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Exploring the mechanism of general anesthesia: kinetic analysis of GABAA receptor electrophysiology.

ABSTRACT: A kinetic model of the effect of agonist and anesthetics on ligand-gated ion channels, developed in earlier work, is further refined and used to predict traces observed in fast-perfusion electrophysiological studies on recombinant GABAA receptors under a wide range of agonist and/or anesthetic concentrations. The model incorporates only three conformational states (resting, open, and desensitized) but allows for the modulation of the conformational free energy landscape connecting these states resulting from adsorption of agonist and/or anesthetic to the bilayer in which the protein is embedded. The model is shown to reproduce the diverse and complex features of experimental traces remarkably well, including both anesthetic-induced and agonist-induced traces, as well as the modulation of agonist-induced traces by anesthetic, either coapplied or continuously present. The solutions to the kinetic equations, which give the time-dependence of each of the nine protein states (three ligation states for each of the three conformations), describe the flow of probability among these states and thus reveal the kinetic underpinnings of the traces. Many of the parameters in the model, such as the desorption rate constants of anesthetic and agonist, are directly related to model-independent experimental measurements and thus can serve as a definitive test of its validity.

SUBMITTER: Lee DK

PROVIDER: S-EPMC4375609 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Exploring the mechanism of general anesthesia: kinetic analysis of GABAA receptor electrophysiology.

Lee Daniel K DK Albershardt Daniel J DJ Cantor Robert S RS

Biophysical journal 20150301 5

A kinetic model of the effect of agonist and anesthetics on ligand-gated ion channels, developed in earlier work, is further refined and used to predict traces observed in fast-perfusion electrophysiological studies on recombinant GABAA receptors under a wide range of agonist and/or anesthetic concentrations. The model incorporates only three conformational states (resting, open, and desensitized) but allows for the modulation of the conformational free energy landscape connecting these states r ...[more]

PMID: 25762320

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Project description:General anesthesia has revolutionized healthcare over the past 200 years and continues to show advancements. However, many phenomena induced by general anesthetics including paradoxical excitation are still poorly understood. Voltage-gated sodium channels (Na V ) were believed to be one of the proteins targeted during general anesthesia. Based on electrophysiological measurements before and after propofol treatments of different concentrations, we mathematically modified the Hodgkin-Huxley sodium channel formulations and constructed a thalamocortical model to investigate the potential roles of Na V . The ion channels of individual neurons were modeled using the Hodgkin-Huxley type equations. The enhancement of propofol-induced GABAa current was simulated by increasing the maximal conductance and the time-constant of decay. Electroencephalogram (EEG) was evaluated as the post-synaptic potential from pyramidal (PY) cells. We found that a left shift in activation of Na V was induced primarily by a low concentration of propofol (0.3-10 μM), while a left shift in inactivation of Na V was induced by an increasing concentration (0.3-30 μM). Mathematical simulation indicated that a left shift of Na V activation produced a Hopf bifurcation, leading to cell oscillations. Left shift of Na V activation around a value of 5.5 mV in the thalamocortical models suppressed normal bursting of thalamocortical (TC) cells by triggering its chaotic oscillations. This led to irregular spiking of PY cells and an increased frequency in EEG readings. This observation suggests a mechanism leading to paradoxical excitation during general anesthesia. While a left shift in inactivation led to light hyperpolarization in individual cells, it inhibited the activity of the thalamocortical model after a certain depth of anesthesia. This finding implies that high doses of propofol inhibit the network partly by accelerating Na V toward inactivation. Additionally, this result explains why the application of sodium channel blockers decreases the requirement for general anesthetics. Our study provides an insight into the roles that Na V plays in the mechanism of general anesthesia. Since the activation and inactivation of Na V are structurally independent, it should be possible to avoid side effects by state-dependent binding to the Na V to achieve precision medicine in the future.

Project description:ObjectiveTo compare the effectiveness and safety of regional anesthesia (RA) and general anesthesia (GA) for percutaneous nephrolithotomy (PNL).Patients and methodsPubMed, EMBASE, The Cochrane Library, and the Web of Knowledge databases were systematically searched to identify relevant studies. After literature screening and data extraction, a meta-analysis was performed using the RevMan 5.3 software.ResultsEight randomized controlled trials (RCTs) and six non-randomized controlled trials (nRCTs) involving 2270 patients were included. Patients receiving RA were associated with shorter operative time (-6.22 min; 95%CI, -9.70 to -2.75; p = 0.0005), lower visual analgesic score on the first and third postoperative day (WMD, -2.62; 95%CI, -3.04 to -2.19; p < 0.00001 WMD, -0.38; 95%CI, -0.58 to -0.18; p = 0.0002), less analgesic requirements (WMD, -59.40 mg; 95%CI, -78.39 to -40.40; p<0.00001), shorter hospitalization (WMD, -0.36d; 95%CI, -0.66 to -0.05; p = 0.02), less blood transfusion (RR, 0.61; 95%CI, 0.41 to 0.93; p = 0.02), fewer modified Clavion-Dindo Grade II (RR, 0.56; 95%CI, 0.37 to 0.83; p = 0.005), Grade III or above postoperative complications (RR, 0.51; 95%CI, 0.33 to 0.77; p = 0.001), and potential benefits of less fever (RR, 0.79; 95%CI, 0.61 to 1.02; p = 0.07), nausea or vomiting (RR, 0.54; 95%CI, 0.20 to 1.46; p = 0.23), whereas more intraoperative hypotension (RR, 3.13; 95%CI, 1.76 to 5.59; p = 0.0001) when compared with patients receiving GA. When nRCTs were excluded, most of the results were stable but the significant differences were no longer detectable in blood transfusion, Grade II and more severe complications. No significant difference in the total postoperative complications and stone-free rate were found.ConclusionsCurrent evidence suggests that both RA and GA can provide safe and effective anesthesia for PNL in carefully evaluated and selected patients. Each anesthesia technique has its own advantages but some aspects still remain unclear and need to be explored in future studies.

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Exploring the mechanism of general anesthesia: kinetic analysis of GABAA receptor electrophysiology.

Publications

Exploring the mechanism of general anesthesia: kinetic analysis of GABAA receptor electrophysiology.

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