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At least 19 recordsLinked to original sources

PubMed1992

The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor.

The thiol reagent, thimerosal, has been shown to cause an increase in intracellular Ca2+ concentration ([Ca2+]i) in several cell types, and to cause Ca2+ spikes in unfertilized hamster eggs. Using single cell video-imaging we have shown that thimerosal evokes repetitive Ca2+ spikes in intact Fura-2-loaded HeLa cells that were similar in shape to those stimulated by histamine. Both thimerosal- and histamine-stimulated Ca2+ spikes occurred in the absence of extracellular (Ca2+ o), suggesting that they result from mobilization of Ca2+ from intracellular stores. Whereas histamine stimulated formation of inositol phosphates, thimerosal, at concentrations that caused sustained Ca2+ spiking, inhibited basal and histamine-stimulated formation of inositol phosphates. Thimerosal-evoked Ca2+ spikes are therefore not due to the stimulated production of inositol 1,4,5-trisphosphate (InsP3). The effects of thimerosal on Ca2+ spiking were probably due to alkylation of thiol groups on intracellular proteins because the spiking was reversed by the thiol-reducing compound dithiothreitol, and the latency between addition of thimerosal and a rise in [Ca2+]i was greatly shortened in cells where the intracellular reduced glutathione concentration had been decreased by preincubation with DL-buthionine (S,R)-sulfoximine. In permeabilized cells, thimerosal caused a concentration-dependent inhibition of Ca2+ accumulation, which was entirely due to inhibition of Ca2+ uptake into stores because thimerosal did not affect unidirectional 45Ca2+ efflux from stores preloaded with 45Ca2+. Thimerosal also caused a concentration-dependent sensitization of InsP3-induced Ca2+ mobilization: half-maximal mobilization of Ca2+ stores occurred with 161 +/- 20 nM InsP3 in control cells and with 62 +/- 5 nM InsP3 after treatment with 10 microM thimerosal. We conclude that thimerosal can mimic the effects of histamine on intracellular Ca2+ spiking without stimulating the formation of InsP3 and, in light of our results with permeabilized cells, suggest that thimerosal stimulates spiking by sensitizing cells to basal InsP3 levels.

Calcium↗

PubMed1992

Cytosolic Ca2+ spikes evoked by the thiol reagent thimerosal in both intact and internally perfused single pancreatic acinar cells.

Cytosolic calcium signals evoked by the sulphydryl-group-oxidising agent, thimerosal, have been investigated in acutely isolated pancreatic acinar cells. Two techniques were employed for the assessment of the cytosolic free-calcium concentration ([Ca2+]i): measurement of calcium-dependent chloride and non-specific cation currents (whole-cell patch-clamp recording) and microfluorimetry (fura-2). Thimerosal (0.5-100 microM) evoked repetitive spikes in both chloride and cation currents as seen by patch-clamp recording, and in [Ca2+]i as seen by microfluorimetry, with a latency of 1-3 min. The response increased in magnitude over time and was not reversed on removal of thimerosal. The thimerosal-induced spikes were reversibly blocked by 2 mM dithiothreitol and by 20 mM caffeine. Inclusion of heparin (200 micrograms/ml) in the pipette solution blocked the thimerosal-induced spikes. The calcium spikes continued after the removal of extracellular calcium; however, low concentrations of thimerosal (0.5-5 microM) were unable to initiate a current response in the absence of external calcium. High concentrations of thimerosal (50-100 microM) could initiate spikes without extracellular calcium. Thimerosal, at concentrations that failed to produce an independent effect, potentiated the acetylcholine-evoked oscillations in [Ca2+]i. We conclude that thimerosal is able to mobilise calcium from an intracellular store; the blockade by heparin may indicate that thimerosal exerts an action on the inositol trisphosphate pathway. The dependence on extracellular calcium for initiation, but not for continuation of the thimerosal-induced calcium spikes suggests that thimerosal may have the additional effect of inhibiting the plasma membrane calcium ATPase.

Action Potentials↗

PubMed1992

Effect of the sulfhydryl reagent thimerosal on cytosolic free Ca2+ and membrane potential of thymocytes.

The sulfhydryl reagent thimerosal at concentrations 5-100 microM has been found to induce a variety of changes in ion transport in rat thymocytes. In particular, [Ca2+]i increases about 10-fold from the basal level. The [Ca2+]i response to thimerosal displays a two-stage time course, with the main [Ca2+]i rise during the second stage. Evidence has been obtained for the depletion of intracellular Ca2+ pools in thimerosal-treated cells, however, Ca2+ mobilization from intracellular stores does not contribute significantly into [Ca2+]i rise. Thimerosal elicits permeability not only for Ca2+, but also for Mn2+ and Ni2+, which is Ca(2+)-dependent. We failed to get any evidence on thimerosal-induced inhibition of the plasma membrane Ca(2+)-ATPase. The induction of Ca2+ influx, rather than inhibition of Ca(2+)-ATPase, accounts for the disturbance of [Ca2+]i homeostasis in thimerosal-treated cells. Thimerosal also elicits changes in monovalent ion fluxes resulting in marked depolarization. The latter seems unrelated to the changes in [Ca2+]i and is suggested to be mediated both by increased permeability for Na+ and a decreased one for K+. Thimerosal significantly stimulates AA release from thymocytes. Evidence has been presented that AA metabolite(s), probably, LO product(s), may mediate the changes in the transport of mono- and divalent cations elicited by the sulfhydryl reagent. Prolonged treatment of thymocytes with thimerosal resulted in cell death.

Animals↗

PubMed1992

Thimerosal blocks stimulated but not basal release of endothelium-derived relaxing factor (EDRF) in dog isolated coronary artery.

1. The effect of an acetly-coA lysolecithin acyltransferase inhibitor, thimerosal, on the release of endothelium-derived relaxing factor (EDRF) was examined in the greyhound isolated coronary artery. 2. Thimerosal (1-10 microM) relaxed fully, ring segments of coronary artery which were contracted with the thromboxane A2-mimetic, U46619 (30 nM). The response was endothelium-dependent, slow in both onset and time to reach maximum. The maximum relaxation to the highest concentration of thimerosal (10 microM) was maintained for 10-20 min before the tissue slowly regained active force (1-2 h) to the same or higher level as that prior to the addition of thimerosal. At this time the endothelium-dependent relaxation responses to acetylcholine (ACh), substance P (SP), bradykinin (BK) and the calcium ionophores, ionomycin and A23187 were abolished. The endothelium-dependent contractions to the nitric oxide synthase inhibitors, NG-nitro-L-arginine (L-NNA; 10-100 microM) and NG-monomethyl-L-arginine (L-NMMA: 10-100 microM), however, were unaffected. 3. Thimerosal (10 microM) did not affect the relaxation curve to sodium nitroprusside (SNP) nor the contraction curve to the thromboxane A2-mimetic, U46619. 4. Both the relaxation response to thimerosal and the selective block of the relaxation responses to stimulated EDRF release were unaffected by either indomethacin (10 microM) or superoxide dismutase (150 u ml-1). 5. L-NNA (100 microM) significantly blocked the relaxation curves to thimerosal and A23187 but not that to SNP.6. Abolition of stimulated EDRF-mediated responses with thimerosal was unlikely to result from maximal and maintained stimulation of EDRF release even when active U46619-induced force had returned to pre-thimerosal levels, since the relaxation curves to glyceryl trinitrate (GTN) and SNP were markedly attenuated in the presence of SNP and GTN respectively when active force was restored with endothelin-1 (ET-1).7. Melittin (1 microM), ionomycin (1 microM) and A23187 (1 microM) each had selective effects on stimulated but not basal EDRF responses, similar to those of thimerosal.8. We propose that stimulated but not 'basal' release of EDRF is dependent on the release of arachidonic acid or one of its non-cyclo-oxygenase metabolites, possibly by Ca2'-dependent activation of phospholipase A2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

The endothelium-dependent effects of thimerosal on mouse pial arterioles in vivo: evidence for control of microvascular events by EDRF as well as prostaglandins.

Thimerosal causes synthesis and/or release of both endothelium-derived relaxing factor (EDRF) and prostaglandins from conductance vessels in vitro. We tested its effects and mechanism of action on mouse pial arterioles in vivo using intravital microscopic techniques. Topical thimerosal dilated pial arterioles. This effect was eliminated by endothelial injury produced by a laser/Evans blue technique. Dilation was also eliminated by topical L-NMMA, a reported inhibitor of EDRF synthesis. Topical thimerosal also reduced the incidence of platelet adhesion/aggregation ("capture") at a site of minimal endothelial damage. This effect was eliminated by L-NMMA pretreatment. The ability of thimerosal to dilate arterioles was eliminated not only by treatments thought to eliminate synthesis/release of EDRF, but also by cyclooxygenase inhibitors. However, inhibition of platelet adhesion/aggregation was not affected by cyclooxygenase inhibition. Thimerosal significantly increased production of prostaglandin E2 recovered from a closed cranial window. We conclude that the dilating effects of thimerosal on diameter require two endothelium-derived agents: EDRF and one or more prostaglandins acting in concert. However, the inhibiting effect of thimerosal on local platelet adhesion/aggregation appears to be caused only by an increase in EDRF at the injured site.

6-Ketoprostaglandin F1 alpha↗

PubMed1979

Human platelet aggregation by thimerosal. Functional and ultrastructural studies.

Thimerosal, a sulfhydryl group inhibitor, produces in an aggregometer a decrease in optical density of normal platelet-rich plasma over a wide range of concentrations. Ultrastructural study shows that the decrease of optical density produced by thimerosal at low doses is due to a true platelet aggregation preceded by a release reaction, whereas the aggregometric curves recorded after addition of thimerosal at high doses can be attributed to marked alterations of platelet morphology. Electron microscopic study shows the presence of electron-dense material between plasma membranes after addition of a low dose, and the early rupture of membranes after a high dose. These findings support previous conclusions that thimerosal binds to plasma membranes. Thimerosal induces a release reaction, seen in ultrastructural study and revealed by measurement of 14C-serotonin release. Moreover, thimerosal-induced aggregation is independent of released ADP and of formation of intermediates of the arachidonate pathway. Thimerosal-induced platelet aggregation is inhibited neither by ADP removal nor by aspirin addition.

Adenosine Diphosphate↗

PubMed1977

Effect of the ophthalmic preservative thimerosal on rabbit and human corneal endothelium.

Widespread use of the mercurial-containing preservative thimerosal as an antibacterial agent in ophthalmic drugs and solutions warranted an investigation into its possible cytotoxic effects on the functional and ultrastructural integrity of the corneal endothelium. No changes in corneal thickness were observed during 5 hours' perfusion of the endothelium of rabbit and human corneas with 0.0001 and 0.0005 percent thimerosal in glutathione bicarbonate Ringer's solution (GBR). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) of the endothelium of the 0.0001 percent group revealed normal ultrastructure. SEM and TEM of the endothelium of corneas perfused with 0.0005 percent thimerosal for 5 hours revealed condensed mitochondria, cytoplasmic vacuoles, and cytoplasmic flaps at the apical end of the cellular junctions. Perfusion of higher concentrations (0.001 and 0.005 perecnt) of thimerosal in GBR resulted in increases in corneal thickness after 2 hours and irreversible ultrastructural damage to the endothelial cells by 5 hours. Corneas perfused with 0.01 and 0.1 percent thimerosal in GBR showed a rapid and immediate increase in corneal thickness and endothelial cell death and necrosis within 1 hour. It is postulated that the mercury in thimerosal becomes bound to the cell membrane protein sulfhydryl groups, causing an increase in cellular permeability; These results suggest that the prolonged exposure of the corneal endothelium to thimerosal in the accepted antimicrobial dosage of 0.005 to 0.001 percent may result in functional and structural damage to the endothelium.

Animals↗

PubMed1976

Platelet aggregation by thimerosal: role of ADP and SH groups.

Thimerosal, a sulphydryl inhibitor, induces aggregation of normal platelet rich plasma over a wide range of concentrations. Low doses induce a monophasic response preceded by a lag phase, high doses produce an immediate biphasic response. Thimerosal induces platelet aggregation through its binding by sulphydryl groups. Thimerosal induced aggregation is not mediated by ADP, it is not influenced by fibrinogen, von Willebrand factor, calcium, and magnesium ions of the medium. Thimerosal induced platelet aggregation is normal in patients affected by thrombocytopathia (defect of ADP release) but not in patients affected by Glanzmann's thrombasthenia. Mercaptopropionglycine, a substance which tends to preserve SH groups, inhibits platelet aggregation induced by thimerosal, thrombin, collagen, and ADP. A mechanism is proposed for thimerosal induced aggregation and the role of SH groups also in ADP, thrombin and collagen induced aggregation is indicated.

Adenosine Diphosphate↗

PubMed1992

Antibody to the inositol trisphosphate receptor blocks thimerosal-enhanced Ca(2+)-induced Ca2+ release and Ca2+ oscillations in hamster eggs.

The sulfhydryl reagent thimerosal enhanced the sensitivity of hamster eggs to injected inositol 1,4,5-trisphosphate (InsP3) or Ca2+ to generate regenerative Ca2+ release from intracellular pools. A monoclonal antibody (mAb) to the InsP3 receptor blocked both the InsP3-induced Ca2+ release (IICR) and Ca(2+)-induced Ca2+ release (CICR). The mAb also blocked Ca2+ oscillations induced by thimerosal. The results indicate that thimerosal enhances IICR sensitized by cytosolic Ca2+, but not CICR from InsP3-insensitive pools, and causes repetitive Ca2+ releases from InsP3-sensitive pools.

Animals↗

PubMed1975

Teratogenicities of ophthalmic drugs. II. Teratogenicities and tissue accumulation of thimerosal.

Under the conditions of this study, systemically or topically applied thimerosal was found to have no teratogenic effect even when given in concentrations approaching the 50% lethal dose of these compounds. A comparison of topical and subcutaneous administration of thimerosal to rabbits shows that a substantial concentration of mercury was present in blood and tissues of the treated animals and their offspring. Thimerosal was found to cross the blood-brain and placenta barriers.

Administration, Topical↗

PubMed1977

Quantitative high-pressure liquid chromatographic determination of thimerosal in pharmaceutical formulations.

A quantitative high-pressure liquid chromatographic method an anion-exchange resin column and an aqueous perchlorate solution as the mobile phase is employed for the determination of thimerosal in pharmaceutical formulations. With a liquid formulation containing large amounts of edetate disodium, calcium chloride is used for complexation to eliminate the interference from edetate disodium.

Chromatography, High Pressure Liquid↗

PubMed1978

Thimerosal determination by high-pressure liquid chromatography.

A sensitive and useful high-pressure liquid chromatographic method for the determination of intact thimerosal was developed. This method is extremely fast and reliable, and its inherent specificity makes it a breakthrough over other common wet chemical methods.

Chromatography, High Pressure Liquid↗

PubMed1992

Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate.

Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, has been well known to often induce photosensitive eruptions within a few days after its administration. It has been reported that this photosensitivity correlates well with a positive patch-test reaction to thimerosal (TMS) and also to thiosalicylate (TOS), which is an active hapten of TMS. But it has not yet been concluded whether this correlation is caused by a cross-reaction among the drugs or not. In our experiments, animals contact-sensitized with TMS or TOS developed positive photopatch-test reactions to PXM, and those photocontact-sensitized with PXM had positive patch-test reactions to TMS and TOS. Photosensitive reactions were also induced by UVA irradiation (photo test) performed 90 min after perioral administration of PXM in the animals contact-sensitized with TMS or TOS. Analysis of the UVA-treated PXM by nuclear magnetic resonance spectrography and thin-layer chromatography revealed that the high dose of UVA induced photodecomposition of PXM, and generated several other chemicals different from PXM. But the PXM treated with the high dose of UVA could not induce positive patch-test reactions in many of the animals contact-sensitized with TMS or TOS. The cross-reacting hapten generated from PXM by UVA treatment may not be stable in the absence of carrier proteins. These results taken together indicate that the PXM photosensitivity in man is induced by contact-sensitization with TMS, as shown in our animal model, and then is photoallergic in nature. But the identity of the cross-reacting substance remains unknown.

Animals↗

PubMed1977