Barchfeld G L, Deamer D W
Biochim Biophys Acta. 1985 Oct 10;819(2):161-9. doi: 10.1016/0005-2736(85)90170-1.
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.
全身麻醉的泵 - 漏假说提出，麻醉剂通过增加膜（特别是突触小泡膜）的功能性质子通透性来发挥作用。由于神经递质积累需要跨膜质子梯度，未补偿的麻醉剂诱导的渗漏导致这种梯度衰减，会致使神经递质从囊泡中丢失，随后出现突触阻滞和麻醉。我们通过测定四种不同全身麻醉剂对脂质体膜对质子和钾离子的相对通透性的影响来检验这一假说。在所有情况下，生理相关水平的麻醉剂都会使离子通透性增加200%至500%。对质子没有明显的偏好，这表明麻醉剂不会诱导针对这种离子种类的特异性渗漏。相反，麻醉剂似乎产生了一种对质子和钾离子都适用的更普遍的缺陷，从而导致质子通透性功能性增加。将这些观察结果与突触小泡ATP酶的质子转运速率的现有数据进行了比较。麻醉剂诱导的渗漏幅度无法被ATP酶补偿，ATP酶在解偶联时速率仅能增加40%。我们认为这些结果与泵 - 漏假说一致。
