Influence of beta-blockers on melatonin release.
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 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.


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 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.


CONCLUSIONS
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.
Stoschitzky
K
K
Department of Medicine, Karl Franzens University, Graz, Austria.
Sakotnik
A
A
Lercher
P
P
Zweiker
R
R
Maier
R
R
Liebmann
P
P
Lindner
W
W
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D001262:Atenolol / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002940:Circadian Rhythm / Q000502:physiology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; C054513:6-sulfatoxymelatonin; D001262:Atenolol; D011433:Propranolol; D014700:Verapamil; D008550:Melatonin