Anesthetics: molecular correlates of voltage- and frequency-dependent sodium channel block in nerve
Kendig, J.J.; Courtney, K.R.; Cohen, E.N.
Journal of Pharmacology and Experimental Therapeutics 210(3): 446-452
1979
ISSN/ISBN: 0022-3565 PMID: 314509 Document Number: 153457
Voltage clamp experiments were carried out in Rana catesbiana nodes of Ranvier to examine the relationship between anesthetic molecular properties and frequency-dependent Na channel block. Nodes were normally clamped at a holding potential of -80 mV. Maximum peak Na current (INa) was elicited by a sequence of a 50 ms hyperpolarizing prepulse to -125 mV, followed by a 7 ms depolarizing test pulse to -20 mV. Representatives of 3 anesthetic drug classes were examined, namely the local anesthetic benzocaine [BC], the volatile general anesthetic diethyl ether [DEE] and the barbiturate phenobarbital [PB] together with the related molecule phenytoin [PT]. At concentrations which depressed maximum peak INa 20-50%, Pb shifted the apparent voltage dependence of Na inactivation (h) very slightly, DEE by 10-15 mV and BC by 25-30 mV. At the normal holding potential the h-shift accounted for 5 to 10% of block by PB, 20% by DEE and 50% by BC. The h-shift induced by BC was identified with an apparent selective effect on removal of inactivation. A similar selective effect could not be confirmed for DEE. Frequency dependence was associated with Na channel block by PB and by PT, but not by BC or DEE. PB frequency dependence was enhanced by a decrease in pH, which increased the ratio of neutral to charged molecules. The results support a single mechanism to account for Na channel block by BC and DEE. The effect of pH on PB frequency dependence is difficult to accommodate within a current (modulated receptor) hypothesis proposed for local anesthetic frequency dependence.