Thiol protein defect in sodium-lithium countertransport in subset of essential hypertension

There is probably a heterogeneous etiology for essential hypertension (EHT), and abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is common in a subgroup of patients with a strong family history of hypertension and cardiovascular disease (EHT-FH patients). The aim of this study was to test the hypothesis that altering a membrane thiol protein could mimic the abnormal Na/Li CT observed in the patients and that a more refined understanding of the mechanism of abnormal Na/Li CT would facilitate a clearer identification of-a subgroup of patients with a homogeneous biochemical abnormality. Na/Li CT kinetics were determined in untreated erythrocytes and after thiol group alkylation with N-ethylmaleimide (NEM). Compared with normal control erythrocytes, untreated erythrocytes from EHT-FH patients had a low K-m of Na/Li CT, with a high ratio of maximum velocity to K-m. This kinetic pattern was reproduced in normal erythrocytes by treatment with NEM in sodium-free medium. The same treatment in EHT-FH erythrocytes caused a markedly abnormal effect with an increase in maximum velocity: indicating an increase in transporter turnover in contrast to the increase in sodium affinity seen in normal control erythrocytes. Frequency distributions of these kinetic changes showed a subgroup of approximate to 75% of EHT-FH patients with abnormal kinetic changes with NEM. Therefore, the key Na/Li CT thiol group that is very reactive to NEM and causes the abnormal Na/Li CT in a subgroup of hypertensive patients may be a useful intermediate phenotype for a disease group within the syndrome of EHT. The single flux assay of Na/Li CT at 140 mmol/L sodium poorly discriminates this group. Identification of the thiol protein involved may lead to a molecular explanation of the altered membrane function in this subgroup of patients.