Structure-Selective Anesthetic Action of Steroids

Abstract

Alphaxalone was a clinically used steroid anesthetic. Its analog delta 16-alphaxalone is nonanesthetic. The only difference between the two is the presence of a double bond at the hydrophobic end of the delta 16-alphaxalone molecule. This study determined the anesthetic potency of alphaxalone and delta 16-alphaxalone in goldfish and compared it with their effects on dipalmitoylphosphatidylcholine (DPPC) membranes and an alpha-helix polypeptide, poly(L-lysine). The goldfish EC50 values were: alphaxalone 5 mumol/L and delta 16-alphaxalone 80 mumol/L. Because these steroids are insoluble to water, the bulk of the steroid in water is absorbed by the fish. Larger containers hold more steroids than smaller containers at the same steroid concentrations. Then, EC50 values vary according to the size of the container. By assuming that the total amount of steroids in the container is distributed into the fish, the EC50 values expressed by the concentration in the fish body become 1.9 mmol/L for alphaxalone, and 30.5 mmol/L for delta 16-alphaxalone. A monoamino acid peptide, poly(L-lysine), can be formed into random-coil, alpha-helix, or beta-sheet. Addition of 0.07 mmol/L alphaxalone to the alpha-helix poly(L-lysine) partially transformed it to a beta-sheet structure. An equivalent change was observed with 3.0 mmol/L delta 16-alphaxalone. These values translate into 3.5 mmol/L for alphaxalone and 0.15 mol/L for delta 16-alphaxalone, when expressed by the concentration in the peptide. The change from alpha-helix to beta-sheet is accompanied by dehydration of the surface of poly(L-lysine). The steroids decreased the phase-transition temperature of DPPC membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of Muscle Nicotinic Acetylcholine Receptors by the Glucocorticoid Hydrocortisone

“…To define a burst, the critical closed time was set at 1 ms. been classically explained by two different mechanisms: (i) a nonspecific mechanism involving membrane perturbation; and (ii) a specific one in which the steroid binds to a protein site. The combination of both mechanisms is operative in some instances (6). Two lines of evidence suggest that HC interacts directly with the AChR protein: (i) the effects of HC on AChR expressed in two different membrane environments, i.e.…”

“…Specific effects of steroids on neuronal AChR have been reported (4,5). A wide range of steroids has been shown to have anesthetic potency (6). Work from our laboratory suggested the occurrence of sites for steroid-like molecules in the AChR microenvironment (see reviews by Barrantes (7,8)).…”

Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: The implication of molecular mechanisms of general anesthesia

“…The first successful public demonstration using ether to end surgical pain also marked the beginning of a painstaking search for the molecular understanding of this medical wonder. For more than a century, thinking has been directed to one of the two putative target sites: the lipid portion of neuronal membranes (1)(2)(3) or the hydrophobic pockets in certain crucial excitable proteins (4)(5)(6). The lipid theory postulates that general anesthetics cause a generalized perturbation to neuronal membranes through nonspecific interactions, whereas the protein theory contends that anesthetics must bind specifically to a set of appropriate molecular dimensions on the membrane proteins to produce the effect.…”

Biologically Structured Water (BSW) - A Review (Part 3): Structured Water (SW) Generation, BSW Water, Bioenergetics, Consciousness and Coherence

“…Medical anesthesia studies also reveal an association between BSW water, coherence, and consciousness. Three studies by Ueda et al [135][136][137] found that general anesthesia released non-freezable, or bound water, from membrane surfaces, i.e., the BSW interfacial water was separated from the membrane surfaces. Riveros-Perez and Riveros [138] and Bond [139] published medical reviews on the interactions of BSW interfacial water and anesthesia involving pain signaling or consciousness of pain.…”