American Heart Journal
Volume 141, Issue 5 , Page E9, May 2001

Acute effects of melatonin administration on cardiovascular autonomic regulation in healthy men☆☆☆

Department of Cardiovascular Medicine, Kumamoto University School of Medicine. Kumamoto, Japan

Received 27 September 2000; accepted 19 January 2001.

Article Outline

Abstract 

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.)

 

The pineal hormone melatonin has been shown to influence several important physiologic functions, including immune function, reproductive function, and sleep.1, 2 Previous studies have suggested that melatonin possibly influences autonomic cardiovascular regulations in animals. Pinealectomy induced hypertension in rats,3 whereas melatonin administration decreased blood pressure and heart rate in pinealectomized and normal rats.4, 5 Melatonin modified the turnover rates of cardiac catecholamine in Syrian hamsters.6 Melatonin inhibited the central sympathoadrenomedullary outflow in rats.7 Also, in human beings, it is probable that melatonin influences autonomic cardiovascular modulation.8

Heart rate variability (HRV) is a measure of the variations in the interbeat intervals (R-R intervals), and HRV is for the most part caused by variations in input to the sinus node from the autonomic nervous system.9, 10 Power spectral analysis of HRV is a useful noninvasive method to provide practical information on autonomic nervous activity.9, 10 The aim of this study was to examine the effects of melatonin administration on HRV in human beings. Power spectral analysis of HRV was performed in the supine position before and 60 minutes after melatonin (2 mg) administration in healthy, nonsmoking men compared with placebo administration. Blood pressure and plasma catecholamine levels were also monitored.

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Methods 

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 the required sleep schedule (between 11 PM to midnight and 6 to 7 AM ) 3 days before examinations. All examinations took place between 10 AM and noon in a quiet, dimly lit room at a comfortable temperature (22°C to 24°C) after the participants consumed a little breakfast free of alcohol- and caffeine-containing beverages. After an adaptation period in the supine position, electrocardiographic data acquisition with a 24-hour Holter electrocardiographic recorder was initiated and continued until completion of the study. Two milligrams of melatonin, mixed with lactose in a gelatin capsule (13 participants), or a matched placebo (13 participants) was orally administered at random and in a single-blind manner, after the electrocardiographic data acquisition for the baseline. Participants were required to remain awake in the supine position for 60 minutes. After the electrocardiographic data acquisition 60 minutes after drug administration, participants stood up at the bedside for 15 minutes, leaning against the wall. For the analysis of HRV, electrocardiographic data with the 24-hour Holter recorder were obtained under controlled respiration synchronized with a 15/min (0.25 Hz) metronome signal for 10 minutes. The synchronization between signal and the respiration was monitored on a polygraph screen with a respiration sensor (Nihon Kohden, Tokyo, Japan). Blood pressure was also measured twice at each point when HRV was analyzed, and the findings were averaged. The entire procedure took 100 minutes.

Blood samples were collected in both the supine and standing positions after electrocardiographic data acquisition for analysis of HRV and blood pressure measurement 60 minutes after drug administration. Collected blood samples were immediately drawn into blood tubes, which contained EDTA-2Na, and these were then centrifuged at –4°C. Plasma samples were kept frozen at –40°C until assayed.

Power spectral analysis of HRV 

The electrocardiographic findings were obtained with a 2-channel Del Mar Avionics recorder and analyzed with a Del Mar Avionics analyzer. Automatically detected and classified electrocardiographic recordings were reviewed on a computer monitor visually as described previously,11 and stationary segments devoid of arrhythmias (5 minutes) were selected for power spectral analysis of HRV.

Power spectral analysis of HRV was performed with Del Mar Avionics software (system E5 ESHRV revision-A), in which a fast-Fourier transform method based on a window periodgram technique was used. Power spectra were quantified by measuring the area in high-frequency (HF, 0.15 to 0.4 Hz) band and low-frequency (LF, 0.04 to 0.15 Hz) band.9, 10, 11 Both spectral components were calculated as absolute units, expressed in natural logarithmic units. The ratios between the LF and HF powers (LF/HF) in the absolute values were also calculated with the power in each band before log transformation of the measurements. In addition, we analyzed the time-domain measures: mean R-R intervals and the square root of the mean of the squared differences between adjacent normal R-R intervals (rMSSD).

Assays 

Assessment of plasma melatonin levels was performed within 1 month from the blood sampling. After diethylether extraction from the plasma, melatonin levels were measured with a commercially available radioimmunoassay kit (Bühlmann Laboratories, Alshwill, Switzerland). Assessment of plasma catecholamine levels was performed within 5 days from the blood sampling. Plasma levels of norepinephrine, epinephrine, and dopamine were determined by high-performance liquid chromatography.

Statistical analysis 

The values are expressed as the mean ± standard error of the mean unless otherwise stated. Variables at each measurement point were compared between the two groups by means of an unpaired t test. Changes in variables in each participant after drug administration were analyzed by means of a paired t test. A probability value of <.05 was considered significant.

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Results 

Power spectral analysis of HRV 

Changes in all parameters of HRV in the supine position after drug administration are shown in Table I.

Table I. Changes in time and frequency parameters of HRV after melatonin administration in the supine position
BaselineAfter administrationP value
Melatonin (n = 13)
R-R intervals (ms)1000 ± 341076 ± 35*<.01
rMSSD (ms)40 ± 451 ± 4*<.01
ln (HF) (ms2)5.5 ± 0.16.5 ± 0.1†<.01
ln (LF) (ms2)6.1 ± 0.26.7 ± 0.2*<.01
LF/HF1.8 ± 0.31.1 ± 0.2*<.01
Placebo (n = 13)
R-R intervals (ms)956 ± 34977 ± 30<.05
rMSSD (ms)36 ± 438 ± 4NS
ln (HF) (ms2)5.9 ± 0.35.7 ± 0.2<.05
ln (LF) (ms2)6.0 ± 0.25.9 ± 0.3NS
LF/HF2.2 ± 0.62.2 ± 0.5NS
*P < .05. †P < .01 vs placebo.

Values are mean ± SEM.

No differences in time and frequency parameters of HRV before drug administration were found between the melatonin administration group and the placebo administration group. The R-R interval was slightly increased (P < .05), but rMSSD was not changed 60 minutes after placebo administration. In contrast, both R-R intervals and rMSSD were clearly increased after melatonin administration (both P < .01). The values 60 minutes after melatonin administration were larger compared with those after placebo administration (R-R interval,P < .05; rMSSD, P < .05).

In the frequency-domain parameters, HF power was slightly decreased after placebo administration (P < .05), but LF power and LF/HF ratio did not change. Melatonin administration resulted in an increase in HF power and LF power (both P < .01), and the values 60 minutes after melatonin administration were larger compared with those after placebo administration (P < .01 and P < .05, respectively). The LF/HF ratio was decreased after melatonin administration (P < .01), and the values 60 minutes after melatonin administration were smaller compared with those after placebo administration (P < .05).

By standing up, the R-R interval, rMSSD values, and HF power were decreased (977 ± 30 ms to 773 ± 24 ms, P < .01; 38 ± 4 ms to 26 ± 3 ms, P < .01; 5.7 ± 0.2 ms2 to 4.5 ± 0.2 ms2, P < .01, respectively), whereas the LF/HF ratio was increased in the placebo administration group (2.2 ± 0.5 to 7.3 ± 1.2, P < .01). Similar changes in HRV parameters were found by standing up in the melatonin administration group (R-R interval, 1076 ± 35 ms to 777 ± 28 ms, P < .01; rMSSD, 51 ± 4 ms to 23 ± 2 ms, P < .01; HF power, 6.5 ± 0.1 ms2 to 4.6 ± 0.2 ms2, P < .01; LF/HF ratio, 1.1 ± 0.2 to 6.2 ± 1.5, P < .01), and no values in the standing position were significantly different from those in the placebo administration group.

Blood pressure and plasma catecholamine levels 

Table II shows blood pressure and plasma catecholamine levels in the supine position after drug administration.

Table II. Blood pressure and plasma catecholamine levels
BaselineAfter administrationP value
Melatonin
Blood pressure (mm Hg)
Systolic114 ± 2107 ± 2*<.01
Diastolic70 ± 166 ± 2<.01
Catecholamine (pg/mL)
Epinephrine–27 ± 8–
Norepinephrine–160 ± 26*–
Dopamine–7 ± 1†–
Placebo
Blood pressure (mm Hg)
Systolic113 ± 2113 ± 2Not significant
Diastolic68 ± 268 ± 2Not significant
Catecholamine (pg/mL)
Epinephrine–35 ± 8–
Norepinephrine–248 ± 30–
Dopamine–11 ± 1–
*P < .05 vs placebo. †P < .01 vs placebo.

Values are mean ± SEM.

Systolic and diastolic blood pressures did not change after placebo administration, whereas systolic and diastolic blood pressures were significantly decreased after melatonin administration (both P < .01). Systolic blood pressure but not diastolic blood pressure, 60 minutes after melatonin administration, was significantly lower compared with values after placebo administration (P < .05). By standing up, systolic and diastolic blood pressures were increased in both groups (placebo group, 113 ± 2 mm Hg to 121 ± 2 mm Hg, P < .01 and 68 ± 2 to 80 ± 2 mm Hg, P < .01, respectively; melatonin group, 107 ± 2 mm Hg to 117 ± 2 mm Hg, P < .01; and 66 ± 2 mm Hg to 80 ± 2 mm Hg, P < .01, respectively). There were no significant differences in blood pressure in the standing position between both groups. Plasma norepinephrine and dopamine levels but not plasma epinephrine levels in the supine position 60 minutes after melatonin administration were lower compared with those after placebo administration (P < .05 and P < .01, respectively). When standing up, plasma norepinephrine, epinephrine, and dopamine levels were increased in both groups (placebo group: epinephrine, 35 ± 8 pg/mL to 43 ± 9 pg/mL, P < .05; norepinephrine, 248 ± 30 pg/mL to 380 ± 30 pg/mL, P < .01; dopamine, 11 ± 1 pg/mL to 13 ± 1 pg/mL, P < .05; and melatonin group: epinephrine, 27 ± 8 pg/mL to 39 ± 13 pg/mL, P < .01; norepinephrine, 160 ± 26 pg/mL to 316 ± 35 pg/mL, P < .01; dopamine, 7 ± 1 pg/mL to 10 ± 2 pg/mL, P < .05). The values were not different between both groups.

Plasma melatonin levels were 523 ± 25 pg/mL 60 minutes after 2 mg of melatonin administration, whereas the levels were 10 ± 2 pg/mL 60 minutes after placebo administration. The plasma levels after melatonin administration were compatible with the levels observed in a previous study.12 Four (31%) men in the melatonin administration group felt mildly faint by standing up, but the symptom was quickly and spontaneously relieved.

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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 physiologic range (25 Hz), which provides a convenient tool to enhance the vagal modulation of heart rate.16 Melatonin administration also resulted in an increase in rMSSD and LF power of HRV and a decrease in heart rate and the LF/HF ratio of HRV. rMSSD and the LF/HF ratio reflect cardiac vagal activity and sympathovagal balance, respectively.9, 10, 13, 14, 17 The interpretation of LF power remains controversial, but it is generally considered as a parameter that encompasses both sympathetic and vagal influences.13, 18 These results, therefore, indicate that melatonin administration increases cardiac vagal tone.

An effect of melatonin administration on sympathetic nervous system remained to be concluded in this study. Experimental studies have demonstrated the suppressive effect of melatonin on sympathetic nervous system.6, 7 In this study, blood pressure was decreased after melatonin administration, and plasma levels of norepinephrine and dopamine after melatonin administration were lower in the supine position compared with placebo administration. Similar results were observed in a previous study in which 1 mg of melatonin was orally administered in healthy men.8 The previous and the current results suggest that sympathetic tone might be suppressed by melatonin administration. However, any significant differences in blood pressure and plasma catecholamine levels were not found between the two groups when standing up, resulting in an increase of sympathetic tone, although their mean values were lower in the melatonin administration group.

Melatonin-specific receptors are widely distributed in the central nervous system, especially the suprachiasmatic nucleus (SCN) of the hypothalamus.1, 2, 19 Cardiac autonomic activity can be controlled by the central nervous system at various levels,20 and increasing evidence further suggests a possible modulation of cardiac autonomic control by the SCN, a circadian center.21, 22 Melatonin might have exerted the autonomic effect through the SCN. The effect of melatonin administration on the autonomic nervous system may be a result of its local modification.6, 23

In human beings, cardiovascular activity has a distinct circadian variation: Blood pressure, heart rate, and vascular tone decrease at night. The nocturnal reduction of cardiovascular activities is at least partially linked to the autonomic activity.24, 25, 26, 27 Melatonin is secreted primarily at night in human beings.1, 2 However, it remains to be elucidated whether endogenous melatonin is physiologically involved in neural regulation of circadian cardiovascular activity in human beings because the current results show the action on cardiac autonomic regulation in 10 or more times the levels of generally observed nocturnal melatonin.2 It has been reported that impaired circadian variation in HRV is linked to increased risk of cardiac events.28, 29 Recent studies have also suggested that failure of the nocturnal decrease in blood pressure is associated with an increase of cardiac and cerebral events.30, 31 In this study, melatonin administration enhanced HRV and decreased blood pressure in resting conditions in healthy men. However, it is now unknown whether nocturnal melatonin administration is effective in their patients.

Limitations 

In this study, blood sampling for the assessment of plasma catecholamine levels was performed only after melatonin or placebo administration. It cannot be completely denied that the differences in the plasma levels between both groups were caused by basal differences.

Conclusions 

These findings indicate that melatonin administration increased cardiac vagal tone in the supine position in awake men. An effect of melatonin administration on the sympathetic nervous system was inconclusive, but the administration may also exert a suppressive effect on sympathetic tone.

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☆ 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: kou@gpo.kumamoto-u.ac.jp

PII: S0002-8703(01)10009-8

doi:10.1067/mhj.2001.114368

American Heart Journal
Volume 141, Issue 5 , Page E9, May 2001

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