After salt: ENaC in self‐sustaining hypertension

Abstract

BackgroundEvery year thousands of hypertensive patients reduce salt consumption in the efforts to control blood pressure. However, most of the studies report a cohort of patients who does not significantly respond to sodium restriction. Generally, most of the studies agreed that about one‐third of the patients had an excellent response, one‐third had only a modest response, and one‐third had little or no response. Irreversibility of high blood pressure is associated with various mechanisms underlying self‐sustaining character of hypertension. Unfortunately, hypertension causes multiple abnormalities in the body which stays even when the trigger, caused the initial blood pressure raise, is gone. We hypothesize that chronic hypertension leads to a significant renal damage and abnormally high sodium reabsorption.MethodsWe used Dahl salt‐sensitive rats for chronic continuous observation of blood pressure with radiotelemetry in conscious free moving animals. Rats were fed a 4% NaCl diet for 3 weeks to induce hypertension and then diet was switched back to normal (0.4% NaCl). Patch‐clamp analysis was performed on freshly isolated split‐open cortical collecting ducts and CHO cells to characterize activity of the epithelial sodium channel (ENaC), responsible for the sodium reabsorption in the aldosterone‐sensitive distal nephron.ResultsWe found that 4% sodium diet significantly increases blood pressure within 3 weeks (from 111±0.9 to 138±3.5 mmHg) and switching back to 0.4% NaCl diet slightly reduces blood pressure (to 133.6±7.6). Patch clamp analysis reveals that development of hypertension was accompanied with elevated ENaC activity which also stayed high (NPo=1.22±0.23, n=8) after the salt challenge. Subsequent blockage of ENaC with a selective inhibitor, benzamil, caused a dramatic drop in blood pressure indicating that ENaC activity contributes to maintain sustaining hypertension in absence of the high salt consumption. We also found significant renal damage caused by hypertension. As earlier studies report that inflammation and reactive oxygen species production are involved in improper renal function and setting high blood pressure, we performed a subset of whole‐cell patch clamp experiments on CHO cells overexpressing mENaC to study effect of hydrogen peroxide on ENaC activity. We found that treatment with 100μM H2O2 within a few seconds to 2 minutes stimulated the ENaC current of the cells (−144±12 pA/pF vs −190±22 pA/pF before and after treatment respectively, n=8, p=0.0078).Based on our earlier publications and the current data we conclude that ENaC activity contributes to both development of salt‐sensitive hypertension and its continuation in the absence of high salt challenge and reactive oxygen species production can keep ENaC active.Support or Funding InformationAcknowledgementASN Carl W. Gottschalk award; R00 HL116603