There is probably a heterogeneous etiology for essential hypertension (EHT)
, and abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is co
mmon 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 underst
anding of the mechanism of abnormal Na/Li CT would facilitate a clearer ide
ntification of-a subgroup of patients with a homogeneous biochemical abnorm
ality. Na/Li CT kinetics were determined in untreated erythrocytes and afte
r 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 kineti
c pattern was reproduced in normal erythrocytes by treatment with NEM in so
dium-free medium. The same treatment in EHT-FH erythrocytes caused a marked
ly abnormal effect with an increase in maximum velocity: indicating an incr
ease in transporter turnover in contrast to the increase in sodium affinity
seen in normal control erythrocytes. Frequency distributions of these kine
tic 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 subgrou
p of hypertensive patients may be a useful intermediate phenotype for a dis
ease 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 t
hiol protein involved may lead to a molecular explanation of the altered me
mbrane function in this subgroup of patients.