A new degradable DDT analog, 2,2-bis-(p-ethoxyphenyl)-3,3-dimethyloxetane, exhibits potent, specific actions on the sodium channel of lobster axons. It greatly prolongs the falling phase of action potential without affecting the resting potential. Under voltage clamp conditions, the sodium current is reduced in peak amplitude and slowed in the falling phase with an increased residual current during prolonged depolarization. The tall current associated with repolarization is markedly slowed. The effects of the drug on sodium channels were analyzed in terms of the Hodgkin-Huxley formulation. Both the steady-state sodium activation (m∞) and inactivation (h∞) curves are shifted in the direction of hyperpolarization. The time constant of sodium channel activation is not affected by the drug. The kinetics of sodium conductance turn-off upon repolarization is greatly slowed inducing protracted tail currents which exhibit 2 voltage-dependent phases with time constants on the order of 10 to 30 and 30 to 350 msec, respectively. The shift in the voltage dependence of sodium activation and inactivation processes may be attributed to a change in the intramembrane electric field as a result of the contribution of the drug to dipole potential. Partial failure of the sodium channel to undergo inactivation together with the long tail current suggests that channels affected by the drug are held in at least 2 open conformations not susceptible to sodium inactivation.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1980|
ASJC Scopus subject areas
- Molecular Medicine