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Abstract: PO1087

Rescuing Low Blood Pressure in Amiloride-Treated Mice by Low-Potassium Diet Relies on NCC Activation

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Magaña, German R., Universidad Nacional Autonoma de Mexico, CDMX, Mexico
  • Carbajal-Contreras, Hector, Universidad Nacional Autonoma de Mexico, CDMX, Mexico
  • Murillo-de-Ozores, Adrian R., Universidad Nacional Autonoma de Mexico, CDMX, Mexico
  • Vázquez, Norma Hilda, Universidad Nacional Autonoma de Mexico, CDMX, Mexico
  • Bobadilla, Norma, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, CDMX, Mexico
  • Gamba, Gerardo, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, CDMX, Mexico
  • Castañeda-Bueno, Maria, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, CDMX, Mexico
Background

NCC activity has been widely recognized to impact on blood pressure levels, as Gitelman syndrome, caused by inactivating mutations in the Slc12a3 gene, features arterial hypotension. In contrast, Familial Hyperkalemic Hypertension (FHHt) is a mendelian disease mainly driven by NCC overactivation. NCC activity is exquisitely regulated by changes in extracellular [K+], and it has been shown that this regulation might be at least in part responsible for the inverse relationship observed between dietary K+ consumption and blood pressure levels in animal models and in human populations. It has been shown that amiloride-induced hyperkalemia results in NCC inhibition, which can be prevented with administration of a low K+ diet. Thus, we decided to evaluate the role of NCC inhibition in the volume depletion and hypotension induced by amiloride treatment.

Methods

We treated 12-week-old C57Bl/6 male mice with amiloride at 25mg/L in the drinking water. During treatment, mice were kept on normal chow (0.4% NaCl, 0.8% K+) for 4 days, then switched to low K+ diet (0.1% K+), and at the 4th day of low K+ diet hydrochlorothiazide (HCTZ, 60 mg/kg/d, in the diet) treatment was started in a subset of mice.

Results

Amiloride-treated mice developed a PHA1-like syndrome (a severe hyperkalemic, salt losing nephropathy, with marked hypotension). Hyperkalemia and hypotension were prevented by low K+ diet. Basal blood pressure levels were re-established by day 4 on low K+ diet, while further treatment with HCTZ produced a steep drop in the blood pressure of these animals. Immunoblot analysis of whole kidney lysates from amiloride-treated mice showed decreased levels of NCC and pNCC that were reversed by low K+ diet.

Conclusion

We show that the salt losing hyperkalemic phenotype induced by amiloride can be fully recovered by low K+ diet and that this recovery is mediated by the increased activity of NCC.

Funding

  • NIDDK Support