Description:
Increases in plasma NaCl concentrations or osmolality are sensed by specialized neurons in the hypothalamus and subsequently stimulate thirst, vasopressin secretion, and increase blood pressure. However, the exact mechanism by which these neurons sense changes in NaCl concentrations or osmolality has not yet been identified. Central administration of the non‐voltage gated sodium channel antagonist, benzamil, attenuates neuroendocrine and pressor responses to central NaCl infusion. Interestingly, a major target of benzamil is the epithelial sodium channel (ENaC), and the ENaC is highly expressed in several sodium‐ or osmosensing areas of the hypothalamus. Therefore, the purpose of the present study was to test the hypothesis that the ENaC contributes to osmoregulatory responses including thirst stimulated by hypernatremia or hyperosmolality. To test this hypothesis, we generated male mice (10–15 weeks of age) with brain‐specific deletion of the various ENaC subunits by breeding ENaCαlox/lox or ENaCϒlox/lox to NestinCre strains. Cumulative water intakes were measured in response to injection (10μL per 1 g body weight, sc) of 0.15M, 0.3M, or 0.5M NaCl. Injection of NaCl produced concentration‐dependent increases in water intake across all strains. However, ENaCαlox/loxNestinCre (n=6) versus ENaCαlox/lox (n=10) mice ingested significantly less water after injection of 0.3M NaCl (0.12±0.03 vs 0.17±0.02mL, respectively; P<0.05) and 0.5M NaCl (0.21±0.04 vs 0.31±0.02mL, respectively; P<0.01). Injection of 0.15M NaCl did not increase water intake in either strain (0.02±0.01 vs 0.01±0.01mL, respectively). In marked contrast, ENaCϒlox/loxNestinCre (n=12) versus ENaCϒlox/lox (n=10) mice ingested similar amount of water after injection of 0.15M (0.05±0.02 vs 0.01±0.01mL, respectively), or 0.5M NaCl (0.31±0.02 vs 0.33±0.03mL, respectively). A second set of experiments were performed to determine whether the ENaC contributes to thirst stimulated by hyperosmolality rather than hypernatremia. Injection of 0.7M mannitol (dissolved in 0.15M NaCl) stimulated similar increases in water intake between ENaCαlox/loxNestinCre versus ENaCαlox/lox mice (0.25±0.02 vs 0.27±0.05mL, respectively) as well as ENaCϒlox/loxNestinCre versus ENaCϒlox/lox mice (0.31±0.03 vs 0.31±0.03mL, respectively). Collectively, these data demonstrate that the ENaCα subunit, but not ENaCϒ subunit, contributes to thirst stimulated by hypernatremia but not hyperosmolality and may represent a putative channel in the brains ability to detect sodium changes.