+) conductances and the Na(+) - K(+)-ATPase.

Animals↗
PubMed1980

Inhibition of highly purified mammalian phospholipases A2 by non-steroidal anti-inflammatory agents. Modulation by calcium ions.

Highly purified Ca2+-dependent phospholipases A2 that were isolated from human platelets, rabbit alveolar macrophages and peritoneal polymorphonuclear leucocytes and were active in the neutral-to-alkaline pH range were inhibited 50% by 75 microM-indomethacin in the presence of 5.0 mM added Ca2+. Sodium meclofenamate and sodium flufenamate were also inhibitory; the sensitivity to inhibition was a function of Ca2+ concentration. The dose for 50% inhibition (ID50) with meclofenamate was 0.4 mM in the presence of 2.5 mM added Ca2+, but 50nM in the presence of 0.5 mM added Ca2+. Thus, inhibition of phospholipase A2 activity by non-steroidal anti-inflammatory agents via Ca2+ antagonism may significantly contribute to the mechanism of drug action.

Animals↗
PubMed2001

Etofenamate levels in human serum and synovial fluid following iontophoresis.

The absorption of etofenamate (CAS 30544-47-9, Rheumon gel) by iontophoresis in 11 patients with low back pain and in 13 patients with synovitis of the knee was evaluated. During the 5-day treatment period, the test gel in a quantity corresponding to 100 mg etofenamate was applied to affected body regions every day by 20-min iontophoresis sessions. Two hours after the fifth application, the concentration of etofenamate in serum and synovial fluid (in patients who had knee joint iontophoresis) were measured by HPLC. Iontophoresis of etofenamate into the lumbar region as well as to the knee joint resulted in consistent serum levels: 219 +/- 136.3 micrograms/l and 191 +/- 84.6 micrograms/l, respectively. In patients with synovitis of the knee, the synovial level of etofenamate (368 +/- 109.2 micrograms/l) was almost twice as high than the serum concentration. The authors conclude that with topical application of etofenamate by iontophoresis the drug appears not only in the serum but also--with higher levels--in the synovial fluid.

Administration, Topical↗
PubMed1990

[Allergic contact eczema to etofenamate and dwarf pine oil].

A typical case of contact dermatitis following topical applications of etofenamat is reported and a short review of literature is given. Considering the frequent administration of etofenamat, contact sensitization is relatively rare.

Administration, Topical↗
PubMed2000

Transmembrane redox sensor of ryanodine receptor complex.

Inositol 1,4,5-trisphosphate receptors (IP(3)R) and ryanodine receptors (RyR) mediate the release of endoplasmic and sarcoplasmic reticulum (ER/SR) Ca(2+) stores and regulate Ca(2+) entry through voltage-dependent or ligand-gated channels of the plasma membrane. A prominent property of ER/SR Ca(2+) channels is exquisite sensitivity to sulfhydryl-modifying reagents. A plausible role for sulfhydryl chemistry in physiologic regulation of Ca(2+) release channels and the fidelity of Ca(2+) release from ER/SR is lacking. This study reveals the existence of a transmembrane redox sensor within the RyR1 channel complex that confers tight regulation of channel activity in response to changes in transmembrane redox potential produced by cytoplasmic and luminal glutathione. A transporter selective for glutathione is co-localized with RyR1 within the SR membrane to maintain local redox potential gradients consistent with redox regulation of ER/SR Ca(2+) release. Hyperreactive sulfhydryls previously shown to reside within the RyR1 complex (Liu, G., and Pessah, I. N. (1994) J. Biol. Chem. 269, 33028-33034) are an essential biochemical component of a transmembrane redox sensor. Transmembrane redox sensing may represent a fundamental mechanism by which ER/SR Ca(2+) channels respond to localized changes in transmembrane glutathione redox potential produced by physiologic and pathophysiologic modulators of Ca(2+) release from stores.

Animals↗
PubMed2002

Increase in cytosolic Ca2+ levels through the activation of non-selective cation channels induced by oxidative stress causes mitochondrial depolarization leading to apoptosis-like death in Leishmania donovani promastigotes.

Reactive oxygen species are important regulators of protozoal infection. Promastigotes of Leishmania donovani, the causative agent of Kala-azar, undergo an apoptosis-like death upon exposure to H2O2. The present study shows that upon activation of death response by H2O2, a dose- and time-dependent loss of mitochondrial membrane potential occurs. This loss is accompanied by a depletion of cellular glutathione, but cardiolipin content or thiol oxidation status remains unchanged. ATP levels are reduced within the first 60 min of exposure as a result of mitochondrial membrane potential loss. A tight link exists between changes in cytosolic Ca2+ homeostasis and collapse of the mitochondrial membrane potential, but the dissipation of the potential is independent of elevation of cytosolic Na+ and mitochondrial Ca2+. Partial inhibition of cytosolic Ca2+ increase achieved by chelating extracellular or intracellular Ca2+ by the use of appropriate agents resulted in significant rescue of the fall of the mitochondrial membrane potential and apoptosis-like death. It is further demonstrated that the increase in cytosolic Ca2+ is an additive result of release of Ca2+ from intracellular stores as well as by influx of extracellular Ca2+ through flufenamic acid-sensitive non-selective cation channels; contribution of the latter was larger. Mitochondrial changes do not involve opening of the mitochondrial transition pore as cyclosporin A is unable to prevent mitochondrial membrane potential loss. An antioxidant like N-acetylcysteine is able to inhibit the fall of the mitochondrial membrane potential and prevent apoptosis-like death. Together, these findings show the importance of non-selective cation channels in regulating the response of L. donovani promastigotes to oxidative stress that triggers downstream signaling cascades leading to apoptosis-like death.

Acetylcysteine↗
PubMed2001

Comparative study of etofenamate and fentanyl for outpatient extracorporeal shockwave lithotripsy.

OBJECTIVE: This study aimed to compare the clinical efficacy and safety of etofenamate (a non-steroidal anti-inflammatory drug) and fentanyl (an opioid analgesic) for outpatient extracorporeal shock wave lithotripsy (ESWL). MATERIAL AND METHODS: 60 non-premedicated patients underwent ESWL for urinary tract calculus with the Multimed 2000 (ELMED Lithotripsy Co.. Turkey) lithotripter. None of patients had previous experience with ESWL treatment. The patients were divided into two groups. A single dose of 1 g etofenamate was given to the patients intramuscularly 25 min before ESWL in group I (n = 30) and 0.1 mg fentanyl was administered intravenously just before ESWL in group II (n = 30). At the end of the treatment a visual analogue score (VAS) of 0 (no pain) to 10 (greatest pain) was used to evaluate the pain. Blood pressure, heart rate and arterial oxygen tension (PaO2) were measured before and during the ESWL. Groups were compared according to the pain scores, stone size, number of shocks, maximum voltage achieved, duration of ESWL and incidence of side-effects of the administered drug. Data were analysed with the Mann-Whitney U-test. RESULTS: No statistical differences were found between the two groups regarding achieved maximal energy levels, pain scores and number of shock waves given (p < 0.01). Satisfactory stone fragmentation was achieved in both groups. There were no changes in blood pressure or heart rate during the ESWL in either group. PaO2 was not affected in the etofenamate group, whereas a transient desaturation in two patients and giddiness in three patients were recorded in the fentanyl group. CONCLUSIONS: Both etofenamate and fentanyl have clinically sufficient effects on pain, and can be used safely for outpatient ESWL procedures.

Adult↗
PubMed1998

Preparative chromatography of furosemide 1-O-acyl-glucuronide from urine using micronized amberiite XAD-2 and its application to other 1-O-acyl-glucuronides.

Furosemide 1-O-acyl glucuronide (Fgnd) was extracted from the urine following oral administration of furosemide. The crude Fgnd was applied to micronized Amberlite XAD-2 column (2.5 cm i.d. x 90 cm length, 75-500 microns particle size). The purified Fgnd was identified by mass spectrometry and beta-glucuronidase treatment. This method was also applicable to the purification of glucuronide of tolmetin (nonsteroidal anti-inflammatory drug, NSAID), suggesting that it was applicable to the other NSAIDs, most of which were known to be metabolized to acyl-glucuronides.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1979

Prostaglandins are necessary for osteoclast-activating factor production by activated peripheral blood leukocytes.

The production of osteoclast-activating factor (OAF) by normal human peripheral blood leukocytes stimulated by phytohemagglutinin was inhibited by a series of structurally unrelated inhibitors of prostaglandin synthetase. Inhibition of OAF production by these agents was reversed by adding prostaglandins of the E series back to the leukocyte suspension. These results indicate that prostaglandin synthesis is necessary for OAF production.

Bone Resorption↗
PubMed1986

Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs.

The homogeneous dihydrodiol dehydrogenase of rat liver cytosol (EC 1.3.1.20) reduces the mutagenicity of benzo[a]pyrene in the Ames test, suggesting that the enzyme may detoxify the trans-dihydrodiol proximate carcinogens formed from this compound. This report directly demonstrates for the first time that the purified dehydrogenase catalyzes the NADP-dependent oxidation of the potent proximate carcinogen [1,3-3H](+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene at physiological pH. An initial velocity of 1.8 nmol [3H]trans-dihydrodiol oxidized/min/mg protein was observed at a substrate concentration of 20 microM. This potential detoxification reaction was potently inhibited by the nonsteroidal anti-inflammatory drug indomethacin, yielding an IC50 value of 10 microM. At higher drug concentrations (30 microM), the inhibition persisted for many hours. In an extension of this work, benzenedihydrodiol (trans-1,2-dihydroxy-3,5-cyclohexadiene) and naphthalenedihydrodiol (trans-1,2-dihydroxy-1,2-dihydronaphthalene) were synthesized as models of the scarce proximate carcinogen trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and examined as substrates. The Km for benzenedihydrodiol was 1.74 mM and the Vmax was 530 nmol substrate oxidized/min/mg protein, while the Km for naphthalenedihydrodiol was 10.71 mM and the Vmax was 268 nmol oxidized/min/mg protein; the former compound was oxidized to catechol. Eight different non-steroidal anti-inflammatory drugs were found to inhibit the oxidation of these model trans-dihydrodiols, yielding IC50 values comparable to or lower than peak plasma concentrations observed in man. These results suggest that therapeutically relevant concentrations of the non-steroidal anti-inflammatory drugs may inhibit the oxidation of trans-dihydrodiol proximate carcinogens by this route.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Bradykinin stimulates the intracellular calcium activity in human mesothelial cells.

AIM: The aim of this study was to investigate the influence of bradykinin on the intracellular calcium activity ([Ca2+]i) in human mesothelial cells in culture. RESULTS: Bradykinin (1-1000 nmol/l) caused a concentration-dependent and reversible increase of [Ca2+]i in mesothelial cells (n = 94); 10 nmol/l bradykinin increased [Ca2+]i from 23 +/- 9 to 670 +/- 170 nmol/l (n = 36). The pattern of the bradykinin-induced [Ca2+]i increase was biphasic with a transient [Ca2+]i peak, which was followed by a sustained [Ca2+]i plateau. The bradykinin-mediated [Ca2+]i plateau, but not the peak, was inhibited in a solution with an extracellular reduced Ca2+ concentration (from 1000 to 1 micromol/l, n = 11). Flufenamate (> or = 10 micromol/l), an inhibitor of non-selective ion channels abolished the bradykinin-mediated increase of [Ca2+], whereas the L-type Ca2+ channel blocker nicardipine (10 micromol/l) had no effect (n = 3-5). The [Ca2+]i response to bradykinin was inhibited by the BK2 antagonist Hoe 140 (IC50 +/- k7 nmol/l, n = 30). CONCLUSIONS: The data indicate that bradykinin stimulates [Ca2+]i in mesothelial cells by a release of Ca2+ from intracellular stores and an influx from Ca2+ through non-selective channels via a BK2 receptor.

Bradykinin↗