Empagliflozin reduces NTS excitability in the Dahl Salt Sensitive model of HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a growing health concern with increases in cases coincident with an increasing aged population > 65 years and the epidemics of hypertension, obesity, and diabetes. In the United States, HFpEF accounts for half of all heart failure cases (≥ 3 million) and disproportionally affects women. HFpEF is associated with high morbidity and mortality and current treatments for HFpEF are limited. Development of novel treatments for HFpEF are challenging because of the varied etiology of disease development in the human population. HFpEF is also associated with autonomic dysregulation characterized by increased sympathetic activity coupled with parasympathetic withdrawal and this autonomic imbalance may contribute to the manifestation of both the chronotropic incompetence and vascular noncompliance associated with the disease. Here, we assess neuronal excitability in the nucleus of the solitary tract (NTS), a brain region associated with the baroreflex, in the Dahl Salt Sensitive (Dahl SS) model of HFpEF. Furthermore, we assess the effects of the sodium-glucose cotransport inhibitor empagliflozin (Empa) on NTS excitability in this rat model of HFpEF. Both male and female Dahl SS rats (n = 12) were acquired at age 60 days. Rats were split in to control diet, high salt (8% NaCl) diet (HS), or HS+Empa (20 mg/kg/day in drinking water). Rats were maintained on their respective diet treatments for 8 weeks prior to in vitro recordings. In addition, male and female Sprague-Dawley rats (60 day, n = 6) were used to study the acute effects of empagliflozin (100 uM) in vitro. For in vitro recordings, rats were anesthetized with isoflurane (2-3%), and coronal slices (300 µm) containing NTS were cut using standard slice procedures. Voltage-clamp loose patch recordings were collected in the NTS to assess spontaneous action potential firing. NTS neurons from HS Dahl SS rats had a higher baseline firing rate than control rats. The elevated basal NTS activity observed in HS rats was attenuated in rats treated with Empa. Furthermore, acute in vitro application of Empa attenuated basal activity of a subset of NTS neurons in a time dependent manner. In addition, a separate population of NTS neurons did not show any change in activity in response to acute Empa. Together, these data suggest NTS hyperactivity in the Dahl SS model of HFpEF may be attenuated by the SGLT2i Empa and that these effects may be due to the direct action of Empa on NTS neurons. This work was supported by Department of Physiology and Anatomy seed grant and a REAP New Investigator seed grant from UNTHSC. 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.