Background Previous studies have suggested that melatonin, a major pineal hormone, possibly modulates the autonomic nervous system in animals. The aim of this study was to examine the effects of melatonin administration on heart rate variability (HRV) in human beings. Methods In 26 healthy men, melatonin (2 mg) or placebo was randomly administered. Power spectral analysis of HRV and blood pressure monitoring were performed in the supine position before and 60 minutes after administration and in the standing position 60 minutes after administration. Plasma catecholamine levels were also assessed. Results No differences in any baseline parameters were found between the two groups. Compared with placebo, melatonin administration within 60 minutes increased R-R interval, the square root of the mean of the squared differences between adjacent normal R-R intervals, high-frequency power, and low-frequency power of HRV and decreased the low-frequency to high-frequency ratio and blood pressure in the supine position (all P <.01). Plasma norepinephrine and dopamine levels in the supine position 60 minutes after melatonin administration were lower compared with placebo (P <.05 and P <.01, respectively). Standing up resulted in the decrease of HRV and the increase of blood pressure and plasma catecholamine levels in both administration groups, and the differences between the groups found in the supine position disappeared. Conclusions These findings indicate that melatonin administration increased cardiac vagal tone in the supine position in awake men. Melatonin administration also may exert suppressive effects on sympathetic tone. (Am Heart J 2001;141:e9.)
Section snippets
Study population
The study consisted of 26 male physicians between 24 and 35 years of age who were nonsmokers and receiving no medications. All participants were healthy as determined by their history and a brief routine examination. Oral informed consent was obtained from all participants, and the study design was in accordance with the guidelines issued by the ethics committee at our institution. The investigation conforms with the principles outlined in the Declaration of Helsinki.
Study protocol
All participants followed
Power spectral analysis of HRV
Changes in all parameters of HRV in the supine position after drug administration are shown in Table I.
. Changes in time and frequency parameters of HRV after melatonin administration in the supine position
Empty Cell
Baseline
After administration
P value
Melatonin (n = 13)
R-R intervals (ms)
1000 ± 34
1076 ± 35*
<.01
rMSSD (ms)
40 ± 4
51 ± 4*
<.01
ln (HF) (ms2)
5.5 ± 0.1
6.5 ± 0.1†
<.01
ln (LF) (ms2)
6.1 ± 0.2
6.7 ± 0.2*
<.01
LF/HF
1.8 ± 0.3
1.1 ± 0.2*
<.01
Placebo (n = 13)
R-R intervals (ms)
956 ± 34
977 ± 30
<.05
rMSSD (ms)
36 ± 4
38 ±
Discussion
This study demonstrates that oral administration of melatonin modifies cardiac neural regulation in the supine position in awake men. Compared with placebo administration, melatonin administration increased HF power of HRV, a pure marker of vagal activity9, 10, 13, 14 in the supine position. The HF component of HRV can be affected by respiratory-related vagal modulation of the R-R interval.15 Analysis of HRV in this study was performed under controlled respiration at frequencies within the
Changes in cardiac autonomic nervous system (ANS) regulation observed in psychiatric disorders may be mitigated by antidepressants. We meta-analyzed and systematically reviewed studies examining antidepressants’ effects on ANS outcomes, including heart rate variability (HRV). We conducted a PRISMA/MOOSE-compliant search of PubMed and Scopus until March 28th, 2022. We included randomized placebo-controlled trials (RCTs) and pre-post studies, regardless of diagnosis. We pooled results in random-effects meta-analyses, pooling homogeneous study designs and outcomes. We conducted sensitivity analyses and assessed quality of included studies. Thirty studies could be meta-analyzed. Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with a reduction in the square root of the mean-squared difference between successive R-R intervals (RMSSD) (SMD= -0.48) and skin conductance response (SMD= -0.55) in RCTs and with a significant increase in RMSSD in pre-post studies (SMD=0.27). In pre-post studies, tricyclic antidepressants (TCAs) were associated with a significant decrease in several HRV outcomes while agomelatine was associated with a significant increase in high frequency power (SMD= 0.14). In conclusion, SSRIs reduce skin conductance response but have no or inconclusive effects on other ANS outcomes, depending on study design. TCAs reduce markers of parasympathetic function while agomelatine might have the opposite effect. Studies are needed to investigate the impact of SSRIs on the recovery of cardiac ANS regulation after acute myocardial infarction, and the effects of newer antidepressants.
The numerous Mel pharmacological activities, including neuroprotective [42], hepatoprotective [43], and gastroprotective [44] were demonstrated in previous studies. In addition, several studies have reported the effect of Mel on autonomic cardiovascular regulation and blood pressure [45,46]. Scheer et al. demonstrated Mel substantially reduced the systolic and diastolic blood pressure (DBP) to the normal range in male patients suffering from essential hypertension [46].
Arsenic (As), a metalloid chemical element, is classified as heavy metal. Previous studies proposed that As induces vascular toxicity by inducing autophagy, apoptosis, and oxidative stress. It has been shown that melatonin (Mel) can decrease oxidative stress and apoptosis, and modulate autophagy in different pathological situations. Hence, this study aimed to investigate the Mel effect on As-induced vascular toxicity through apoptosis and autophagy regulation. Forty male rats were treated with As (15 mg/kg; oral gavage) and Mel (10 and 20 mg/kg, intraperitoneally; i.p.) for 28 days. The systolic blood pressure (SBP) changes, oxidative stress markers, the aorta histopathological injuries, contractile and relaxant responses, the level of apoptosis (Bnip3 and caspase-3) and autophagy (Sirt1, Beclin-1 and LC3 II/I ratio) proteins were determined in rats aorta. The As exposure significantly increased SBP and enhanced MDA level while reduced GSH content. The exposure to As caused substantial histological damage in aorta tissue and changed vasoconstriction and vasorelaxation responses to KCl, PE, and Ach in isolated rat aorta. The levels of HO-1 and Nrf-2, apoptosis markers, Sirt1, and autophagy proteins also enhanced in As group. Interestingly, Mel could reduce changes in oxidative stress, blood pressure, apoptosis, and autophagy induced by As. On the other hand, Mel led to more increased the levels of Nrf-2 and HO-1 proteins compared with the As group. In conclusion, our findings showed that Mel could have a protective effect against As-induced vascular toxicity by inhibiting apoptosis and the Sirt1/autophagy pathway.
There is a strong correlation of HRV and circadian markers in humans (salivary cortisol and urinary 6-sulfatoxy-melatonin) [22]. Likewise, it has been shown that the administration of melatonin increased HRV parameters in healthy men [23]. It has been demonstrated in vitro that the melatonin release in a pineal cell culture from 13 and 14 day old chick embryos increased during the dark phase and decreased during the light phase of a 12 h light – 12 h dark cycle [24].
In healthy individuals, a major factor influencing the heart rate variability (HRV) is the circadian rhythm. The role of melatonin as an essential component of the circadian rhythm in the adult human organism and the beneficial effects of a treatment with melatonin during the fetal period is well described. Toxic effects of melatonin are discussed less frequently.
Since pharmacological studies cannot be carried out on pregnant women, the establishment of an equivalent in vitro model is important. We therefore tested whether melatonin can influence the beat rate variability (BRV) of spontaneously beating cardiomyocytes derived from murine embryonic stem cells (mESCs) and whether melatonin exhibits toxic effects in this in vitro model.
Microelectrode Arrays recorded extracellular field potentials of spontaneously beating cardiomyocytes. Melatonin was applied in a concentration range from 10−11 M to 10–5 M. The analysis of the BRV focused on time domain methods.
In line with clinical observations, melatonin decreased the beating frequency and increased the BRV. The effect of melatonin up to a concentration of 10−6 M was reversible, whereas the application of higher concentrations induced an irreversible effect.
The study underlines the potential of this in vitro model to help explore the development of circadian rhythms and their modulation by melatonin in the embryonic phase. The results imply that melatonin influences the heart rhythm as early as during the embryonic heart development. Furthermore, the results indicate a potentially toxic effect of melatonin that has not been described in detail before.
Supported in part by a Grant-in-Aid for Scientific Research (No. C07670794) from the Ministry of Education, Tokyo, Japan; and a Research Grant for Biomedical Research Grant for Cardiovascular Disease (7A-3 and 9A-3) from the Ministry of Health and Welfare, Tokyo, Japan.
Reprint requests: Koichi Nishiyama, MD, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City, Japan. E-mail: [email protected]
