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 (EC(50)) 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 EC(50)s for solutes with log K (ow)s < 0.29 obtained previously, the solute EC(50)s could be predicted as a function of the fractional molar volume (dV/dm = [dV/dn]/100), polarity (P) and the hydrogen bond acceptor basicity (beta) by the following equation: EC(50) = 2.612({-2.117[dv/dm]+0.6424P+2.628 beta}) Fluidity changes cannot explain the EC(50)s. Each of the solutes blocks Na(+) channels with little or no change in kinetics. Na(+) channel block explains much of the EC(50) data. EC(50)s 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 EC(50). The results are consistent with the hypothesis that the solutes bind to channel crevices to cause Na(+) channel and AP block.
Hahin
R
R
Biological Sciences Department, Northern Illinois University, DeKalb, IL, 60115, USA. hahin@niu.edu
Larsen
J
J
Gasser
K
K
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002074:Butanones / Q000633:toxicity; D002725:Chloroform / Q000633:toxicity; D003512:Cyclohexanones / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000633:toxicity; D008560:Membrane Fluidity / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000633:toxicity; D011894:Rana pipiens; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000633:toxicity*; D012997:Solvents
D002074:Butanones; D003512:Cyclohexanones; D005021:Ethylamines; D026941:Sodium Channel Blockers; D012997:Solvents; C036468:cyclohexanone; D011189:Potassium Chloride; C005222:methylethyl ketone; D002725:Chloroform; C016162:triethylamine