Hypertension affects approximately 50 million individuals in the United States and constitutes a prime risk factor for adverse cardiovascular events. Beta-Blockers constitute first-line therapy in the treatment of hypertension, angina, and arrhythmia. Side effects of beta-blockers include nighttime insomnia and daytime fatigue. Because melatonin has a sleep promoting action, the suppression of nighttime melatonin by beta-blockers may be involved in those side effects. Thus, the primary clinical aim is to determine if these side effects may be reversed by nighttime melatonin supplementation in hypertensive patients treated with beta-blockers. Anatomical and physiological disturbances of the circadian system have recently been shown in patients with essential hypertension. Because melatonin can amplify and even restore disturbed circadian rhythmicity, we recently investigated the potential beneficial effect of melatonin supplementation on nighttime sleep and BP in patients with essential hypertension who were not treated with beta-blockers. We demonstrated that 3-week nighttime melatonin supplementation significantly increased total sleep time and sleep efficiency, and decreased BP. Thus, in hypertensive patients with pharmacologically suppressed melatonin levels (i.e., by beta-blocker therapy), melatonin supplementation may be even more beneficial. In terms of underlying mechanism, to investigate whether or not a change in circadian regulation could underlie aforementioned changes, recordings applying a Circadian Protocol are required. The long-term objective of the present proposal is to investigate the efficacy of nighttime melatonin supplementation as a counter measure against side effects of beta-blockers. The study is designed to test the hypothesis that 3-week nighttime melatonin supplementation in hypertensive patients treated with beta -blockers: 1A) improves sleep quantity and quality; 1B) that this correlates with an increased circadian rhythm amplitude of autonomic, endocrine, and hemodynamic variables; and 2) assists in lowering BP. We propose to investigate the hypotheses in a randomized, placebo-controlled, double blind study by comparing the physiological variables before, during, and after 3-week (melatonin/placebo) supplementation episodes. Constant Routine conditions will be employed, enabling the accurate assessment of the endogenous circadian rhythms in autonomic, endocrine, and hemodynamic variables. This proposal may assist in developing counter measures against insomnia as side effect of beta-blockers. Furthermore, supplementation of suppressed nighttime melatonin levels may lead to a novel strategy in the treatment of essential hypertension. ?

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZAT1-JH (05))
Program Officer
Stoney, Catherine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Scheer, Frank A J L; Morris, Christopher J; Garcia, Joanna I et al. (2012) Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep 35:1395-402
Hu, Kun; Van Someren, Eus J W; Shea, Steven A et al. (2009) Reduction of scale invariance of activity fluctuations with aging and Alzheimer's disease: Involvement of the circadian pacemaker. Proc Natl Acad Sci U S A 106:2490-4
Scheer, Frank A J L; Hilton, Michael F; Mantzoros, Christos S et al. (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106:4453-8
RĂ¼ger, Melanie; Scheer, Frank A J L (2009) Effects of circadian disruption on the cardiometabolic system. Rev Endocr Metab Disord 10:245-60
Hu, Kun; Scheer, Frank A J L; Buijs, Ruud M et al. (2008) The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats. Cardiovasc Res 80:62-8
Scheer, Frank A J L; Shea, Thomas J; Hilton, Michael F et al. (2008) An endogenous circadian rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the biological night. J Biol Rhythms 23:353-61