Simulation Research On Anesthetics Based On Uterine Smooth Muscle Cell Computational Model

Labor force is one of the important factors affecting the progress of labor.In the first labor process,labor force is mainly uterine contractility,while in the second labor process,labor force is mainly composed of contractility of uterine muscle,abdominal muscle and diaphragm.The labor force will make the parturient feel the labor pain during the delivery stage.The labor analgesia technology using local anesthetics can effectively alleviate this labor pain,but local anesthetics are also recognized as having a direct inhibitory effect on the contractility of the uterus.This inhibition will lead to maternal uterine weakness,thus prolonging the labor process,which may endanger the lives of mother and fetus.Therefore,when using anesthetics for labor analgesia,we need to consider both its positive analgesic effect and its negative concentration related inhibition of uterine contractility.Studies have confirmed that the generation of uterine contractility is the result of excitation-contraction coupling of uterine smooth muscle cells.Therefore,researchers need to deeply explore the action mechanism of drugs on ion channels in uterine smooth muscle cells,and how drugs of different concentrations affect the contraction of cells by blocking ion movement,so as to evaluate the safety and practicability of anesthetics,and develop anesthetics with less impact on uterine contractility.At present,due to ethical and moral problems,most of the samples for anesthetics research are animal cell tissues during pregnancy or isolated human cell tissues.Relying only on these samples is not enough to explore the mechanism of changes in cell ions and molecular motion during labor and the mechanism of action of anesthetics.However,the computational model of cell electrophysiology can make up for the defects in biological experiments to a certain extent.Therefore,in this paper,a computer-simulated uterine smooth muscle cell electrophysiological computational model was used to evaluate the effect of anesthetics.The research contents of this paper are as follows:（1）Effect of single ion channel blocking on cell electrophysiology.In this paper,we explored the effects of the change of single ion current on the action potential,calcium concentration and contractility of uterine smooth muscle cells by blocking the ion current in the standard model to varying degrees.The simulation result showed that blocking I_CaL during labor reduced the action potential repolarization frequency and action potential amplitude of the uterine smooth muscle cell,reduced the concentration of intracellular calcium ions,and reduced the contractile strength of cells.Blocking I_K（HERG）ion channel could increase the calcium concentration,while I_k2 mainly affected the frequency of cell action potential.Therefore,the above three ion currents are important ion currents that affect cell physiological activities.（2）A study of the effects of anesthetics blocked by multiple ion channels on single cell electrophysiology.This paper constructed drug models based on the single-cell standard model.Through the single-cell normal group model and drugs group models,we simulated and quantified the electrophysiological activity curves of cells,and explored the effects of anesthetics on the physiological activities of uterine smooth muscle cells and its mechanism.The simulation results showed that both bupivacaine and ropivacaine could affect the amplitude and frequency of action potential and cell contractility of uterine smooth muscle cells during labor.Increasing the drug concentration would further inhibit the intensity of contractility.Taking the early stage of labor as an example,at this stage,the amplitude of cell contractile force decreased by 44.68%,59.57%and 93.62%respectively under the action of three concentrations of bupivacaine,while ropivacaine only reduced the contractile force by 19.15%,49.94%and 89.36%respectively,which was less than that of bupivacaine with the same concentration.At the same concentration,the blocking effect of bupivacaine on I_CaL,I_KCNQ1,I_K（Ca）and I_K2 currents was greater than that of ropivacaine,and the blocking effect on I_K（HERG）current was obvious.Therefore,in general,bupivacaine has a greater impact on contractility,which is more likely to lead to maternal uterine weakness and affect the delivery process.（3）A study of the effects of anesthetics on electrophysiology of cell population.The simulation results based on single cell model could not characterize the effect of anesthetics in the population.Therefore,the normal group model population and drug group model population were used to explore the impact of drugs on the physiological activities of cell population.The simulation results showed that,similar to the simulation results of single cell model,bupivacaine and ropivacaine of three concentrations inhibited the electrophysiological activities of cell population in varying degrees during labor.Taking the early stage of labor as an example,the inhibitory degrees of low,medium and high concentrations of bupivacaine on cell contractility were 44.4%,69.4%and 91.7%respectively,while the inhibitory degrees of ropivacaine at the same concentration were 22.2%,50.0%and 86.1%respectively.The cell contractility was less affected by ropivacaine because the blocking effect of ropivacaine on the currents of I_CaL,I_K（HERG）,I_KCNQ1 and I_k2 was lower than that of bupivacaine.Therefore,ropivacaine has more advantages in labor analgesia and is more suitable for wide application in diverse biological populations.Researchers can take these four ion currents as targets to develop anesthetics specifically with less inhibition of uterine contraction.（4）Design and implementation of a simulation platform for risk grading assessment of anesthetics.In order to facilitate the exploration of the effects of other drugs on different cell models,we have developed a more universal anesthetics effects simulation evaluation platform to provide an auxiliary tool for researchers to develop new anesthetics or predict the effect of anesthetics.