The effect of general anesthetics on the proton and potassium permeabilities of liposomes.

The pump-leak hypothesis of general anesthesia proposes that anesthetics act by increasing the functional proton permeability of membranes, particularly those of synaptic vesicles. Since transmembrane proton gradients are required for neurotransmitter accumulation, decay of such gradients by an uncompensated anesthetic-induced leak would result in loss of neurotransmitter from the vesicles, followed by synaptic block and anesthesia. We have tested this hypothesis by determining the effect of four different general anesthetics on the relative permeabilities of liposome membranes to protons and potassium ions. In all cases, physiologically relevant levels of anesthetics caused a 200 to 500 percent increment in ionic permeability. There was no marked preference for protons, suggesting that the anesthetics did not induce a leak specific for this ionic species. Instead the anesthetics appeared to produce a more general defect available to both protons and potassium ions which resulted in a functional increment in proton permeability. These observations were compared with available data on proton transport rates by synaptic vesicle ATPase enzymes. The magnitude of the anesthetic-induced leak could not be compensated by the ATPase, which is only capable of a 40 percent increase in rate when uncoupled. We consider these results to be consistent with the pump-leak hypothesis.