Effect of ethacrynic acid on the sodium- and potassium-activated adenosine triphosphatase activity and expression in Old Order Amish bipolar individuals

Abstract: Background: There are numerous reports of abnormalities in the expression of the sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) in response to an ionic stress with ethacrynic acid (ECA) challenge in bipolar subjects. However, all of these studies have been in out-bred populations. In an attempt to reduce the genetic variability associated with this observation, we examined this phenomenon within an isolated breeding population. Methods: We studied 36 lymphoblastoid cell lines obtained from Old Order Amish individuals who had bipolar disorder, type I (16), or were unaffected siblings of the same gender (9) or unrelated normal controls(11). Cells were treated with10− 5 M ECA for 3days after which Na,K-ATPase alpha1 protein expression and activity ([3H]-ouabain binding, 86Rb-uptake, and intracellular sodium and potassium concentrations) were measured. Results: Cells from bipolar patients expressed less Na,K-ATPase as measured by immunoblot analysis after ECA treatment (0.94±SD 0.13 relative units) compared to unaffected siblings (1.06±0.12, P =0.029) and Old Order Amish normal controls (1.06±0.14, P =0.0004). None of the other variables studied were different. Limitations: This is a study of peripheral cells which do not express all of the Na,K-ATPase expressed in the brain. The observed difference is small. Conclusions: Ethacrynic-acid-stimulated lymphoblast sodium pump expression in Old Order Amish bipolar subjects is reduced compared to Amish controls. [Copyright &y& Elsevier]