Ablation of Angiotensin II Type 1 Receptors in Cholinergic Neurons Alters Autonomic Tone

Background: In addition to modulating blood pressure, the renin angiotensin system is a key regulator of autonomic balance. Emerging evidence shows that the angiotensin-II (Ang-II) type 1 receptor (AT1R) is expressed in cholinergic vagal centers including the nucleus ambiguus and the dorsal motor nucleus. While these cholinergic centers contribute to the maintenance of parasympathetic tone, the physiological relevance of AT1Rs within these cholinergic neurons remains unexplored. Here, we examined the contribution of AT1Rs in cholinergic neurons to hemodynamic and autonomic homeostasis. We hypothesized that ablating AT1R expression in cholinergic neurons would enhance vagal outflow and confer protection against Ang-II induced hypertension. Methods: We crossed Chat-Cre and AT1R-Flox mice to generate mice with a cholinergic neuron-specific deficiency of the Agtr1a gene (KO). Age/sex-matched Cre-negative littermates were used as controls (WT). Ang-II (490 ng/kg/min) was continuously administered for 8 weeks by osmotic minipump infusion. Blood pressure (BP), heart rate (HR), and heart rate variability (HRV) were measured by radiotelemetry in male mice during light (LP) and dark phases of the circadian cycle at baseline, and after 3 and 8 weeks of Ang-II infusion. Cardiac function was assessed by echocardiography at the same timepoints. Results: At baseline, hemodynamic and autonomic parameters were equivalent between groups LP-BP: 123±2mmHg vs 127±2, LP-root mean squared of successive differences (RMSSD); 4.2±0.3ms vs. 4.4±0.4, cardiac output (CO): 11.5±1.0mL/min vs. 13.4±0.9. WT and KO mice exhibited an equivalent pressor response following 3 weeks of Ang-II infusion (LP-BP: 146±7 vs. 155±6, ns). This was coupled with a mild compensatory decrease in CO, which was not different between groups (10.7±0.8 vs. 11.1±0.5, ns). However, at 8 weeks of Ang-II infusion, a divergence in cardiac vagal tone was observed. In the KO, a trending exacerbation in LP BP elevation (WT:144±3, KO:162±7; p=0.06) was coupled with a trending bradycardia (WT:542±12 vs. KO:498±4; p=0.06). This suppression of HR was driven by an elevation in vagal tone, evidenced by a higher RMSSD (WT:5.5±.3, KO:11.4±1.6; p=.02) and pNN6 (WT:19±1%, KO:33±3; p=.007). An increase in the standard deviation of normal-to-normal intervals (SDNN; WT:10±1ms, KO:15±1; p=.008) further corroborates that the KO retained superior autonomic dynamic range. Notably, these autonomic changes occurred in the context of non-different cardiac output (17.1±2.1 vs. 15.5±0.9, ns). Conclusions: We conclude that within cholinergic neurons, the AT1R serves a critical role in suppressing parasympathetic modulation in the LP under chronic hypertensive conditions. Deleting these receptors reveals a protective autonomic compensation. Contrary to our hypothesis, this occurs in the context of an exacerbated elevation in BP, indicating that there may be a divergence in the hemodynamic and autonomic contributions of AT1Rs in cholinergic neurons. Further investigation is warranted to distinguish the relative effect of AT1R signaling in central and peripheral cholinergic neurons This work has been supported by: HL153101 and T32-HL007852 from the NIH, 23CDA1048244 from the AHA, 5520639 and 5520879 from the AHW initiative, and the Michael Keelan Award from the MCW Cardiovascular Center. This abstract was presented at the American Physiology Summit 2026 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.