Slow inactivation and blockade of sodium channels of excitable membranes by chemical compounds
Khodorov, B.I.
Patologicheskaia Fiziologiia i Eksperimental'naia Terapiia 4: 24-30
1992
ISSN/ISBN: 0031-2991 PMID: 1338921 Document Number: 391472
Inactivation of sodium channels during membrane depolarization is accompanied by a dramatic increase in the affinity or accessibility of the channel receptors to local anesthetics (LAs) and related drugs, including a number of antiarrhythmics and anticonvulsants. When bound to inactivated Na channels this drugs induced channels transition to a new slowly reactive state conventionally called as a state of "drug-induced slow inactivation" (DSI). This leads to deepening of the LAs-induced tonic block and to a development of the phasic, "use dependent" block (UDB) during repetitive membrane stimulation. The UDB caused by drugs interacting preferentially with inactivated Na channels (UDB-1) differs from the UDB caused by open-channel blockers (UDB-II) by a number of properties: 1) it depends not only on a frequency of membrane stimulation but also on pulse duration; 2) it can be attenuated by raising the external Ca concentration and practically fully abolished by chemicals eliminating fast Na inactivation (e. g. chloramine T); 3) UDB-I, in contrast to UDB-II, cannot be enhanced by a strong membrane depolarization. In many respects DSI is similar to the normal slow Na inactivation (SI) developing in untreated membrane during 1-3-s membrane depolarization. A detailed comparative analysis of this two processes suggests that DSI results from modulation of the physiological SI. The molecular mechanism of interaction of drugs with inactivated Na channels remains to be solved. We believe that transition of the Na channels to the inactivated conformation leads to exposure of a high affinity "receptor" for LAs (and related drugs) located at the protein: lipid interface of the channel wall.