Relationship Between The Quantum Effects Of Hydroxide Ions And The Mechanism Of Inhaled Anesthetics

ObjectiveGeneral anesthesia plays an important role in modern medicine,millions of surgical procedures and invasive examinations are performed under general anesthesia every year.Consciousness is nature’s greatest mystery and is difficult to study because consciousness is difficult to define and measure.General anesthesia is a drug-induced reversible state of unconsciousness that is considered the flip side of consciousness.Therefore,general anesthesia is shown as a path to an experimental approach to consciousness.Currently the widely accepted protein theory holds those inhaled anesthetics act on the hydrophobic pockets within the target proteins.However,the mere presence of inhaled anesthetics molecules in the hydrophobic pockets of the protein presents an insurmountable problem.Protein pockets are usually highly selective for ligand shape and size,but inhaled anesthetics have various shape and size.Therefore,fitting inhaled anesthetics with highly diverse chemical structures into structurally selective pockets is thus problematic.Apparently,components that bridge inhaled anesthetics and protein pockets should be needed.Because from fundemental level,everything obeys the laws of quantum mechanics,and quantum processing can eliminate the differences between the chemical structures of inhalation anesthetics,providing a quantum processing mechanism for unifying disparate inhaled anesthetics into a common anesthetic effect.In fact,the assumption that consciousnessproducing elements must have a nuclear spin of 1/2 has been proposed based on the fact that singlet states formed by nuclear spin 1/2 can last for a long time and are immune to the electric fields generated by neurons in the brain.Experiments on the isotope dependence of xenon anesthesia indirectly confirm this hypothesis,the 129Xe with nuclear spin 1/2 is less potent than the xenon isotope with zero nuclear spin,which strongly indicates the quantum processing effect.How does nuclear spin participate in the effects of xenon anesthesia,and can quantum processing extend from xenon to all inhaled anesthetics?If there is a component in the brain that explains neural excitability through quantum processing of nuclear spins,then these questions are answered,because inhaled anesthetics inhibit neuronal excitability by explicitly reducing this component and thereby produce general anesthesia.Therefore,the candidate component must have three properties—crucial importance in all living organisms,nuclear spin or total nuclear spin of 1/2,and a size small enough to exert quantum effects.Phosphorus and hydrogen are the only two light elements in biology with a nuclear spin of 1/2,and phosphorus has been experimentally ruled out,leaving only hydrogen as the only candidate.In living systems,most hydrogen exists in water molecules,the importance of liquid water for the existence of life on Earth is undeniable.The dissociation reaction of water,2H2O→H3O++OH-,produces a pair of hydronium ions(H3O+)and hydroxide(OH-)ions,both of which have a total nuclear spin of 1/2,are both small enough to exert quantum effects,and both are involved in biochemical effects.The purpose of this study was to investigate whether the mechanism of inhaled anesthetic drugs is related to the quantum effect of hydroxide ions.Methods and ResultsPart 1.Effects of acids and bases on anesthetic potency of sevofluraneMethods:Sixty C57BL/6 mice were randomly divided into six groups:normal saline group,ammonium chloride group,sodium acetate group,ammonium acetate group,heparin sodium group and xanthohumol group,with 10 mice in each group.First,the basal median effective dose(ED50)value of sevoflurane-induced loss of righting reflex in mice was measured,and then the mice underwent intracerebroventricular cannulation.After 1 day of recovery,each group was injected with 2 μl of normal saline,1 mmol/L ammonium chloride,1 mmol/L sodium acetate,1 mmol/L ammonium acetate,62.5 U/ml heparin sodium or 74μmol/L xanthohumol through the catheter,and then the ED50 values of sevoflurane-induced loss of righting reflex in mice were immediately measured.Results:The effects of normal saline(1.04 ± 0.15%vs 1.02 ± 0.19%,P>0.05)and ammonium acetate(1.02 ± 0.13%vs 1.02 ± 0.12%,P>0.05)on the ED50 values of sevoflurane-induced loss of righting reflex were not statistically significant,two acids ammonium chloride(1.03 ± 0.11%vs 0.82 ± 0.12%,P<0.001)and heparin sodium(1.12± 0.11%vs 0.85 ± 0.11%,P<0.001)reduced the ED50 values of sevoflurane-induced righting reflex,while the two alkalis sodium acetate(1.01 ± 0.13%vs 1.22 ± 0.15%,P<0.001)and xanthohumol(1.02 ± 0.20%vs 1.22 ± 0.16%,P<0.001)increased the ED50 values of sevoflurane-induced loss of righting reflex.Conclusions:Weak acids enhanced the anesthetic potency of sevoflurane,while weak base weakened the anesthetic potency of sevoflurane,that is,H+enhanced the anesthetic potency of sevoflurane,and OH-weakened the anesthetic potency of sevoflurane.Part 2.Effects of acids and bases on firing frequencies of neuronsMethods:Cortical neurons of C57BL/6 fetal mice at 18 days of gestational age were used as research objects.After 11-14 days of primary culture,patch clamp was used to investigate the effects of weak acids of 1 mmol/L ammonium chloride and 62.5 U/mL heparin sodium,and the weak bases of 1 mmol/L sodium acetate and 74 μmol/L xanthohumol on the excitability of cortical neurons in mice.The firing frequency of neurons before and after treatment were recorded.Results:Weak acids 1 mmol/L ammonium chloride(16.8 ± 3.7 vs 9.0 ± 3.3,P<0.01)and heparin sodium 62.5 U/mL(15.4 ± 3.9 vs 9.8 ± 4.9,P<0.001)reduced the firing frequencies of primary cultured mouse cortical neurons.Weak bases 1 mmol/L sodium acetate(12.9 ± 2.0 vs 15.0 ± 2.5,P<0.05)and 74μmol/L xanthohumol(14.0 ± 2.3 vs 18.3± 4.0,P<0.01)increased the firing frequency of primary cultured mouse cortical neurons.Conclusions:Weak acids reduced the firing frequencies of neurons,while weak bases increased the firing frequencies of neurons,that is,H+decreased the excitability of neurons,and OH-increased excitability of neurons.Part 3.Establishment of the multiple-water entanglement network model and the relationship between binding energy and potency of inhaled anestheticsMethods:The formation of multiple-water entanglement network and its ability to amplify pre-existing H3O+or OH-were illustrated using a one-dimensional Ising model.The binding energy of inert gas Ar,Kr,129Xe,131Xe and 134Xe with a water molecule were calculated using the QZVPP basis set at coupled-cluster singles and doubles with perturbative triple correction[CCSD(T)]at the def2-QZVPP level of theory using the ORCA suite of programs.The binding energy of conventional anesthesia(isoflurane,desflurane,sevoflurane and nitrous oxide)and 1-chloro-1,2,2-trifluorocyclobutane with a water molecule were calculated at density functional theory(DFT)and the B3LYP/def2-TZVPPD level of theory,which were implemented in Gaussian suite of programs.The minimum alveolar concentration(MAC)values of inhaled anesthesia were obtained from the same laboratory.According to Henry’s law,the MAC values was converted to the ED50 values of aqueous solution at 37℃.The logarithm of the above molecular binding energy and the logarithm of the ED50 value of aqueous solution at 37℃ were analyzed by linear regression.Results:1.Multiple-water entanglement network model was verified,which had a power to amplify one pre-existing hydronium or hydroxide ion to 250 ions at 10-2 s interval.2.The coefficient of determination R2 of the linear regression equation is 0.9880,indicating that the anesthetic potency of inhaled anesthetics is significantly related to its absolute binding energy.Conclusions:Multiple-water entanglement network can amplify H+and OH-,inhaled anesthetics produce anesthesia by attenuating the formation of multiple-water entanglement network.Part 4.The relationship between the quantum effect of hydroxide ions and common anesthesia phenomenaMethods:1.The binding energy of nonimmobilizers(He and Ne)with a water molecule were calculated using the QZVPP basis set at coupled-cluster singles and doubles with perturbative triple correction[CCSD(T)]at the def2-QZVPP level of theory using the ORCA suite of programs.The binding energy of nonimmobilizers(1,2dichloroperfluorocyclobutane and 2,3-dichlorooctafluorobutane),S-(+)-isoflurane and R(-)-isoflurane with a water molecule were calculated at DFT and the B3LYP/def2-TZVPPD level of theory,which were implemented in Gaussian suite of programs.The binding energy of the nonimmobilizers obtained through the above calculation were substituted into the linear regression equation obtained in the part 3 respectively to obtain the ED50 values of the aqueous solution at 37℃.Finally,the MAC values predicted by the nonimmobilizers were obtained through transformation.2.Three bottles of deoxygenated 129Xe,131Xe and 134Xe aqueous solutions were prepared,and four samples of each isotope were prepared.The values of T1 in 129Xe,131Xe and 134Xe aqueous solutions were measured by MRI.Results:1.The predicted MAC values of non-braking agents He,Ne,F6 and F8 were 81143 atm,6 382atm,31 436 atm and 4 210 atm respectively.2.The binding energies ofS-(+)-isoflurane and R-(-)-isoflurane are the same,both of which are-6.01 kcal/mol.3.The T1 ratio of 129Xe,131Xe and 134Xe was quantitatively consistent with the ratio of LORR ED50.Conclusions:The MAC values of nonimmobilizers are too high to be anesthetic.The anesthetic potency of isoflurane is not stereoselective.The nuclear spin dependence of xenon anesthesia is due to the cross-relaxation of the nuclear spins of 129Xe and 131Xe themselves with the hydrogen nuclei in water,which reduces the T1 value of hydrogen in water.ConclusionsIn this study,it was found that OH-can bridge inhaled anesthetics and the hydrophobic pockets of proteins,while the multiple-water entanglement network has the effect of amplifying OH-,neuronal excitability is related to the OH-amplified by the entangled water network,and inhaled anesthetics produce anesthetic effects by inhibiting the formation of multiple-water entanglement.The present study also explained some phenomena that cannot be explained by current anesthesia theories,including nuclear spin dependence of xenon anesthesia,nonimmobilizers,stereoselectivity of anesthetics and pressure-reversal of anesthesia.