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Previous studies have suggested that melatonin alters sympathetic outflow in humans. The purpose of the present study was to determine in humans the effect of melatonin on sympathetic nerve activity and arterial blood pressure during orthostatic stress. Fifty minutes after receiving a 3 mg tablet of melatonin or placebo (different days), muscle sympathetic nerve activity (MSNA), arterial blood pressure, heart rate, forearm blood flow and thoracic impedance were measured for 10 min at rest and during 5 min of lower body negative pressure (LBNP) at -10 and -40 mmHg (n= 11). During LBNP, MSNA responses were attenuated after melatonin at both -10 and -40 mmHg (P < 0.03). Specifically, during the placebo trial, MSNA increased by 33 ± 8 and 251 ± 70 % during -10 and -40 mmHg, respectively, but increased by only 8 ± 7 and 111 ± 35 % during -10 and -40 mmHg with melatonin, respectively. However, arterial blood pressure and forearm vascular resistance responses were unchanged by melatonin during LBNP. MSNA responses were not affected by melatonin during an isometric handgrip test (30 % maximum voluntary contraction) and a cold pressor test. Plasma melatonin concentration was measured at 25 min intervals for 125 min in six subjects. Melatonin concentration was 14 ± 11 pg ml−1 before ingestion and was significantly increased at each time point (peaking at 75 min; 1830 ± 848 pg ml−1). These findings indicate that in humans, a high concentration of melatonin can attenuate the reflex sympathetic increases that occur in response to orthostatic stress. These alterations appear to be mediated by melatonin-induced changes to the baroreflexes.
Melatonin is secreted by the pineal gland in a circadian fashion at night (Reiter, 1991). The use of exogenous melatonin is widespread in the general public. Melatonin use is reported to be greater than the consumption of vitamin C tablets (Bonn, 1996). Melatonin has been linked to improved sleep, prevention of jet lag, enhanced immune response, antioxidant actions, and prevention of tumour growth (Brzezinski, 1997). In addition, data suggests that melatonin affects cardiovascular function (Krause et al. 1999). Melatonin has been reported to reduce arterial blood pressure in normal and hypertensive rats (Kawashima et al. 1987; Chuang et al. 1993; K-Laflamme et al. 1998). Studies in humans indicate that 1 mg of melatonin decreases arterial pressure and the plasma levels of noradrenaline during standing (Cagnacci et al. 1998; Arangino et al. 1999). Melatonin has been taken by astronauts to help improve sleep during spaceflight. However, because up to two-thirds of astronauts have orthostatic intolerance or hypotension after spaceflight (Buckey et al. 1996), the use of melatonin may exacerbate this serious physiological problem, and that which occurs in the large number of individuals who experience orthostatic intolerance in the general population (Robertson, 1999).
It has been reported that there is a close association between sympathetic nerve innervation and melatonin release (Bruce et al. 1991). It is not yet known whether the reported melatonin-mediated reductions in plasma noradrenaline observed during standing are the result of decreased central sympathetic outflow. The purpose of the present study was to determine the effect of melatonin on muscle sympathetic nerve activity (MSNA) and arterial blood pressure during orthostatic stress in humans. Based on previous studies, it was hypothesized that melatonin would attenuate MSNA responses during an orthostatic challenge induced by lower body negative pressure (LBNP). The findings of the current study support the concept that melatonin attenuates sympathetic nerve responses to orthostatic stress.
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There were two major findings from the current study. First, MSNA responses to LBNP were significantly attenuated following melatonin ingestion. In contrast, MSNA responses to the isometric handgrip and cold pressor test, two other sympathoexcitatory stimuli, were not altered by melatonin. Together these findings suggest that melatonin has specific physiological effects during baroreflex unloading. Second, despite reductions in MSNA during LBNP with melatonin, forearm vascular resistance remained unchanged. This finding suggests that forearm vascular control is altered by melatonin.
It is clear from study 2 that ingestion of 3 mg of melatonin elicits marked increases in plasma melatonin concentration. The plasma levels observed in this study are certainly unphysiological (1830 pg ml−1) as compared to peak normal physiological levels 60 pg ml−1 (Brzezinski, 1997). However, the use of this amount of melatonin (3 mg) as a supplement is not uncommon in the population. In addition, this dose is not beyond the levels taken by astronauts during spaceflight to improve sleep. Therefore, it is apparent that the responses observed in this study do have physiological relevance.
It has been reported that increases in plasma noradrenaline during standing are attenuated in both men and women after ingesting 1 mg of melatonin (Cagnacci et al. 1998; Arangino et al. 1999). The present results indicate that attenuated increases in MSNA during baroreceptor unloading contribute to this response. Whether changes in noradrenaline kinetics at the sympathetic nerve junction also contribute to reductions in plasma noradrenaline remain untested.
What is responsible for the attenuated increase in MSNA during LBNP after melatonin? Both the isometric handgrip and cold pressor responses were unaffected by melatonin. Thus, the effect of melatonin on MSNA was specific to LBNP and baroreceptor unloading. This finding suggests that melatonin alters the baroreflex control of MSNA. Because the MSNA responsiveness to -10 and -40 mmHg LBNP was reduced, this suggests that both the cardiopulmonary and arterial baroreflexes are affected. The aspect of the baroreflex arc that is affected by melatonin (i.e. afferent and efferent limb or central integration) remains unclear. In birds, melatonin receptors have been identified in the atria, ventricles and septum of the heart (Pang et al. 1996). Thus, modulation of cardiac mechanoreceptor stimulation by melatonin might occur. However, thoracic impedance data indicate that altered loading of the low-pressure cardiac mechanoreceptors is an unlikely explanation, because thoracic impedance increased similarly during LBNP with and without melatonin. Further studies are needed to identify the exact mechanism by which melatonin exerts its influence on the baroreflexes.
Despite reductions in MSNA responsiveness to LBNP after melatonin, mean arterial blood pressure was not reduced. This finding is in contrast to those obtained in studies in which subjects were made to stand, which reported a reduction in mean arterial pressure with melatonin (Cagnacci et al. 1998; Arangino et al. 1999). One explanation for this difference in arterial blood pressure response is that the orthostatic stress induced by LBNP at -40 mmHg is not as strong as that induced by standing. The lack of change in forearm vascular resistance with melatonin is consistent with the observation of no change in arterial blood pressure.
The lack of a reduction in arterial blood pressure and forearm vascular resistance during LBNP could be the result of the melatonin-induced augmentation of noradrenaline-induced vasoconstriction (Vandeputte et al. 2001). Thus, the lower sympathetic outflow during LBNP could be compensated by an augmented vascular sensitivity to noradrenaline. In addition, two different melatonin receptors have been identified with opposite vascular effects: MT1 receptors mediate vasoconstriction and MT2 receptors mediate vasodilatation (Doolen et al. 1998). It could be that in humans, melatonin preferentially activates MT1 receptors to elicit vasoconstriction to compensate for the diminished MSNA that occurs during LBNP. Finally, because MSNA was recorded from the leg, it is possible that MSNA responses in the leg do not reflect changes in the arm during LBNP with melatonin. Future studies are needed in humans to determine whether melatonin elicits differential vascular responses across various vascular beds (e.g. those of the limbs, kidneys or viscera).
MSNA at rest was not affected by melatonin. This finding was associated with no reductions in resting arterial blood pressure in both of the studies reported here. Thus, our studies do not support the concept of a strong depressor effect of melatonin in humans at rest. These findings together question whether the vasodilatation induced by melatonin in isolated vessels represents physiological responses in the intact organism.
The attenuated increase in MSNA during LBNP suggests that melatonin impacts negatively on orthostatic tolerance. MSNA has an important role in regulating peripheral resistance in humans. Failure of MSNA to increase appropriately during an orthostatic challenge renders an individual susceptible to reduced perfusion pressure. In astronauts, reductions in total peripheral resistance contribute importantly to post-spaceflight orthostatic intolerance (Buckey et al. 1996). Therefore, melatonin use may precipitate orthostatic intolerance in astronauts and in the general population. However, this study does not determine how long the effect of melatonin on MSNA persists. This information would be critical in determining when melatonin consumption should be stopped in order to prevent any untoward effects upon return from microgravity for astronauts and whether bedtime consumption of melatonin in the general population affects orthostasis during the daytime.
Heart rate variability studies in humans have indicated that melatonin increases cardiac vagal tone (Nishiyama et al. 2001). However, in Study 2 of the current report, no changes in heart rate were observed for 125 min following the ingestion of 3 mg of melatonin. Thus, the data from the present study do not provide support for this concept in humans, and are in agreement with earlier studies employing spectral analysis of respiratory sinus arrhythmias (Burgess et al. 2001; Harris et al. 2001).
A high concentration of melatonin can alter sympathetic outflow and forearm vascular control in humans during orthostatic stress. During cardiovascular challenges, the effects of melatonin appear to be specific to baroreceptor unloading, because MSNA responses were attenuated during LBNP but not during either exercise or a cold pressor test. The attenuation of MSNA during LBNP supports the concept that melatonin might have a negative impact on orthostatic tolerance in the general population and may be deleterious to astronauts who are susceptible to post-spaceflight orthostatic intolerance.