ETB receptors regulate circadian timing and amplitude of blood pressure in rats on a high salt diet

Circadian rhythms are ~24-hour processes, which control a variety of physiologicalsystems including blood pressure and Na homeostasis. High salt diet increasesendothelin-1 (ET-1) production that facilitates Na excretion via the ETB receptor. Wealso know that the molecular clock directly controls the Edn1 gene that codes for ET-1.ETA and ETB receptors show time of day dependent expression further strengtheningevidence that the endothelin axis is in part regulated by the circadian clock. Wehypothesized that the ETB receptor functions to regulate blood pressure rhythmicityunder constant conditions. Our hypothesis predicts that ETB blockade during high saltfeeding will exacerbate a phase delay in blood pressure rhythms in constant conditions(constant darkness, DD). Male and female Sprague Dawley rats at 8-12 weeks of agewere implanted with telemetry transmitters, allowed recovery for at least 7 days, andmaintained under DD for 3 weeks to ensure a free running status of the circadian clock.Rats were fed ad libitum with normal salt (NS, 0.49% NaCl, n=19) or high salt (HS, 4%NaCl, n=19) diets starting the day of release into DD. After a week of DD, rats weregiven an ETB antagonist (A-192621, 10 mg/kg/day) in the food (n=9 NS; n=10 HS).Circadian analysis of telemetry data for the last 11 days were used to determine the freerunning circadian period (FRP) using Clocklab actimetrics software. Amplitude andMESOR were determined via cosinor analysis using the last 6 days of antagonisttreatment to ensure a stable blood pressure phenotype. Cosinor.Online was used todetermine blood pressure acrophase for each animal using data from the last 6 days oftreatment. A 2-Way ANOVA followed by a Tukey’s post-hoc test was used to determinesignificance between groups for all parameters. Treatment with the ETB antagonistincreased the robustness of the blood pressure rhythms. The amplitude of mean arterialpressure (MAP) was only in increased significantly in rats treated with an ETBantagonist and high salt (MAP pinteraction= 0.0128, pantagonist=0.0513, and pdiet=0.0219).This was similar to our findings for SBP and DBP amplitude. DBP amplitude exhibited asignificant main effect of antagonist treatment (pantagonist=0.0164) exhibited by a patternof amplitude reduction in the NS ETB antagonist treated group opposite of what wasexpected. Treatment with an ETB antagonist increased the MAP MESOR in both NSand HS fed rats (pinteraction=0.0004, pantagonist< 0.0001, pdiet=0.0152). However, MAPMESOR was highest in the HS and ETB antagonist treated group (post-hoc p< 0.0001).SBP MESOR exhibited similar findings to those reported above for MAP MESOR. Incontrast, DBP MESOR was only increased in HS and ETB antagonist treated rats(pinteraction=0.0026, pantagonist< 0.0001, pdiet=0.036). Lastly, ETB antagonism exhibited asignificant phase delay of MAP in rats on NS compared to the NS control group(pinteraction=0.0065, pantagonist< 0.0001, pdiet= 0.1537). Rats fed a HS diet alone alsoexhibited a phase delay in MAP compared to the NS control group. These phase delayfindings were consistent in SBP and DBP rhythms. Interestingly rats treated with HS dietand ETB antagonist did not display a phase delay in blood pressure rhythms contrary toour hypothesis. Despite phase delays in the timing of blood pressure rhythms, therewere no differences in the FRP of MAP, SBP, or DBP. These data suggest that thecircadian clock may differentially regulate DBP and SBP rhythms. Lastly, these findingssuggest that the ETB receptor is necessary for facilitating a phase delay in BP responseto a high salt diet.2 / 2119% 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.