Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W
Department of Medicine, Karl Franzens University, Graz, Austria.
Eur J Clin Pharmacol. 1999 Apr;55(2):111-5. doi: 10.1007/s002280050604.
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 beta1- and alpha1-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.
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).
Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in microg): 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.
These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-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.
褪黑素是生物过程昼夜节律建立中的一种介质。它主要在夜间由肾上腺素能β1和α1受体的刺激作用于松果体产生。睡眠障碍是β受体阻滞剂常见的副作用。此前尚未在人体中研究过特异性β受体阻滞以及α和β受体联合阻滞对褪黑素产生的影响。
我们对15名健康志愿者进行了一项随机、双盲、安慰剂对照的交叉研究。受试者于18:00口服单剂量40毫克（R）-普萘洛尔、40毫克（S）-普萘洛尔、50毫克（R）-阿替洛尔、50毫克（S）-阿替洛尔、25毫克（R,S）-卡维地洛、120毫克（R,S）-维拉帕米或安慰剂。在22:00至06:00收集尿液，并用放射免疫分析法（RIA）测定6-硫酸氧褪黑素（aMT6s），它是褪黑素的主要代谢产物，几乎完全从尿液中排出。
服药后尿液中aMT6s的夜间平均排泄量如下（以微克计）：安慰剂26；（R）-普萘洛尔24（-7%，无统计学意义）；（S）-普萘洛尔5（-80%，P<0.001）；（R）-阿替洛尔27（+7%，无统计学意义）；（S）-阿替洛尔4（-86%，P<0.01）；（R,S）-卡维地洛23（-10%，无统计学意义）；（R,S）-维拉帕米29（+14%，无统计学意义）。这些数据表明，只有普萘洛尔和阿替洛尔的特异性β受体阻滞（S）-对映体降低了褪黑素的夜间产生，而非β受体阻滞（R）-对映体则无影响。出乎意料的是，同时抑制α和β肾上腺素能受体（R,S）-卡维地洛并未降低褪黑素的产生。
这些发现表明β受体阻滞剂通过特异性抑制肾上腺素能β1受体来减少褪黑素的释放。由于夜间褪黑素水平降低可能是睡眠障碍的原因，进一步的临床研究应调查口服褪黑素是否可以避免β受体阻滞剂这一众所周知的副作用。（R,S）-卡维地洛不影响褪黑素产生的原因仍有待确定。
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