Sodium flux

Lithium salts are used in the treatment of bipolar affective disorder (i.e., manic depression) and occasionally in mania (but its slow onset of action is somewhat of a disadvantage in this case). Its mechanism of action is still open to debate, but lithium has effects on brain monoamines, on neuronal transmembrane sodium flux, and on cellular phosphatidylinositides related to second messenger systems. Lithium is administered in two salt forms, lithium carbonate (8.98) and lithium citrate (8.99). Side effects are common and include diarrhea, kidney failure, and drowsiness with tremor. 

A medium throughput approach to evaluating sodium channel activity is the measurement of sodium flux across cell membranes [103]. In these experiments, a tracer that permeates the channel and is easily quantifiable is used to analyze sodium influx. Traditionally, radioactive tracers such as 22Na+ or [14C]guanidinium have been used. Alternatively, Li+ can be used as a tracer and analyzed by atomic absorption spectrometry. Sodium flux assays can be used to test approximately 105 compounds per year. They offer a robust readout of channel activity, but lack voltage control and temporal resolution. To examine sodium channel blockade by measuring sodium flux,... 

Amino-6-nitrobenzothiazole as a sodium flux inhibitor (anticonvulsant activity) has been synthesized from nitroaniline via a one-pot procedure (Scheme 2.104) [587],... 

The effects of pumiliotoxin B on sodium channels appear to be due to interaction with a subdomain of the site at which batrachotoxin acts scorpion toxins and brevetoxin can potentiate the effects of pumiliotoxin B and of congeneric pumiliotoxins and allopumiliotoxins (102,112). Certain pumiliotoxin congeners appear to block sodium channel activation and may act as antagonists or reverse agonists (106). Structure-activity relationships with respect to stimulation of sodium flux and phosphoinositide breakdown have been studied (106). The nature of the side chain is critical to activity. For example, whereas pumiliotoxin B is one of the most potent of these alkaloids, its 15,16-erythro isomer has much lower activity (106,112). 

Amiloride has a specific effect on sodium flux in the renal tubules severe hyponatremia has been reported with the combination of a thiazide diuretic and amiloride. 

Hays, S.J., Rice, M.J., Ortwine, D.F., Johnson, G., Schwarz, R.D., Boyd, D.K., Copeland, L.F., Vartanian, M.G. and Boxer, P.A. (1994). Substituted 2-Benzothiazolamine as Sodium Flux Inhibitors Quantitative Structure-Activity Relationships and Anticonvulsant Activity. J.Pharm.ScL, 83,1425-1432. 

Hays SJ, Rice MJ, Ortwine DF, Johnson G, Schwarz RD, Boyd DK, et al. Substituted 2-benzothiazolamines as sodium flux inhibitors Quantitative structure-activity relationships and anticonvulsant activity. J Pharm Sci 1994 83 1425-32. 

Thermal Behavior of Anhydrite in Lithium and Sodium Fluxes... 

After reaching the upper temperature set limit, the temperature was held constant (isothermal hold) for several hours. The weight-loss curves (TG) are shown in Fig. 1. The weight losses recorded on lithium and sodium fluxes alone (Spec-troflux 100 and 200) caused by thermal decomposition above i000°C were negligible. Similar results were obtained with mixtures of anhydrite and sodium tetraborate. The latter showed a weight loss of less than 0.1% when heated at lOOO C for 1 h. 

Preparation of synaptosomes. Synaptosomes were prepared from the brains of male mice (20-30 g Blue Spruce Farms, Altamont, NY) either by a modification of the method of Hajos (8) or by the method of Dodd et al. (9). Both preparations gave qualitatively similar results, but the magnitude of all sodium fluxes per mg of synaptosomal protein was much greater with the latter preparation. A preparation enriched in synaptosomes was prepared from the brains of juvenile rainbow trout (Salmo gairdneri obtained from the New York State Fish Hatchery, Bath, NY) by homogenization in 14 volumes of 0.7 M sucrose, and centrifugation first at 2000 for 10 min and then at 31000 for 30 min. The pellet from the second centrifugation was resuspended in sodium-free buffer identical to that used in previous studies (7) except that it also contained 370 mM sucrose. 

Finally, it is possible that these techniques can be extended successfully to insect CNS preparations. Methods now exist to prepare functional insect synaptosomes from insect ganglia (1 ), and these preparations have been used to demonstrate veratridine-dependent neurotransmitter release and enhancement of this release by deltamethrin in a superfusion assay (2j)). Further refinement of these methods should allow direct measurement of sodium channel-mediated sodium fluxes in insect CNS preparations, thus allowing the investigation of target site differences not only between mammals and insects but also between susceptible and resistant insect strains. 

However, surface annealing caused by sodium flux is not entirely equivalent to activation at high temperatures. Undoped catalysts calcined at 850 °C still produce polymers of higher MI than alkali-doped catalysts activated at lower temperatures. This result may indicate that alkali-doped silica still retains a higher silanol population at maximum MI than undoped catalysts at maximum MI. Alternatively, perhaps the presence of alkali metal creates basicity on the surface, which can influence the chromium. Whatever the explanation, after activation at low temperatures, alkali metals do improve catalyst activity and polymer MI. 

Because the magnitude of cr depends on the degree of depolarization, the permeability increase is voltage-dependent. Also, when the inward sodium flux decreases and the membrane potential starts to return to resting conditions, the resultant shift causes the channel to close and the ion permeability... 

To the extent that sodium flux is increased, potassium flux may also be decreased. However, the drug has a substantially decreased effect on the blockade of outward potassium current, as compared to that of sodium. 

Toxins that bind to sodium channels and promote sodium flux. Examples of these include tetrodotoxin (puffer fish toxin), and scorpion venom. 

For example, to measure unidirectional sodium fluxes, Rojas and Canessa-Fischer [16] used the chamber diagrammatically shown in Fig. 2a. 

Sodium fluxes were computed by multiplying the measured flow of radioactivity in cpm/cmYs by the reciprocal of the specific activity of the solution measured in pmol, 10 M/cpm. Fig. 2b shows part of the time course of a typical sodium efflux experiment. Intracellular perfusion was begun with 600 mM KF after 13 min, this solution was replaced by 500 mM KF, 100 mM NaF and then, after 23 min, by a solution of the same composition, but with Na added. 

It is clear from this figure that the sodium influx again remained almost constant during the internal perfusion with a given sodium concentration. Table 1 summarises the data on resting sodium fluxes obtained by internal perfusion with different concentrations of sodium. As shown in Table 1 the resting sodium efflux is affected by the internal sodium concentration. There is an increase in sodium efflux from 0.1 pmol/cm s to 34 pmol/cm s as the internal sodium concentration is increased from 2 to 200 mM. To calculate resting values from the data in Table 1 we... 

Fig. 3 shows the results of measurements of the total inward tracer sodium flux (open circles) resulting from voltage-clamped depolarising pulses of about 3 ms duration as a function of the absolute membrane potential during the pulse. (Potential is referred to the external solution as ground. Flux is plotted upward but inwardly directed currents would be negative quantities.)... 

Fig. 3, Comparisons between the measured tracer sodium flux (O) and electrically measured ionic flux during the early transient current following a depolarising voltage-clamp pulse of about 3 ms duration ( ). Axons from Dosidicus gigas internally perfused with 550 mK KF, pH 7.3 immersed in K-frec artificial sea water. Temp. 17°C. Control experiments with tetrodotoxin were used (u.sing the same axon) to subtract current components due to potassium. (Used with permission from Atwater el al. [I7J.)...

The results of Fig. 3 are for the total flux per cycle. In order to compare the flux which occurs during the pulse, for different pulse durations it is necessary to subtract that component which occurs during the tail following the pulse. Control experiments demonstrate that this current is indeed sodium and for these experiments TEA was added to the internal perfusion fluid with the result that potassium channel currents were virtually eliminated. The filled circles of Fig. 4 are a plot of the measured inward sodium flux as measured with the radioactive Na ions minus the tail component as computed from the measured membrane current. The dotted line is the inward flux during the long pulse shown in part A of Fig. 4 as calculated from the current. 

It is possible to show that a positive electric field in the channel is sufficient to block the sodium flux. Thus, using the theory of rate processes [59] and assuming an... 

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