Influence of beta-blockers on melatonin release
Influence of beta-blockers on melatonin release
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DOI：
10.1007/s002280050604
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发表时间：
1999-04-01
影响因子：
2.9
通讯作者：
Lindner, W
中科院分区：
文献类型：
--
作者：
Stoschitzky, K;Sakotnik, A;Lindner, W
目的：褪黑素是生物过程昼夜节律建立的中介物。它主要在夜间通过肾上腺素能β(1)和α(1)受体的刺激在松果体产生。睡眠障碍是β-受体阻滞剂常见的副作用。特定的β-受体阻滞剂以及α-和β-受体阻滞剂联合作用对人体褪黑激素产生的影响还没有被研究过。方法：我们对15名健康志愿者进行了随机、双盲、安慰剂对照的交叉研究。受试者在1800h内单次口服40 mg(R)-心得安、40 mg(S)-心得安、50 mg(R)-阿替洛尔、50 mg(S)-阿替洛尔、25 mg(R，S)-卡维地洛、120 mg(S)-维拉帕米或安慰剂。结果：服药后夜间尿中褪黑素的平均排泄量为：安慰剂26例；心得安24例(-7%，NS)；S心得安5例(-80%，P<；0.001)；阿替洛尔27例(+7%，NS)；阿替洛尔4例(-86%，P<；)。(右，S)-卡维地洛23(-10%，NS)；(R，S)-维拉帕米29(+14%，NS)。这些数据表明，只有特异β阻滞型(S)对映体心得安和阿替洛尔才能减少夜间褪黑素的产生，而非β阻滞型(R)对映体没有影响。意外的是，同时抑制α受体和β受体的(R，S)-卡维地洛并没有减少褪黑素的产生。结论：β受体阻滞剂通过特异性抑制肾上腺素能β(1)受体而减少褪黑素的释放。由于夜间褪黑激素水平较低可能是睡眠障碍的原因，进一步的临床研究应该调查口服褪黑激素是否可以避免这种众所周知的β-受体阻滞剂的副作用。(R，S)-卡维地洛不影响褪黑素产生的原因尚不清楚。
Objective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta(1)- and alpha(1)-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before.Methods: We performed a randomized, double-blind; placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol, 120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA).Results: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in mu g): placebo 26; (R)-propranolol 24 (-7%, NS); (S)-propranolol 5 (-80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)atenolol 4 (-86%, P < 0.01); (R,S)-carvedilol 23 (-10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production.Conclusion: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta(1)-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.