Project Summary Hypertension (HTN) is a leading cause of morbidity and mortality in the United States and affects approximately 45% of US adults. Blood pressure (BP) is almost invariably higher during the day; however, the relative drop in overnight BP is a better predictor of overall CV risk than daytime BP. Generally, patients with HTN are classified into: (1) dipping, where the average nighttime BP drops by ≥10% from the daytime average; and (2) non-dipping, where the average nighttime BP does not dip by 10%. More than 30% of patients with HTN have a non-dipping BP profile, which is associated with a significantly increased risk for adverse outcomes, including end-organ damage, and mortality, compared to patients with dipping HTN. It is unclear what causes non-dipping HTN, but the circadian system and sleep likely play a role because both systems affect the day-night variation in BP. Our goal is to determine, in patients with untreated HTN, the separate contributions of the internal circadian system and sleep to the non-dipping BP profile and the day/night variability in associated CV variables, including estimates of sympathetic and parasympathetic activity, renin-angiotensin-aldosterone system activity, and vascular endothelial function. Our specific aims are to determine: 1) if circadian rhythms in BP are altered in non-dipping HTN and 2) the role of sleep in non-dipping HTN. We hypothesize that: 1) BP circadian rhythms are altered in non-dipping compared to dipping HTN, resulting in a reduced nocturnal BP decline; 2) sleep duration is shorter in non-dipping than dipping HTN, and 3) the absence of sleep attenuates overnight BP drop in dipping HTN more than non-dipping HTN. An exploratory aim is to determine if two weeks of sleep regularization increases overnight BP dipping. Thirty-two participants (16 dippers, 16 non-dippers, 16 females, and 16 males) will partake in all studies. We will first quantify sleep duration using unattended polysomnography in participants’ homes. Second, we will uncover circadian rhythms in BP by employing a 40-h constant routine protocol, where all participants will be monitored in the laboratory during uninterrupted rested wakefulness in a semi-recumbent posture, dim light, and without time cues. Third, we will conduct a randomized crossover trial in dim light in the laboratory, during which overnight sleep is permitted or not. BP and mechanistic CV markers are continuously measured in the circadian study and the crossover trial. In the crossover trial, we will also measure sympathetic activity using microneurography and 24-h BP on the days of the trials. Finally, we will pilot test a two-week sleep regularization schedule, including maintaining a self-selected bedtime, to its impact on overnight BP dipping. These highly controlled experiments will enable us to document the separate roles of the circadian system and sleep in non-dipping HTN. Understanding underlying CV mechanisms will provide potential pharmac...