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 approximately 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.
Mead
P
P
Department of Medicine (Nephrology), University of Newcastle-on-Tyne, Newcastle-on-Tyne, UK.
Wilkinson
R
R
Thomas
T H
TH
D000959:Antihypertensive Agents / Q000494:pharmacology; D017920:Antiporters / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005033:Ethylmaleimide / Q000494:pharmacology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects; D008094:Lithium / Q000097:blood*; D008297:Male; D012964:Sodium / Q000097:blood*; D013438:Sulfhydryl Compounds / Q000097:blood*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D000959:Antihypertensive Agents; D017920:Antiporters; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D014280:Triglycerides; C045885:sodium-lithium countertransporter; D002784:Cholesterol; D008094:Lithium; D012964:Sodium; D005033:Ethylmaleimide