The action of sodium pump inhibitors on neuromuscular transmission.
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Biomedical subjects
Publications and source records attributed to M W Cohen.
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1. Experiments were performed to determine the relative contribution of the blood plasma and of the cerebrospinal fluid (c.s.f.) to the ionic environment of neurones and glial cells within the brain of the amphibian Necturus maculosus.2. The concentrations in the blood plasma of untreated control animals were 99 +/- 2 mM for Na(+) and 2.0 +/- 0.1 mM for K(+). In the c.s.f. the corresponding values were 112 +/- 2 mM-Na(+) and 1.9 +/- 0.1 mM-K(+).3. By keeping animals in K(+)-rich water it was possible to raise chronically the concentrations of K(+) in the blood plasma up to almost 5 times the normal value, close to 9 mM, while the c.s.f. concentration of K(+) was only doubled, to about 4 mM. This behaviour of Necturus, tending to keep the K(+) in the c.s.f. low, resembles that of mammals.4. The membrane potential of glial cells in the optic nerve can be used as an accurate indicator for determining the K(+) concentration in the intercellular spaces. Such determinations were made in vivo, and it was shown that the glial cells adjust their membrane potential to the changes of K(+) concentrations in the c.s.f. and not to those of the blood plasma. In contrast, the membrane potential of skeletal muscle fibres changes according to the K(+) concentration in the blood plasma.5. It is concluded that the cells within the optic nerve are surrounded by an ionic environment which corresponds to that of the c.s.f. and not to that of the blood plasma. The intercellular spaces are open and ions diffuse freely into them from the c.s.f. A homeostatic mechanism operates, keeping the ion concentrations around neurones and glia within a narrow range and relatively independent of large changes in the blood plasma. This may provide relative stability for the signalling system. Similarities between the optic nerve and other parts of the central nervous system in respect to their relation to c.s.f. and blood are discussed. It seems likely that the mechanisms which control the electrolyte concentrations are similar in Necturus and in mammals.
Serial determinations of serum lactic-acid dehydrogenase (LDH), phosphohexose isomerase (PHI), alkaline phosphatase (AP), and glutamic oxaloacetic transaminase (GOT) were carried out in 30 patients with primary and four with secondary neoplasms of the lung. Enzyme values were correlated with the stage of illness, with tumour histology, with chemotherapy and with the extent and site of metastases as determined at autopsy. The activity of the enzymes LDH and PHI was most frequently elevated; their values correlated closely. AP and GOT tended to become elevated only shortly before death. Although, in general, enzyme activity increased with tumour extension and often in relation to chemotherapy, assays provided little assistance in early diagnosis or prognosis except that, in most instances, elevated values of any of the four enzymes indicated the presence of metastases.
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Selenium (Se) is an essential nutritional factor that affects the development and expression of cell-mediated immune responses directed toward malignant cells. These studies have shown that dietary (2 ppm for 8 wk) or in in vitro (1 x 10(-7)M) supplementation with Se (as sodium selenite) results in a significant enhancement of the proliferative responses of spleen lymphocytes from C57Bl/6J mice in response to stimulation with mitogen or antigen. Se deficiency (0.02 ppm for 8 wk) had the opposite effect. The alterations in the ability of the cells to proliferate, which occurred in the absence of changes in the endogenous levels of interleukin-2 (Il2) or interleukin 1, were apparently related to the ability of Se to alter the kinetics of expression of high-affinity Il2 receptors on the surface of activated lymphocytes. This resulted in an enhanced or delayed clonal expansion of the cells, and in an increased or decreased frequency of cytotoxic cells within a given cell population. The changes in tumor cytotoxicity were paralleled by changes in the amounts of lymphotoxin produced by the activated cells. Dietary Se modulations had a comparable effect on macrophage-mediated tumor cytodestruction. The results also suggested that Se exerts its effect 8-24 h after stimulation, and that it most likely affects processes in the cytoplasmic and/or nuclear compartments of activated lymphocytes.
Selenium (Se) is an essential nutritional factor that was shown by us to alter the expression of the high affinity interleukin 2 receptor (Il2-R) and its subunits, cell proliferation, and clonal expansion of cytotoxic T-lymphocytes in mice. This study shows that dietary supplementation of Se-replete humans with 200 micrograms/d of sodium selenite for 8 wk, or in vitro supplementation with 1 x 10(-7) M Se (as sodium selenite), result in a significant augmentation of the ability of peripheral blood lymphocytes to respond to stimulation with 1 microgram/mL of phytohemagglutinin or alloantigen (mixed lymphocyte reaction) and to express high affinity Il2-R on their surface. There was a clear correlation between supplementation with Se and enhanced 3H-thymidine incorporation into nuclear DNA, preceded by enhanced expression of high affinity Il2-R. Supplementation with Se can apparently modulate T-lymphocyte mediated immune responses in humans that depend on signals generated by the interaction of interleukin 2 with Il2-R.
This study examined the effect of dietary (200 micrograms/d for 8 wk) supplementation with selenium (as sodium selenite) on the ability of human peripheral blood lymphocytes to respond to stimulation with alloantigen, develop into cytotoxic lymphocytes, and to destroy tumor cells, and on the activity of natural killer cells. The participants in the study were randomized for age, sex, weight, height, and nutritional habits and given selenite or placebo tablets; all participants had a selenium replete status as indicated by their plasma Se levels prior to supplementation. The data indicated that the supplementation regimen resulted in 118% increase in cytotoxic lymphocyte-mediated tumor cytotoxicity and 82.3% increase in natural killer cell activity as compared to baseline values. This apparently was related to the ability of the nutrient to enhance the expression of receptors for the growth regulatory lymphokine interleukin-2, and consequently, the rate of cell proliferation and differentiation into cytotoxic cells. The supplementation regimen did not produce significant changes in the plasma Se levels of the participants. The results indicated that the immunoenhancing effects of selenium in humans require supplementation above the replete levels produced by normal dietary intake.