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      Comparing Beta-Blocking Effects of Bisoprolol, Carvedilol and Nebivolol

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          Objective: Bisoprolol, carvedilol and nebivolol have been shown to be effective in the treatment of heart failure. However, the beta-blocking effects of these drugs have never been compared directly. Methods: Therefore, we performed a randomized, double-blind, placebo-controlled, cross-over trial in 16 healthy males. Subjects received 10 mg bisoprolol, 50 mg carvedilol, 10 mg nebivolol and placebo on the first morning followed by 5 mg bisoprolol once daily, 25 mg carvedilol twice daily, 5 mg nebivolol once daily and placebo for 1 week. Heart rate and blood pressure were measured at rest and exercise 3 and 24 h following intake of the first dose, and immediately before and 3 hours following intake of the last dose of each drug. In addition, effects of the drugs on nocturnal melatonin release were determined, and quality of life (QOL) was evaluated. Results: Heart rate at exercise was decreased at 3 h following intake of the first single dose of each drug by bisoprolol (–24%), carvedilol (–17%) and nebivolol (–15%), and at 24 h following intake of the respective last dose of each drug following 1 week of chronic administration by bisoprolol (–14%), carvedilol (12 h; –15%) and nebivolol (–13%) (p < 0.05 in all cases). Thus, trough-to-peak-ratios at long-term were as follows: Bisoprolol, 58%; carvedilol (12 h), 85%; nebivolol, 91%. Nocturnal melatonin release was decreased by bisoprolol (–44%, p < 0.05) whereas nebivolol and carvedilol had no effect. QOL with carvedilol was slightly but significantly lower than with the other drugs, whereas bisoprolol and nebivolol did not alter QOL. Conclusions: These data show that peak beta-blocking effects of bisoprolol appear stronger than those of nebivolol and carvedilol. On the other hand, nebivolol exerts the highest trough-to-peak-ratio. However, beta-blocking effects of all the three drugs are similar at trough. Only bisoprolol but neither nebivolol nor carvedilol decreased nocturnal melatonin release, a feature which might cause sleep disturbances. Finally, only carvedilol slightly decreased QOL, whereas nebivolol and bisoprolol did not affect QOL. We conclude that different beta-blockers may exert clinically relevant different effects.

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          Most cited references 20

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          Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology.

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            Influence of beta-blockers on melatonin release.

            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.
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              Melatonin biosynthesis in the mammalian pineal gland.

               Kent Sugden (1989)
              Rhythmic production of melatonin by the mammalian pineal occurs in response to noradrenergic stimulation which produces a cascade of biochemical events within the pinealocyte. In the rat, massive changes in NAT activity result from an increase in intracellular c-AMP levels produced by a synergistic interaction whereby an alpha 1 activation amplifies beta-adrenergic stimulation. The intracellular events mediating this effect are described. A major aspect of the temporal control of melatonin production is the programmed down-regulation of responses to noradrenergic stimulation once the initial surge of c-AMP is produced. Noradrenergic activation of the gland also influences other enzymic functions, including tryptophan hydroxylase and HIOMT activities, and produces a dramatic increase in intracellular c-GMP levels. Other neurotransmitters and neuropeptides, e.g. VIP, may also influence pineal function and comparisons are made between the rat, the subject of the bulk of experimental studies, and other species.

                Author and article information

                S. Karger AG
                November 2006
                15 November 2006
                : 106
                : 4
                : 199-206
                Divisions of aCardiology and bEndocrinology, Department of Medicine, Medical University of Graz, Graz, Austria
                93060 Cardiology 2006;106:199–206
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 38, Pages: 8
                Original Research


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