Abstract P282: Low Dose LNAME Causes Salt Sensitive Hypertension via Activation of NCC

Abstract

Background: Blood pressure is regulated both by vascular resistance and blood volume. Our group recently clarified norepinephrine activates sodium channel (sodium chloride cotransporter: NCC) via epigenetic modulation (Nat Med 2011). The accumulating data strongly suggest that vasoactive substances are not only act on vasculature but also effect on sodium homeostasis. We hypothesized that blockade of nitric oxide synthesis by L-NAME has a direct effect on sodium channels in the kidney. Method: C57BL/6J Mice were treated with 8%NaCl (high salt; HS) or 8%NaCl +L-NAME (0.7mg/10ml). Blood pressure was measured by telemetry. After 4 weeks’ treatment, the function of sodium channel was monitored by pharmacologically and molecular biologically. mDCT cell was used to observe the direct effect of L-NAME on NCC. Result: Low dose L-NAME or high salt loading alone did not change blood pressure in the C57BL/6J mouse, but L-NAME shifted the pressure natriuresis curve toward the right and induced salt-sensitive hypertension in HS group. No significant changes were observed in morphological changes in the kidney. However, significant changes of sodium and chloride excretion were observed after hydrochlorothiazide challenge test but not in amiloride test, which was consistent with increases in membrane NCC. This highly suggested NCC, not ENaC was activated by L-NAME to cause salt-sensitive hypertension. To determine whether L-NAME active NCC directly or not, we treated mDCT cells with L-NAME. The membrane NCC expression was increased in a time and dose depended manner. Conclusion: Low dose L-NAME inappropriately and directly activate NCC in both vivo and vitro, and finally induces salt-sensitive hypertension.