Predictions of the EC50 for Action Potential Block for Aliphatic Solutes

Predictions of the EC50 for Action Potential Block for Aliphatic Solutes Experiments were conducted to test the hypothesis that aliphatic hydrocarbons bind to pockets/crevices of sodium (Na+) channels to cause action potential (AP) block. Aliphatic solutes exhibiting successively greater octanol/water partitition coefficients (K ow) were studied. Each solute blocked Na+ channels. The 50% effective concentration (EC50) to block APs could be mathematically predicted as a function of the solute’s properties. The solutes studied were methyl ethyl ketone (MEK), cyclohexanone, dichloromethane, chloroform and triethylamine (TriEA); the K ow increased from MEK to TriEA. APs were recorded from frog nerves, and test solutes were added to Ringer’s solution bathing the nerve. When combined with EC50s for solutes with log K ows < 0.29 obtained previously, the solute EC50s could be predicted as a function of the fractional molar volume (dV/dm = [dV/dn]/100), polarity (P) and the hydrogen bond acceptor basicity (β) by the following equation: $${\text{EC}}_{{50}} = 2.612{\left( {10^{{{\left\{ { - 2.117{\left[ {{\text{dv}}/{\text{dm}}} \right]} + 0.6424{\text{P}} + 2.628\beta } \right\}}}} } \right)}$$ Fluidity changes cannot explain the EC50s. Each of the solutes blocks Na+ channels with little or no change in kinetics. Na+ channel block explains much of the EC50 data. EC50s are produced by a combination of effects including ion channel block, fluidity changes and osmotically induced structural changes. As the solute log K ow increases to values near 1 or greater, Na+ channel block dominates in determining the EC50. The results are consistent with the hypothesis that the solutes bind to channel crevices to cause Na+ channel and AP block. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Predictions of the EC50 for Action Potential Block for Aliphatic Solutes

, Volume 221 (2) – Jan 16, 2008
13 pages

/lp/springer_journal/predictions-of-the-ec50-for-action-potential-block-for-aliphatic-EF0tW0UTi0
Publisher
Springer-Verlag
Subject
Life Sciences; Human Physiology ; Biochemistry, general
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-007-9087-z
Publisher site
See Article on Publisher Site

Abstract

Experiments were conducted to test the hypothesis that aliphatic hydrocarbons bind to pockets/crevices of sodium (Na+) channels to cause action potential (AP) block. Aliphatic solutes exhibiting successively greater octanol/water partitition coefficients (K ow) were studied. Each solute blocked Na+ channels. The 50% effective concentration (EC50) to block APs could be mathematically predicted as a function of the solute’s properties. The solutes studied were methyl ethyl ketone (MEK), cyclohexanone, dichloromethane, chloroform and triethylamine (TriEA); the K ow increased from MEK to TriEA. APs were recorded from frog nerves, and test solutes were added to Ringer’s solution bathing the nerve. When combined with EC50s for solutes with log K ows < 0.29 obtained previously, the solute EC50s could be predicted as a function of the fractional molar volume (dV/dm = [dV/dn]/100), polarity (P) and the hydrogen bond acceptor basicity (β) by the following equation: $${\text{EC}}_{{50}} = 2.612{\left( {10^{{{\left\{ { - 2.117{\left[ {{\text{dv}}/{\text{dm}}} \right]} + 0.6424{\text{P}} + 2.628\beta } \right\}}}} } \right)}$$ Fluidity changes cannot explain the EC50s. Each of the solutes blocks Na+ channels with little or no change in kinetics. Na+ channel block explains much of the EC50 data. EC50s are produced by a combination of effects including ion channel block, fluidity changes and osmotically induced structural changes. As the solute log K ow increases to values near 1 or greater, Na+ channel block dominates in determining the EC50. The results are consistent with the hypothesis that the solutes bind to channel crevices to cause Na+ channel and AP block.

Journal

The Journal of Membrane BiologySpringer Journals

Published: Jan 16, 2008

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