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Lithium's inhibition of erythrocyte cation countertransport involves a slow process in the erythrocyte
Insights
Chronic lithium administration slows erythrocyte Li+/Na+ countertransport. This inhibition develops gradually within red blood cells (RBCs), indicating a slow intracellular process rather than immediate membrane effects.
Area of Science:
- Physiology
- Biochemistry
- Pharmacology
Background:
- Chronic lithium (Li+) administration in humans reduces Li+/Na+ countertransport in erythrocytes (RBCs).
- The slow development of this inhibition suggests it's not an immediate effect on the RBC membrane.
Purpose of the Study:
- To investigate the underlying mechanisms responsible for the slow inhibition of Li+/Na+ countertransport by lithium in human RBCs.
- To differentiate between pharmacokinetic delays, humoral factors, and intrinsic RBC processes.
Main Methods:
- Human RBCs were incubated in sterile culture for extended periods (up to two weeks) using a method allowing prolonged viability.
- Incubated RBCs were treated with 2 mM Li+, and Li+/Na+ countertransport inhibition was measured along with other viability parameters.
- The time course of inhibition, reversibility, and effect of Li+ entry point (inside vs. outside) were assessed.
Main Results:
- Incubated RBCs remained viable for two weeks with minor intracellular changes.
- Treatment with 2 mM Li+ inhibited countertransport by 48% without affecting Li+ leak efflux.
- The inhibition developed slowly, reaching half-maximal effect after 1-2 days and maximal effect by 4-7 days, and was reversible.
Conclusions:
- The slow time course of Li+ inhibition of countertransport in vivo is only partly explained by pharmacokinetic delays.
- Lithium inhibits countertransport slowly and to a similar degree from both inside and outside the RBC.
- The findings strongly suggest an unidentified, slow intracellular process within the RBC is responsible for the delayed inhibition.
Abstract:
Chronic administration of lithium (Li+) to human subjects results in reduction of Li+/Na+ countertransport in their erythrocytes (RBC). The time course of development of inhibition is much slower than one would expect for an immediate effect of Li+ on the RBC membrane. Possible explanations include pharmacokinetic delays, a mediating humoral agent, and a slow process in the RBC. To discriminate among these possibilities, we incubated human RBC in sterile culture by the method of Freedman (Freedman, J.C. 1983. J. Membrane Biol. 75:225--231), which permits much longer incubations than other methods. As gauged by eight measures, the incubated RBC remain viable for two weeks. Small changes in intracellular concentrations with time during incubation are in the same direction as the changes associated with natural aging of RBC in vivo, except for a rise in ATP and related cation shifts during the first few days of incubation. Treatment of incubated RBC with 2 mM Li+ inhibits countertransport by 48% without affecting Li+ leak efflux. The inhibition develops slowly: it is half-maximal after 1--2 days and maximal by 4--7 days. Differences between in vivo results and our incubated cells in the time course of inhibition are as expected from the pharmacokinetic delays operating in vivo. The inhibition is reversible on removing Li+. Li+ inhibits countertransport similarly slowly and to a similar degree from inside the RBC and from outside. Hence the slow time course of inhibition in vivo is not due to a humoral factor or to the time required for intracellular Li+ accumulation and is only partly due to pharmacokinetic delays. The delay must involve an unidentified slow process at the level of the RBC.