Melatonin Supplementation in Hypertensive Patients

描述（由申请人提供）：高血压影响美国约5000万人，并构成不良心血管事件的主要风险因素。β受体阻滞剂是治疗高血压、心绞痛和心律失常的一线药物。β受体阻滞剂的副作用包括夜间失眠和白天疲劳。由于褪黑激素具有促进睡眠的作用，β受体阻滞剂对夜间褪黑激素的抑制可能与这些副作用有关。因此，主要的临床目的是确定这些副作用是否可以通过夜间补充褪黑激素来逆转接受β受体阻滞剂治疗的高血压患者。近年来，原发性高血压患者的昼夜节律系统出现了解剖学和生理学紊乱。由于褪黑激素可以放大甚至恢复被扰乱的昼夜节律，我们最近研究了补充褪黑激素对未接受β受体阻滞剂治疗的原发性高血压患者夜间睡眠和血压的潜在有益作用。我们证明，3周的夜间补充褪黑激素显着增加总睡眠时间和睡眠效率，并降低血压。因此，在药理学抑制褪黑激素水平的高血压患者中（即，通过β受体阻滞剂治疗），补充褪黑激素可能更有益。在潜在机制方面，为了研究昼夜节律调节的变化是否可能是上述变化的基础，需要应用昼夜节律方案进行记录。本提案的长期目标是研究夜间补充褪黑激素作为对抗β受体阻滞剂副作用的措施的功效。该研究旨在检验以下假设：在用β受体阻滞剂治疗的高血压患者中补充3周的夜间褪黑激素：1A）改善睡眠量和质量; 1B）这与自主神经、内分泌和血液动力学变量的昼夜节律幅度增加相关;以及2）有助于降低BP。我们建议在一项随机、安慰剂对照、双盲研究中，通过比较3周（褪黑激素/安慰剂）补充事件之前、期间和之后的生理变量来调查这些假设。将采用恒定的常规条件，以便准确评估自主神经、内分泌和血液动力学变量的内源性昼夜节律。这一建议可能有助于制定针对β受体阻滞剂副作用失眠的对策。此外，补充抑制夜间褪黑激素水平可能会导致原发性高血压的治疗新策略。

DESCRIPTION (provided by applicant): 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.