A reduction in the extracellular concentration of potassium to 0.5 mM (low K) in Epstein-Barr (EB) virus-transformed lymphocytes caused changes in the number and activity of Na+/K+ pumps in the cell membrane, with increases in the Bmax and apparent Kd of ouabain binding, and concomitant increases in the Vmax and apparent Km of potassium (rubidium) influx. However, recovery from the effects of low K occurred more quickly than the original up-regulation. Furthermore, there were differences in the time-courses of the separate rates of recovery of the Bmax and Kd of ouabain binding after the cells were returned to normal K, the rate of recovery of the Kd being quicker than that of the Bmax, which was biphasic, with slow and fast rates of recovery. Inhibition of protein synthesis by emetine caused an increase in the rate of recovery of the Bmax of ouabain binding, but no effect on the Kd, suggesting that the slow phase of recovery of the Bmax is attributable to the synthesis and insertion of new protein, while the rapid phase of recovery is independent of protein synthesis and may represent internalization. The results suggested that during up-regulation of pump number in response to low K about 40% of the newly inserted Na+/K+ pumps are normal and the rest are abnormal. The half-time of removal of the abnormal pumps from the cell membrane during recovery from low K stress was 2.8 hr and the half-time of internalization of the normal pumps was 4.3 hr.

Cell Line, Transformed↗

PubMed1992

Potassium channels in nervous tissue.

There is a multiplicity of potassium channels in nervous tissue. These have been characterized on the basis of their electrophysiological actions but more information is required on their structures and on the functions of the different subtypes of channel in different parts of the nervous system. We currently also lack drugs which are specific in opening or closing individual subtypes of channel. However, when more is known about the structure and function of these channels and when more specific modulators of their activity are available, it is likely that the use of such compounds may be of great value in the treatment of a variety of conditions affecting the nervous system, including epilepsy, the damage due to cerebral anoxia, neurodegenerative disorders and demyelinating disorders.

4-Aminopyridine↗

PubMed1992

Penicillin.

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History, 16th Century↗

PubMed1992

Increase in Na+/K+ pump numbers in vivo in healthy volunteers taking oral lithium carbonate and further upregulation in response to lithium in vitro.

1. We have measured [3H]-ouabain binding to lymphocyte membranes in eight healthy volunteers before and after they had taken lithium carbonate for 14 days in doses which maintained the serum lithium concentration in the range 0.5-1.0 mmol 1-1. 2. There was a statistically significant increase in the [3H]-ouabain binding capacity of the lymphocyte membranes (reflecting the number of Na+, K+-ATPase molecules) after 14 days of lithium administration in vivo. This suggests that a failure to increase pump numbers after similar exposure to lithium in vivo in patients with manic-depressive psychosis is a primary abnormality associated with the disease. 3. In vivo lithium administration did not alter the normal adaptive (upregulatory) response of lymphocyte Na+, K+-ATPase to standard pharmacological challenges, involving in vitro incubation for 3 days with lithium chloride (8 mmol 1-1) or sodium ethacrynate (1 mumol 1-1). 4. We have previously found that there is an impaired response of the Na+, K+-ATPase to these in vitro stimuli in patients with manic-depressive psychosis, and our present data suggest that this abnormality is attributable to the disease itself and not to in vivo lithium therapy. 5. The data also suggest that the increase in vivo Na+/K+ pump activity which we have previously described in healthy volunteers after 21 days of lithium administration is at least partly due to an increase in Na+/K+ pump numbers.

Administration, Oral↗

PubMed1992

Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease.

5-Aminosalicylic acid (5ASA), 4ASA, their N-acetylated metabolites N-acetyl-5ASA and N-acetyl-4ASA, olsalazine, and colchicine impair interferon-gamma (IFN gamma) induced HLA-DR expression on a colonic cell line, HT-29. The mechanism of this effect is now reported. HT-29 cells were cultured with 50 U/ml IFN gamma with or without drug, and northern blot analysis was performed using a probe for the beta chain of the DR molecule. IFN gamma led to a noticeable increase in HLA-DR mRNA which was attenuated by the drugs. Analysis of the specific binding of increasing concentrations of 125I-IFN gamma by non-linear regression showed a Kd of 1.35 x 10(-10) M and 2.3 x 10(5) binding sites per HT-29 cell. Binding of 125I-IFN gamma was reduced by incubation with increasing concentrations of unlabelled IFN gamma but not with IFN alpha. Incubation with therapeutic concentrations of drugs led to the following reductions in binding: 10 mM 5ASA, 20% (p < 0.001); 10 mM N-acetyl-5ASA, 24% (p < 0.01); 10 mM 4ASA, 21% (p < 0.005); 10 mM N-acetyl-4ASA, 29% (p < 0.001); and 1 mM olsalazine, 29% (p < 0.001). Colchicine (10(-7) M) and 10(-5) M prednisolone had no effect. Incubation with higher concentrations of the drugs revealed a dose-response effect on binding with complete inhibition by 100 mM 4ASA and 10 mM olsalazine, and lesser degrees of inhibition by 100 mM 5ASA, N-acetyl-5ASA, and N-acetyl-4ASA. At concentrations found in the rectal lumen, the salicylates used in inflammatory bowel disease impair the binding of IFN gamma to its receptor on colonic epithelial cells.

Aminosalicylic Acid↗

PubMed1991

The effect of beta 2-adrenoceptor stimulation and blockade of L-type calcium channels on in vivo Na+/H+ antiporter activity in rat skeletal muscle.

We have studied the in vivo response of the Na+/H+ antiporter in skeletal muscle to beta 2-adrenoceptor stimulation with isoprenaline and the effect of blocking L-type calcium channels with nifedipine. Na+/H+ antiporter activity in skeletal muscle in vivo increased after beta 2-adrenoceptor stimulation with isoprenaline; nifedipine attenuated that effect. This suggests that opening of L-type calcium channels is necessary for full activation of the Na+/H+ antiporter in skeletal muscle. Bleeding also increased Na/H+ antiporter activity, which we believe could be explained by an increase in sympathetic nervous system activity as a result of hypotension. This may be one of the mechanisms by which animals under stress prepare their skeletal muscle for exercise as part of the 'fright and flight' reaction.

Adenosine Triphosphate↗

PubMed1991

Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport.

Lithium (1-8 mM) caused a dose-dependent increase in the number of [3H]ouabain binding sites and in sodium/potassium (Na/K) pump activity in normal lymphocytes after incubation for 72 h. The increase in Na/K pump activity was due to an increase in the Vmax of the pump, with no change in the apparent affinity (Km) for potassium (rubidium). There was no change in the turnover number of the pump and the intracellular sodium concentration fell. The increase in [3H]ouabain binding sites was prevented by the addition of myo-inositol (10 mM), by inhibition of the protein kinase C with staurosporine (100 nM) and by inhibition of the Na/H antiport with dimethylamiloride (50 microM). These results suggest that the increase in Na/K pump activity caused by lithium is due to an increase in pump numbers and not due to increased activity of individual pumps or to an alteration in the affinity of the pumps for potassium. The increase in Na/K pump numbers and activity in lymphocytes exposed to lithium for 72 h may be related to altered Na/H antiport activity secondary to inhibition of phosphoinositol breakdown by lithium.

Adult↗

PubMed1991

Antibiotics policies in the developing world.

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Anti-Bacterial Agents↗

PubMed1991

Altered in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase in patients with manic depressive psychosis.

When lymphocytes from healthy subjects are incubated in lithium (8 mM) or ethacrynate (1 microM) they show a time-dependent adaptive response, which consists of a significant increase in the number of Na+,K(+)-ATPase molecules in the lymphocyte membrane. We have studied the lymphocytes from nine euthymic drug-free patients with a history of manic depressive psychosis, and have found that this normal adaptive response was absent. It was also absent from the lymphocytes of euthymic patients taking lithium. We conclude that this altered in vitro adaptive response of lymphocyte Na+,K(+)-ATPase represents an enduring trait marker in manic depressive psychosis.

Bipolar Disorder↗