Alterations in Membrane Physical
State
Further studies of the molecular changes occurring on the insertion
of anesthetic molecules into lipid membranes led to the suggestion that anesthetics
act by increasing the mobility of membrane components, a proposal called the fluidization
theory of anesthesia. The ability of an anesthetic to fluidize a lipid
bilayer depends on the agent examined, the composition of the lipid bilayer, and
the membrane position at which fluidity is measured.[117]
The incorporation of cholesterol[117]
or gangliosides
[123]
into neutral phospholipid membranes enhances
the membrane-disordering effects by a given partial pressure of inhaled anesthetic.
Inhaled anesthetics can produce a small decrease in the fluidity of palmitoyloleoylphosphatidylcholine
membranes near the head group region and increase fluidity in regions deep in the
membrane bilayer.[119]
The nonimmobilizers 1,2-dichlorohexafluorocyclobutane
and 2,3-dichlorooctafluorobutane (see Fig.
4-10
) do not fluidize membrane lipids.[119]
[124]
It has been suggested that even small changes in lipid fluidity
may profoundly change membrane function. Some investigators have speculated that
the increased decay rate of postsynaptic currents and accelerated decay rate of open
membrane channels (see Fig. 4-11
)
caused by inhaled agents may result from an increased fluidity of the postsynaptic
membrane, allowing a more rapid relaxation (i.e., return to the closed configuration)
of the proteins involved in the conductance change after activation. However, such
theories are compromised by the fact that small increases in temperature increase
membrane fluidity to approximately the same extent as clinical concentrations of
inhaled anesthetics and therefore should, but do not, augment anesthesia.
Other theories of anesthetic action on lipids include anesthetic-induced
alterations in membrane electrical properties or membrane pressures. Inhaled agents
(at about 1 MAC) can alter dipole potentials at a lipid membrane interface by approximately
10 mV, and it has been suggested that such changes in membrane potential could modulate
conformational transitions of membrane channel proteins.[125]
Insertion of inhaled anesthetics into a lipid bilayer is predicted to redistribute
lateral pressures in the membrane and promote a shift in the conformational equilibrium
of ion channels.[126]
