Daytime melatonin and light independently affect human alertness and body temperature

Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin‐induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within‐subject design, lasting from noon to 04:00 pm . Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin‐induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin‐induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime.     

No influence of melatonin on cerebral blood flow in humans

Melatonin has been attributed a role in a number of physiological processes. Changes in distal skin temperature and blood pressure after intake of melatonin suggest that melatonin induces peripheral vasodilation. The effect on the cerebral blood flow is still unknown. We examined the effect of a single pulse of melatonin on cerebral and peripheral blood flow, using the latter as a positive control. Ten male healthy volunteers (mean age, 22 +/- 3.2 yr) participated in a double-blind, randomized, placebo-controlled, cross-over study. On one occasion 10 microg melatonin were infused i.v., and on the other occasion saline was infused as the matching placebo. Cerebral blood flow was measured using phase contrast magnetic resonance imaging. Peripheral blood flow was determined from changes in the distal to proximal skin temperature gradient and finger pulse volume. Serum melatonin concentration increased from 12 +/- 5 pg/ml at baseline to 487 +/- 377 pg/ml at 5 min and 156 +/- 68 pg/ml at 10 min after melatonin administration. There was no significantly different time course for cerebral blood flow and cerebrovascular resistance. Compared with placebo, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume. These data demonstrate that melatonin does not have an acute regulatory effect on cerebral blood flow in humans.     

Blocking low-wavelength light prevents nocturnal melatonin suppression with no adverse effect on performance during simulated shift work

Decreases in melatonin production in human and animals are known to be caused by environmental lighting, especially short-wavelength lighting (between 470 and 525 nm). We investigated the novel hypothesis that the use of goggles with selective exclusion of all wavelengths less than 530 nm could prevent the suppression of melatonin in bright-light conditions during a simulated shift-work experiment. Salivary melatonin levels were measured under dim (<5 lux), bright (800 lux), and filtered (800 lux) light at hourly intervals between 2000 and 0800 h in 11 healthy young males and eight females (mean age, 24.7 +/- 4.6 yr). The measurements were performed during three nonconsecutive nights over a 2-wk period. Subjective sleepiness was measured by self-report scales, whereas objective performance was assessed with the Continuous Performance Test. All subjects demonstrated preserved melatonin levels in filtered light similar to their dim-light secretion profile. Unfiltered bright light drastically suppressed melatonin production. Normalization of endogenous melatonin production while wearing goggles did not impair measures of performance, subjective sleepiness, or alertness.     

Physiological responses to high intensity, constant-load arm exercise in COPD

The aim of the study was to compare the metabolic, ventilatory and dyspnoea responses of a single bout of high intensity, constant-load arm exercise to peak arm exercise in people with chronic obstructive pulmonary disease (COPD). Thirty people with COPD (mean age+/-SD=65+/-8 years; FEV1% predicted=56+/-12%) were included. All subjects performed an incremental arm exercise test to peak work capacity on an arm ergometer and, on a separate day, a constant-load arm exercise test at 80% of the peak work rate achieved on the incremental test. Throughout both exercise tests, oxygen consumption (VO2), minute ventilation (VE), dyspnoea and rate of perceived exertion (RPE) were measured each minute. Peak work rate on the incremental test was 33.0+/-10.1 W with a mean duration of 6.6+/-2.0 min. The mean duration of the constant-load test of 7.1+/-2.9 min was not significantly different to the incremental test (p=0.3). At end exercise, VE, dyspnoea and RPE for the constant-load test was significantly higher compared to the incremental test (VE: 41.3+/-14.4 L/min and 38.3+/-11.8 L/min; dyspnoea: 5.6+/-2.7 and 4.6+/-2.1; RPE: 7.1+/-2.3 and 6.0+/-2.0; all p<0.05). Constant-load arm exercise at 80% peak work rate elicits higher ventilatory, dyspnoea and RPE responses at end exercise compared to incremental arm exercise in people with COPD. This finding suggests that an intensity of 80% peak work rate may be too high as an initial training intensity for supported arm exercise in people with COPD.     

Exogenous melatonin administration modifies cutaneous vasoconstrictor response to whole body skin cooling in humans

Humans and other diurnal species experience a fall in internal temperature (T(int)) at night, accompanied by increased melatonin and altered thermoregulatory control of skin blood flow (SkBF). Also, exogenous melatonin induces a fall in T(int), an increase in distal skin temperatures and altered control of the cutaneous active vasodilator system, suggesting an effect of melatonin on the control of SkBF. To test whether exogenous melatonin also affects the more tonically active vasoconstrictor system in glabrous and nonglabrous skin during cooling, healthy males (n = 9) underwent afternoon sessions of whole body skin temperature (T(sk)) cooling (water-perfused suits) after oral melatonin (Mel; 3 mg) or placebo (Cont). Cutaneous vascular conductance (CVC) was calculated from SkBF (laser Doppler flowmetry) and non-invasive blood pressure. Baseline T(int) was lower in Mel than in Cont (P < 0.01). During progressive reduction of T(sk) from 35 degrees C to 32 degrees C, forearm CVC was first significantly reduced at T(sk) of 34.33 +/- 0.01 degrees C (P < 0.05) in Cont. In contrast, CVC in Mel was not significantly reduced until T(sk) reached 33.33 +/- 0.01 degrees C (P < 0.01). The decrease in forearm CVC in Mel was significantly less than in Cont at T(sk) of 32.66 +/- 0.01 degrees C and lower (P < 0.05). In Mel, palmar CVC was significantly higher than in Cont above T(sk) of 33.33 +/- 0.01 degrees C, but not below. Thus exogenous melatonin blunts reflex vasoconstriction in nonglabrous skin and shifts vasoconstrictor system control to lower T(int). It provokes vasodilation in glabrous skin but does not suppress the sensitivity to falling T(sk). These findings suggest that by affecting the vasoconstrictor system, melatonin has a causal role in the nocturnal changes in body temperature and its control.     

Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer" syndrome.

The aim of this study was to assess the effects of diamorphine on breathlessness and exercise tolerance in patients with severe chronic airflow obstruction and normal arterial carbon dioxide tension (PCO2) levels ("pink puffer" syndrome). In this double-blind, cross-over, randomized study we examined both acute and chronic effects of single and multiple doses of oral diamorphine in 14 "pink puffer" patients. Their mean resting forced expiratory volume in one second (FEV1) was 36% predicted normal, mean arterial oxygen tension (PaO2) was 9.2 kPa and mean PaCO2 was 5.2 kPa. Ten patients took either diamorphine 2.5 or 5 mg or placebo elixir 6 hourly for 2 weeks, recording on a diary card dyspnoea, sleepiness and well-being on a visual analogue scale (VAS). The final treatment was given 30 min before measuring spirometry, arterial blood gases, plasma morphine levels, 6 min walking distances, time walked on treadmill and self-assessment of dyspnoea on a VAS scale after exercise. On two further days, eight patients took two doses, 4 h apart, of either diamorphine 7.5 mg or placebo elixir. Spirometry, 6 min walking distance with a VAS score for dyspnoea were measured before and at 1 h after each dose. Morphine levels and blood gases were also measured. Whether given in single or repeated doses, oral diamorphine had no significant effect on exercise tolerance and breathlessness when compared with placebo. Diamorphine 2.5-7.5 mg produced neither sleepiness nor a deterioration in blood gases. However, plasma levels associated with analgesic efficacy were not achieved with these doses. Thus, as given in this study, oral diamorphine is unlikely to have therapeutic potential in the treatment of dyspnoea in the "pink puffer" syndrome.     

EFFECT OF ORAL ADMINISTRATION OF MELATONIN ON GH RESPONSES TO GRF 1–44 IN NORMAL SUBJECTS

In order to investigate the role of melatonin on the neuroregulation of GH secretion, eight healthy male volunteers each underwent four separate tests in random order separated by at least 1 week. Following oral administration of melatonin (500 mg at -60 min and at -30 min) plasma GH levels were higher than after placebo at 45 min (mean +/- SEM 2.9 +/- 0.8 vs 0.9 +/- 0.4 ng/ml, P less than 0.01) and 60 min (mean +/- SEM 2.9 +/- 0.4 vs 0.8 +/- 0.1 ng/ml, P less than 0.05). Likewise, after prior administration of melatonin, GH responses to GRF 1-44 (1 micrograms/kg i.v. at 0 min) were greater than placebo plus GRF at 15 min (mean +/- SEM 22.4 +/- 6.1 ng/ml vs 11.3 +/- 2.3 ng/ml, P less than 0.05), 45 min (mean +/- SEM 26.2 +/- 5.3 ng/ml vs 13.3 +/- 2.5 ng/ml, P less than 0.01) and 60 min (mean +/- SEM, 24.7 +/- 7.4 ng/ml vs 11.1 +/- 2.5 ng/ml, P less than 0.05). In contrast we did not observe any effect of either 10(-9)M, 10(-7)M melatonin on in-vitro basal GH release and GH responses to 10(-8)M GRF by rat anterior pituitary cells in monolayer culture. These data suggest that melatonin plays a facilitatory role in the neuroregulation of GH secretion, probably by acting at the hypothalamic level.     

Acute moderate-intensity exercise induces vasodilation through an increase in nitric oxide bioavailiability in humans

BACKGROUND: Long-term moderate-intensity exercise augments endothelium-dependent vasodilation through an increase in nitric oxide (NO) production. The purpose of this study was to determine the effects of different intensities of acute exercise on hemodynamics in humans. METHODS: We evaluated forearm blood flow (FBF) responses to different intensities of exercise (mild, 25% maximum oxygen consumption [VO2max]; moderate, 50% VO2max; and high, 75% VO2max; bicycle ergometer, for 30 min) in eight healthy young men. The FBF was measured by using a strain-gauge plethysmography. RESULTS: After exercise began, moderate-intensity exercise, but not mild-intensity exercise, promptly increased FBF from 2.8+/-1.1 mL/min/100 mL to a plateau at 5.4+/-1.6 mL/min/100 mL at 5 min (P<.01) and increased mean arterial pressure from 84.7+/-11.8 mm Hg to a plateau at 125.7+/-14.3 mm Hg at 5 min (P<.01). Moderate-intensity exercise decreased forearm vascular resistance (FVR) from 29.2+/-5.4 to 16.8+/-3.2 mm Hg/mL/min/100 mL tissue (P<.01). The administration of NG-monomethyl-L-arginine, an NO synthase inhibitor, abolished moderate exercise-induced augmentation of vasodilation. Although we were not able to measure FBF during high-intensity exercise because of large body motion, high-intensity exercise markedly increased mean arterial pressure from 82.6+/-12.2 to 146.8+/-19.8 mm Hg. High-intensity exercise, but not mild-intensity or moderate-intensity exercise, increased plasma concentration of 8-isoprostane, an index of oxidative stress, from 24.1+/-10.8 to 40.2+/-16.7 pg/mL (P<.05) at 10 min after the end of exercise. CONCLUSIONS: These findings suggest that acute moderate-intensity exercise induces vasodilation through an increase in NO bioavailability in humans and that high-intensity exercise increases oxidative stress.     

Effects of melatonin ingestion on cAMP and cGMP levels in human plasma

The effects of daytime melatonin treatment (0.3 mg) on cAMP and cGMP levels in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were investigated in 14 normal human subjects (age+/-s.e.m. 26.2+/-3. 2 years). Plasma levels of cAMP, cGMP and melatonin were measured before and at intervals for 3 h after the treatment was administered at 1300 h. Plasma melatonin concentrations reached peak levels 1 h after the treatment (mean+/-s.d. 182.3+/-43.5 pg/ml). The mean areas under the curve (AUC) for the time-cGMP concentration curves in PPP and in PRP were significantly increased after melatonin treatment compared with those observed after placebo treatment (P=0.001). No significant difference in cGMP levels was observed between PPP and PRP. Increase in self-reported sleepiness after melatonin treatment positively correlated with increase in plasma cGMP levels (r=0.92). The mean AUC for the time-cAMP concentration in PRP, but not in PPP, was increased 1 h after melatonin treatment compared with that observed after placebo treatment, but not thereafter. No correlation between individual PRP or PPP cAMP levels and subjective sleepiness was observed. These results demonstrate a stimulating effect of melatonin treatment on plasma cGMP levels in humans and suggest a correlation between the increase in circulating cGMP levels and the sleep-promoting effect of the pineal hormone.     

Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease

Peripheral arterial disease (PAD) is a major cause of morbidity and mortality. Endothelial function, which is a measure of vascular health, is impaired in patients with PAD. We examined the effects of 6 months of aerobic exercise rehabilitation on brachial artery endothelial function, assessed using high-frequency ultrasonography, and calf blood flow in 19 older PAD patients (age 69 +/- 1 years, mean +/- SEM) with intermittent claudication (ankle to brachial artery index of 0.73 +/- 0.04). After exercise, the time to onset of claudication pain increased by 94%, from 271 +/- 49 to 525 +/- 80 seconds (p <0.01), and the time to maximal claudication pain increased by 43%, from 623 +/- 77 to 889 +/- 75 seconds (p <0.05). Exercise rehabilitation increased the flow-mediated brachial arterial diameter by 61%, from 0.18 +/- 0.03 to 0.29 +/- 0.04 mm (p <0.005), as well as the relative change in brachial arterial diameter from the resting state by 60%, from 4.81 +/- 0.82% to 7.97 +/- 1.03% (p <0.005). Maximal calf blood flow (14.2 +/- 1.0 vs 19.2 +/- 2.0 ml/100 ml/min; p = 0.04), and postocclusive reactive hyperemic blood flow (9.8 +/- 0.8 vs 11.3 +/- 0.7 ml/100 ml/min; p = 0.1) increased 35% and 15%, respectively. In conclusion, exercise rehabilitation improved ambulatory function, endothelial-dependent dilation, and calf blood flow in older PAD patients with intermittent claudication.     

Different circulatory response to melatonin in postmenopausal women without and with hormone replacement therapy

In young men and women, melatonin influences vascular reactivity and reduces blood pressure and norepinephrine levels. Herein, we investigated whether these effects are conserved in postmenopausal women without and with hormone replacement therapy (HRT). Oral melatonin (1 mg) or placebo was randomly and in double blind fashion administered to 18 untreated and 13 postmenopausal women who were treated continuously with transdermal estradiol (50 microg/day) plus cyclic medroxyprogesterone acetate (5 mg/day x 12 days every 28 days). Internal carotid artery pulsatility index (PI), an index of downstream resistance to blood flow, blood pressure and catecholamine levels were evaluated. In untreated postmenopausal women, melatonin was ineffective, while in HRT-treated women, studied during the only estrogenic phase, melatonin reduced, within 90 min, systolic (-8.1 +/- 9.9 mmHg; P = 0.054), diastolic (-5.0 +/- 7.0 mmHg; P = 0.049) and mean (- 6.0 +/- 6.6 mmHg; P = 0.037) blood pressure. Norepinephrine (-50.1 +/- 66.7 pg/mL; P = 0.019), but not epinephrine levels, were also significantly reduced. Similarly, resistance to blood flow in the internal carotid artery, as evaluated by the PI, decreased (-0.190 +/- 0.15; P = 0.0006) in a way that was linearly related to pre-existing PI values (r2 = 0.5; P = 0.0059). These data show that the circulatory response to melatonin is conserved in postmenopausal women on HRT but not in untreated postmenopausal women. Possible physiological and pharmacological implications of these data on the cardiovascular risk of postmenopausal women can be envisioned.     

Circulatory effects of mental stress during exercise in coronary artery disease patients

We examined the effects of mental stress during steady-state exercise on heart rate, blood pressure, pressure-rate product, and oxygen uptake in 10 coronary artery disease patients. Subjects walked at three mph with grade increases of 4% every two minutes until the target heart rate (60% peak heart rate from a previous symptom-limited exercise test) was reached. A computerized Stroop-Color-Word Test (mental stress) was added one minute after the subject reached steady-state exercise and lasted 11 +/- 4 minutes. When mental stress was added to steady-state exercise it significantly (p less than 0.01) increased the heart rate (101 +/- 15 to 108 +/- 19 beats per min), systolic (154 +/- 26 to 170 +/- 26 mmHg) and diastolic (86 +/- 10 to 92 +/- 13 mmHg) blood pressure, and pressure-rate product (158 +/- 42 to 179 +/- 48 x 10(-2)). This increase in the mean response during exercise and mental stress was not observed for oxygen uptake (17 +/- 6 to 18 +/- 5 ml/kg/min). The circulatory changes probably reflect increased sympathetic activity with both centrally mediated cardioacceleratory (and probably cardiac output) and vasoconstrictor effects during the combination of mental stress and steady-state exercise. The altered hemodynamics without concomitant changes in oxygen uptake has major implications concerning the safety of competitive exercise for people with coronary artery disease.     

Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia

Abstract: Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) associated with hypertension, insulin resistance and a systemic inflammatory response. We evaluated the effects of melatonin on vasodilation, capillary perfusion in hamster cheek pouch and insulin resistance, hypertension, and reactive oxygen species (ROS) and nitrate/nitrite levels after IH for 4 wk. Syrian hamsters were divided into four groups: control group (CON), IH group, and melatonin (10 mg/kg) intraperitoneally administered daily for 4 wk/30 min before intermittent air (MEL) or IH (IH + MEL) exposure. IH alone caused elevated blood pressure, increased hematocrit, fasting hyperglycemia, elevated ROS and nitrite/nitrate levels, and vasoconstriction and reduced microvascular perfusion. Melatonin treatment of IH‐exposed animals decreased blood pressure, blood glucose, and ROS and nitrite/nitrate levels, and increased vasodilation and capillary perfusion. An oral glucose tolerance test was performed after 4 wk of IH. During the last 30 min of the hyperinsulinemic euglycemic clamp, blood glucose, and insulin levels were identically matched between groups, but the glucose infusion rate was significantly reduced in IH (29.9 ± 1.9 mg/kg/min) versus IH + MEL group (45.4 ± 1.5 mg/kg/min, P < 0.05) demonstrating a decrease in insulin sensitivity. These results suggest that ROS and nitrite/nitrate levels play important roles in the microvascular dysfunction in IH and that this process is attenuated by melatonin. In conclusion, protection induced by melatonin against functional and metabolic impairment in IH is related to the regulation of ROS and nitrite/nitrate levels in the microcirculation. These observations may have importance to OSA pathological changes.     

Exercise training produces nonuniform increases in arteriolar density of rat soleus and gastrocnemius muscle

OBJECTIVE: Exercise training has been shown to increase regional blood flow capacity to muscle tissue containing fibers that experience increased activity during exercise. The purpose of this study was to test the hypothesis that the increased blood flow capacity is partially the result of increases in arteriolar density (number of arterioles/mm2 of tissue), specifically in skeletal muscle tissue, with the largest relative increase in muscle fiber activity during training bouts. METHODS: This hypothesis was tested by comparing and contrasting the effects of endurance exercise training (ET) and interval sprint training (IST) on arteriolar density in soleus muscle (S) red (Gr) and white (Gw) portions of gastrocnemius muscle of male Sprague Dawley rats. ET rats completed 10 weeks of treadmill training 30 m/min, 15% grade, 60 min/day, 5 days/week, while IST rats completed 10 weeks of IST consisting of six 2.5-min exercise bouts, with 4.5-min rest between bouts (60 m/min, 15% incline), 5 days/week. The hypothesis would be supported if ET increased arteriolar density in S and Gr and if IST increased arteriolar density in Gw. RESULTS: ET increased arteriolar density above values of sedentary rats (SED) in both the Gw (ET = 0.93 +/- 0.19 arterioles/microm2; SED = 0.44 +/- 0.09 arterioles/microm2) and Gr (ET = 0.97 +/- 0.1 arterioles/microm2; SED = 0.51 +/- 0.06 arterioles/microm2) muscles, but not in S (ET = 1.69 +/- 0.45 arterioles/microm2; SED = 1.51 +/- 0.34 arterioles/microm2) muscle. In contrast, IST did not alter arteriolar density in Gw or Gr muscle tissue. Although arterial wall thickness was greater in S (3.95 +/- 0.40 microm) and Gr (6.24 +/- 0.59 microm) than Gw (2.76 +/- 0.18 microm), neither ET or IST altered mean wall thickness in either muscle. CONCLUSION: Increases in blood flow capacity produced in Gr and Gw by ET appear to be due in part to increased arteriolar density. In contrast, increased arteriolar density does not contribute to increased blood flow capacity of Gw in IST rats.     

Haemodynamic contributions to post-exercise hypotension in young adults with hypertension and rapid resting heart rates.

The haemodynamic effects of 45 min of treadmill exercise (at 70% of resting heart rate reserve) were determined in 5 young adults with hypertension and rapid resting heart rates (greater than 90 beats/min in clinic) and were compared with those of 5 age-matched normotensive subjects. Blood pressure was lower after exercise in the hypertensive, but not the normotensive subjects. Mean cardiac output before exercise was similar in the two groups, and fell from 6.8 +/- 0.6 before to 5.4 +/- 0.6 l/min 60 min after exercise in the hypertensive group (P less than 0.01). Total peripheral resistance tended to be higher at this time. Neither variable was affected by prior exercise in the normotensive group. The depressor effects of prior exercise on mean arterial pressure (-8.6 +/- 1.0 vs. -1.4 +/- 2.5 mmHg; P less than 0.04) and cardiac output (-1.4 +/- 0.3 vs. -0.1 +/- 0.1 l/min; P less than 0.005) and the increase in total peripheral resistance (+3.0 +/- 1.2 vs. 0.0 +/- 1.0 Units; P less than 0.05) were greater in the hypertensive group. Thus, the post-exercise hypotension in this selected group of young hypertensive subjects with rapid resting heart rates was mediated by a decrease in cardiac output and stroke volume disproportionate to the fall in blood pressure, suggesting sustained compromise of their cardiac performance after acute exercise.     

Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients

An open pilot study on the safety and efficacy of melatonin in the treatment of insomniac patients was conducted in 22 subjects (16 females), mean +/- S.D. age 60.1 +/- 9.5 years. All patients received 3 mg of gelatin melatonin capsules per os daily for 6 months, 30 min before expected sleep time. Twenty of 22 patients were on benzodiazepine treatment and they continued this treatment for part of or for the entire melatonin administration period. Serum concentrations of prolactin, follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), or estradiol were measured by radioimmunoassay (RIA) in morning samples at the beginning and after 6 months of melatonin administration, and standard clinical laboratory tests for blood components were performed. Urinary 6-sulphatoxymelatonin (aMT6s) excretion was measured by RIA before treatment. Serum concentrations of prolactin, FSH, TSH, or estradiol did not exhibit changes after 6 months of melatonin administration, nor were any indications of hematologic or blood biochemistry alteration found. Melatonin augmented significantly the quality and duration of sleep, and decreased sleep latency and the number of awakening episodes, as assessed from sleep logs filled by the patients (first 21 days) and from structured interviews performed by incumbent physicians (up to 6 months). Estimates of next-day function (i.e., alertness in the morning and during the day) also improved significantly during melatonin treatment. The observed effect lasted for the entire period examined (up to 6 months), with 22 out of 22 patients showing improved sleep at the end of treatment. The urinary excretion of aMT6s before starting administration of melatonin correlated negatively and significantly with age, but not with the intensity of sleep the disorder or the outcome of treatment. In 13 of 20 patients taking benzodiazepines together with melatonin, benzodiazepine use could be stopped, and in another four patients, benzodiazepine dose could be decreased to 25-66% of the initial dose. The results of this open, subacute administration trial indicate that melatonin is a safe and useful treatment for sleep disturbances in middle-aged or elderly patients, either by itself or together with benzodiazepines.     

Effect of the sympathetic nervous system on limb circulation and metabolism during exercise in patients with heart failure

During exercise in patients with heart failure, activation of sympathetic vasoconstrictor nerves may impair vasodilation in active skeletal muscle and thereby interfere with skeletal muscle blood flow. To investigate this hypothesis, we examined the effect of acute alpha-adrenergic blockade with systemic administration of prazosin (10 patients) or regional administration of phentolamine (eight patients) on blood flow, vascular resistance, oxygen consumption (VO2), and lactate release in the leg during maximal bicycle exercise in patients with heart failure. During control exercise, systemic VO2 increased to 12.6 +/- 4.3 ml/min/kg (normal greater than 20 to 25 ml/min/kg), leg blood flow to 2.8 +/- 1.8 liters/min, and leg lactate release to 362 +/- 256 mg/min. Prazosin decreased systemic vascular resistance (12.5 +/- 3.2 to 9.7 +/- 2.5 units; p less than .003) and mean arterial pressure (101 +/- 20 to 87 +/- 22 mm Hg; p less than .002) at maximal exercise, supporting the presence of substantial sympathetic vasoconstrictor nerve activity. Prazosin also decreased leg resistance during exercise. However, the magnitude of leg blood flow, leg oxygen extraction, and leg VO2 during exercise were unchanged, suggesting that vasodilation in the leg was produced by an autoregulatory response to the drop in blood pressure rather than by blockade of sympathetic vasoconstriction. Maximal systemic VO2 and leg lactate release were also not improved. Regional blockade with phentolamine did not substantially drop the arterial blood pressure and had no effect on vasodilation, blood flow, VO2, and lactate release in the leg during exercise. These data suggest that during exercise in patients with heart failure, the sympathetic nervous system helps to sustain arterial blood pressure and that this beneficial effect is not associated with adverse effects on blood flow to working skeletal muscle.     

Response of upper limb blood flow to handgrip exercise after Blalock-Taussig operation (for tetralogy of Fallot) or subclavian flap operation (for aortic isthmic coarctation)

To evaluate the effects of long-term reductions in perfusion pressure on blood flow responses to increased functional demand, 5 patients (aged 12 to 26 years) without normal aortic to subclavian artery blood flow to 1 arm as a result of surgery to treat congenital heart disease were studied. Five age- and sex-matched healthy (control) subjects were also studied. In the patients, forearm blood flow was not different in the surgical and normal arms at rest (3.6 +/- 0.6 vs 4.0 +/- 0.7 ml/min/100 ml, respectively, mean +/- standard error, difference not significant) despite lower systolic blood pressure in the surgical arm (87 +/- 2 vs 115 +/- 2 mm Hg, p less than 0.05). The increases in heart rate, systolic blood pressure, forearm electromyographic activity (index of muscle fatigue) and postexercise forearm blood flow (index of muscle oxygen deficit) were not different in response to 2.5 minutes of submaximal rhythmic handgrip exercise (50% of maximal force) performed with the surgical versus the normal arms. Peak forearm blood flow elicited by combined ischemia and maximal isometric handgrip exercise was not significantly different in surgical and normal arms in the group as a whole (39 +/- 4 vs 43 +/- 3 ml/min/100 ml, difference not significant), although some bilateral deficit (20 to 38%) was observed in 2 patients. No bilateral differences were observed in the control subjects under any condition. The finding of normal physiologic adjustments to submaximal rhythmic handgrip exercise with the surgical arm suggests that oxygen delivery during exercise was adequate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood pressure-lowering effect of melatonin in type 1 diabetes

Our long-term goal is to determine the utility of melatonin in prevention of hypertension in type 1 diabetes. We recently reported that 5 mg melatonin taken at bedtime increases the nocturnal drop of diastolic blood pressure (BP) in adolescents with type 1 diabetes. The present study tested the hypothesis that a higher dose of melatonin, 10 mg, lowers both systolic and diastolic BP in these patients. The design was an open-label trial of 10 mg melatonin taken at bedtime daily for 7 days. Nine normotensive adolescents with type 1 diabetes, 16.2 +/- 0.3 yr old, and eight healthy controls, 16.6 +/- 0.6 yr old participated. BP was measured every 20 min by ambulatory monitoring device for 24 hr before treatment onset and on the last treatment day; sleep was monitored by diary and wrist actigraphy. Outcome measures were BP during wake, sleep and over a 24-hr period. Sleep duration and number of awakenings were used as covariates. Significance for this pilot study was set at P < 0.10. In patients with diabetes the mean BP during sleep was lower on melatonin than before treatment: systolic 104.0 +/- 2.4 and 108.4 +/- 2.4 mmHg (P = 0.085) and diastolic, 57.1 +/- 1.9 and 59.3 +/- 1.9 mmHg (P = 0.079), respectively. In controls there was no significant effect of melatonin on BP. There was no significant effect of sleep duration or number of awakenings on the BP responses. We conclude that the present results justify phase III therapeutic trials to determine the utility of melatonin in prevention of hypertension and cardiovascular complications in type 1 diabetes.