NaX Channel Does Not Contribute to the Central NaCl-Induced Cardiovascular Response in Rats

Increases in extracellular NaCl concentrations elevate sympathetic nerve activity and arterial blood pressure (ABP) through specialized NaCl-sensing cells located in circumventricular organs. The NaX (Scn7a) channel is the putative Na + sensor in mice yet mice have a much higher osmotic set point and plasma [Na+] than other species including humans and rats. Therefore, we tested the extent by which the NaX channel contributes to the central NaCl-induced cardiovascular response in rats by using a novel Scn7a-/- rat. Using CRISPR/Cas9, we generated a 8,613 bp deletion spanning exons 2-7 of the Scn7a gene. Deletion of Scn7a was confirmed by sequencing and the absence of mRNA expression in brain using RNAscope. Male and female rats (6–8 males; 6–7 females/group; 210–350 g) were chronically instrumented with a lateral ventricle cannula for intracerebroventricular (ICV) infusion, arterial radiotelemetry, and venous catheters to record ABP and administer drugs, respectively. After at least 4 days of recovery, ABP and HR were measured in response to ICV infusion (10 μL over 10 minutes) of artificial aCSF, 0.3 M NaCl, and 0.6 M NaCl. There were no differences between WT and Scn7a-/- rats in baseline mean ABP (WT: 100 ± 0.9 mmHg vs. KO: 99 ± 1.2 mmHg). However, heart rate was lower in KO rats compared to WT (WT: 368 ± 4 bpm vs. KO: 354 ± 4 bpm). There were also no differences between strains for plasma osmolality (WT: 299 ± 2 vs. KO: 302 ± 2), plasma Na+ (WT: 139.4 ± 0.5 vs. KO: 140.3 ± 0.6), plasma Cl- (WT: 106.8 ± 1.3 vs. KO: 104.6 ± 1.1) or CSF Na+ (WT: 145.2 ± 0.7 vs. KO: 146.0 ± 0.5) and CSF Cl- (WT: 121.0 ± 0.4 vs. KO: 122.3 ± 0.5). ICV infusion of NaCl produced dose-dependent increases in ABP of both WT and Scn7a-/- rats; however, the magnitude of these responses did not differ between strains at 0.3M NaCl (AUC WT: 184 ± 34 mmHg vs. KO: 189 ± 30 mmHg) or 0.6M NaCl (AUC WT: 266 ± 25 mmHg vs. KO: 283 ± 24 mmHg). ICV infusion of AngII (100ng/10uL/10min) increased ABP similarly in both strains (AUC WT: 234 ± 26 mmHg vs. KO: 243 ± 27 mmHg). In a final set of experiments, hypernatremia (2 M NaCl IV; 2.5mL over 30 min) was induced in a separate group of WT (1 male;1 female) and Scn7a-/- (2 males;1female) rats to assess whether deletion of Scn7a altered neuronal activation in circumventricular organs via Fos protein immunoreactivity. Hypernatremia induced similar neuronal activation in the organum vasculosum of the lamina terminalis in both WT and KO groups (WT: 144 ± 1 vs. KO: 135 ± 7). These results suggest that the NaX channel does not contribute to the central NaCl-sensing or NaCl-induced cardiovascular responses in rats. NIH R01HL163906 and HL145875. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.