Local anesthetics and arrhythmic drugs induce both tonic and phasic blockade of voltage-dependent sodium channels in the neuronal membrane. The phasic blockade of molecular receptors depends on their previous activity and, thus, is qualified as use-dependent. Concentrations of the above-mentioned agents necessary for the induction of phasic blockade are one or two orders smaller than those necessary for the induction of tonic blockade. The molecular mechanisms underlying use-dependent blockade remain unstudied. We examined the effect of a novel analgesic, D57, a pyrrole imidazole derivative, on sodium channels in neurons of the rat sensory ganglia (the above blocker demonstrates the effects of both types). Concentrations providing 50% blocking of sodium currents in the resting state (tonic blocking) were 360 ± 18 and 420 ± 27 μM, while the Hill coefficients were 1.87 ± 0.09 and 1.41 ± 0.1 for tetrodotoxin-sensitive (ТТХ-S) and tetrodotoxin-resistant (TTX-R) sodium currents, respectively. Parameters of inactivation of the channels of both types changed significantly upon application of D57. For example, alterations of the voltage of half-inactivation (ΔV 0.5) in the presence of 250 μM D57 were −11.2 ± 0.4 and −16.7 ± 0.5 mV for ТТХ-S and TTX-R sodium currents, respectively. After approximation of the ΔV0.5 shifts in solutions containing different concentrations of D57 with the use of the modified Bean equation, we obtained a mean power equal to 2.2 ± 0.3. Analysis of the dependence of macroconstants of the blockade on the membrane potential and the frequency of stimulating impulses showed that, in the case of a shift of the potential from −120 to −80 mV, the constant of dissociation of D57 from channel molecules decreased 10 times, while the efficiency of the blockade of currents demonstrated only a 4.5-fold enhancement. An increase in the stimulation frequency from 0.5 to 3.3 sec−1 led to a 30-fold rise in the rate constant of the direct reaction (K on ), whereas the reverse reaction rate (K off ) increased 2.5 times. Analysis of the kinetics of the blockade using the Chernov model showed that a change in the stimulation frequency from 0.5 to 3.3 sec−1 led to an increase in the rate of association of the analgesic with sodium channels at the membrane potential of −120 mV, while dissociation at the potential of −80 mV was intensified two to three times. At the potentials of –80 mV and −120 mV, association and dissociation were accelerated 15–20 and 5–6 times, respectively. A probable molecular mechanism underlying phasic blockade is discussed. We hypothesize that phasic blockade is based on the formation of a planar structure under conditions of interaction of the corresponding aromatic groupings in the molecules of pharmacological agents with a certain phenyl residue of polypeptide chains of sodium channel α subunits (aromatic-aromatic interaction).
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Neirofiziologiya/Neurophysiology, Vol. 40, Nos. 5/6, pp. 389–398, September-December, 2008.
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Parkhomenko, N.T., Yatsenko, L.N., Limansky, Y.P. et al. Analysis of the Kinetics of Blockade of Tetrodotoxin-Sensitive and Tetrodotoxin-Resistant Sodium Channels Induced by an Analgesic, D57, in Neurons of the Rat Afferent Ganglia. Neurophysiology 40, 325–332 (2008). https://doi.org/10.1007/s11062-009-9056-5
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DOI: https://doi.org/10.1007/s11062-009-9056-5