Reversal by Ranolazine of Doxorubicin-Induced Prolongation in the Inactivation of Late Sodium Current in Rat Dorsal Root Ganglion Neurons

The Evidence for Effective Inhibition of INa Produced by Mirogabalin ((1R,5S,6S)-6-(aminomethyl)-3-ethyl-bicyclo [3.2.0] hept-3-ene-6-acetic acid), a Known Blocker of CaV Channels

“…Under this experimental protocol, we were able to detect the emergence of an inward current (i.e., inward flux of cations) which displayed the rapidly activating and inactivating time course ( Figure 1 A). In response to a brief rectangular pulse, this type of transient inward current was sensitive to inhibition or stimulation by tetrodotoxin (TTX, 1 μM) or tefluthrin (Tef, 10 μM), respectively; it has hence been identified as a TTX-sensitive voltage-gated Na + current ( I Na ) [ 24 , 32 , 34 , 35 , 36 , 38 ]. It is of note that one minute after cells were exposed to MGB, the amplitude of peak I Na (or transient I Na , [ I Na(T) ]) progressively decreased in combination with a concomitant increase in the inactivation time course of the current.…”

“…However, under our experimental conditions, the voltage-activated inward currents shown herein were either sensitive to stimulation by Tef or subjected to inhibition by TTX and ranolazine. Tef and ranolazine have been reported to be activators or inhibitors of I Na , respectively [ 24 , 32 ]. In the continued presence of MGB, further addition of Tef could reverse its suppression of I Na(W) or I Na(R) .…”

“…When rapid depolarization is established, Na V channels readily go through rapid transitions from the closed (resting) state to the open state and then swiftly to the inactivated state. Genetic defects (i.e., gain-of-function) in Na V channel inactivation that led to small, sustained Na + currents ( I Na ) (i.e., late Na + current [ I Na(L) ]) following the occurrence of action potential firing are recognized to have devastating consequences, including neuropathic pain [ 21 , 22 , 23 , 24 ].…”

“…The Na V 1.7 and Na V 1.8 subtypes have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury [ 26 , 27 , 28 , 29 , 30 ]. Several activators or inhibitors have been increasingly reported to preferentially modify the late component of the voltage-gated Na + current (i.e., I Na(L) ) [ 24 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. However, to date, the issue of whether or how MGB could perturb the magnitude, kinetic gating, or hysteresis of membrane ionic currents (e.g., I Na ) is poorly characterized.…”

Midazolam’s Effects on Delayed-Rectifier K+ Current and Intermediate-Conductance Ca2+-Activated K+ Channel in Jurkat T-lymphocytes

“…For example, MDZ at a concentration of 30 µM progressively decreased the channel open probability by 85.7 ± 2.5 % from 0.147 ± 0.008 to 0.021 ± 0.002 (n = 12). Moreover, in continued presence of 30 µM MDZ, further addition of DCEBIO, an activator of IK Ca channels [29,31,41], was capable of reversing MDZ-induced reduction of IK Ca -channel activity, as evidenced by a significant elevation of channel open probability to 0.121 ± 0.006 (n = 10). Similar to the effect of MDZ, the addition of TRAM-34 (3 µM), a blocker of IK Ca channels [30,31], was effective at decreasing the probability of IK Ca -channel openings (data not shown).…”