Anesthetics May Act by Collapsing pH Gradients

Abstract

This study was aimed at providing a possible, testable explantation for the state of deep unconsciousness that ensues in an animal when anesthetic molecules reach a concentration of 3-5 mol/100 mol of membrane lipid. Liposomes initially used as models for synaptic vesicles accumulated and retain catecholamines provided their interior aqueous compartment is more acid than the exterior. This is because bimolecular phospholipid membranes are very much more permeable to nonionized than to ionized solutes, including H+ and OH-. When a low intraliposomal pH is maintained, catecholamine bases remain charged and trapped. Anethetics (butanol, hexanol, chloroform and halothane) at activities (c/co, where c and co are the concentrations of the test and aqueous-saturated solutions, respectively) appropriate to general anesthesia (0.01-0.10) increase the proton permeability of liposomes, promoting the collapse of any pH gradient and indirectly facilitating the rapid outward permeation of the now uncharge, membrane-permeable transmitter substances. Synaptic vesicles from rat brain accumulate catecholamines is response to a pH gradient and anesthetics over a range of general and local concentrations release them. A mode of anesthetic action may be the release of catecholamines from synaptic storage vesicles, initially into the nerve terminal cytosol, leading to depressed neurotransmission, perhaps involving both inhibitory and excitatory pathways.