Remarks on Concentration-Effect Relationship

The veratridine concentrations employed in the various studies differ widely. Some such differences can be explained by the different temperatures at which the experiments are performed since the effects are much reduced in the cold (see Sect. 6). The alkaloid action also depends on pH, with, as mentioned above, more alkaline values increasing the effect. Another modulator may be the Ca + concentration, whose increase shifts the relationship between the permeability of modified channels and membrane potential to more positive potentials and leads to a reduced effect over a wider potential range (see Ulbricht 1969a, Fig. 31). This paper also discusses earlier hypotheses of a more direct veratridine-calcium interaction. More recently a direct competition between Ca and veratridine has been postulated from Na uptake studies, as mentioned above (Cat-terall 1975a). For frog muscle the apparent Kd of such veratridine-en-hanced uptake is reported to decrease considerably when the membrane is depolarized by doubling [K ]o from 2.5 to 5 mM (McKinney and Ratzlaff 1987). 

Clearly larger values stem from flux measurements on N18 neuroblastoma cells (Kd=80 pM Catterall 1975a) and various other cell lines with apparent Kd values higher than 100 pM, attributed to higher Ca + concentrations than employed in other experiments (Stallcup 1977). 

Dose-response curves from Na+ currents are hard to determine since saturation seems to require damagingly high concentrations. However, if one assumes a one-to-one stoichiometry one can attempt to fit the equilibrium results at lower concentrations. Thus in frog nerve fibers the relative stationary permeability in 1.5,4.5,15, and 45 pM veratridine is 1,2.5,4.0, and 4.9, which can be reasonably fitted with Kd=5 pM (at pH 8.1 Ulbricht 1972b). At pH 7.2 the average Kd derived from tail currents is 7.9 pM 

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