The paper by Bertil Hille explores the mechanisms by which local anesthetics affect sodium channels in myelinated nerve fibers. The study focuses on the effects of different types of anesthetics—neutral, amine, and quaternary—on sodium channel gating and block. Key findings include: 1. **Na Channel Properties**: Neutral, amine, and quaternary anesthetic compounds alter the properties of sodium channels in the node of Ranvier. The kinetics of sodium currents are influenced by voltage- and time-dependent gating processes, with drug-induced block also being voltage- and time-dependent. 2. **Inactivation Curves**: Conventional measurements using 50-ms prepulses show a significant negative shift in the inactivation curve for neutral benzocaine and some ionizable amines like lidocaine and tetracaine, but not for quaternary QX-572. However, when repetitive application of a prepulse-testpulse waveform is used, a shift is observed with quaternary cations applied internally. 3. **Hyperpolarization Effects**: 1-minute hyperpolarizations of fibers treated with lidocaine or tetracaine restore two to four times more channels to the conducting pool compared to 50-ms hyperpolarizations. Increasing the external Ca++ concentration also significantly unblocks channels. 4. **Drug Forms and Receptor Pathways**: Lipid-soluble drug forms likely interact with the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass through a hydrophilic region (the inner channel mouth). The hydrophilic pathway is only open when the channel gates are open, and any drug form in the channel increases the probability of closing the inactivation gate, effectively shifting the voltage dependence of inactivation negatively. 5. **Modeling the Receptor**: A modulated receptor model is proposed, where the receptor is sensitive to voltage and time-dependent changes in the channel's state. The receptor has both hydrophobic and hydrophilic pathways, with the hydrophobic pathway being accessible only when the channel gates are open. The hydrophilic pathway is always available but is only effective when the channel is in an inactivated state. 6. **Conclusion**: The differences in the actions of neutral, amine, and quaternary anesthetics are explained by the varying rates of on and off reactions at the receptor. The model suggests that the receptor is a single, specific site in the sodium channel that is affected by all local anesthetics, and the occupancy of this site is equated with channel block. The model also explains the observed shifts in inactivation curves and the cumulative effects of repetitive stimulation. This work provides a comprehensive understanding of how local anesthetics interact with sodium channels and contributes to the field of pharmacology and physiology.The paper by Bertil Hille explores the mechanisms by which local anesthetics affect sodium channels in myelinated nerve fibers. The study focuses on the effects of different types of anesthetics—neutral, amine, and quaternary—on sodium channel gating and block. Key findings include: 1. **Na Channel Properties**: Neutral, amine, and quaternary anesthetic compounds alter the properties of sodium channels in the node of Ranvier. The kinetics of sodium currents are influenced by voltage- and time-dependent gating processes, with drug-induced block also being voltage- and time-dependent. 2. **Inactivation Curves**: Conventional measurements using 50-ms prepulses show a significant negative shift in the inactivation curve for neutral benzocaine and some ionizable amines like lidocaine and tetracaine, but not for quaternary QX-572. However, when repetitive application of a prepulse-testpulse waveform is used, a shift is observed with quaternary cations applied internally. 3. **Hyperpolarization Effects**: 1-minute hyperpolarizations of fibers treated with lidocaine or tetracaine restore two to four times more channels to the conducting pool compared to 50-ms hyperpolarizations. Increasing the external Ca++ concentration also significantly unblocks channels. 4. **Drug Forms and Receptor Pathways**: Lipid-soluble drug forms likely interact with the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass through a hydrophilic region (the inner channel mouth). The hydrophilic pathway is only open when the channel gates are open, and any drug form in the channel increases the probability of closing the inactivation gate, effectively shifting the voltage dependence of inactivation negatively. 5. **Modeling the Receptor**: A modulated receptor model is proposed, where the receptor is sensitive to voltage and time-dependent changes in the channel's state. The receptor has both hydrophobic and hydrophilic pathways, with the hydrophobic pathway being accessible only when the channel gates are open. The hydrophilic pathway is always available but is only effective when the channel is in an inactivated state. 6. **Conclusion**: The differences in the actions of neutral, amine, and quaternary anesthetics are explained by the varying rates of on and off reactions at the receptor. The model suggests that the receptor is a single, specific site in the sodium channel that is affected by all local anesthetics, and the occupancy of this site is equated with channel block. The model also explains the observed shifts in inactivation curves and the cumulative effects of repetitive stimulation. This work provides a comprehensive understanding of how local anesthetics interact with sodium channels and contributes to the field of pharmacology and physiology.