Impaired skin blood flow response to environmental heating in chronic heart failure.

AIMS: We examined the thermoregulatory response to heat exposure in patients with chronic heart failure. METHODS AND RESULTS: Skin blood flow (SkBF) was measured in HF subjects and matched controls. Cutaneous vascular conductance (CVC) was calculated from laser-Doppler SkBF and blood pressure. To assess the nitric oxide contribution to thermoregulatory responses, subcutaneous microdialysis membranes were placed beneath the laser-Doppler probes to infuse N(G)-nitro-l-arginine methyl ester (l-NAME), or Ringer's solution. Core (T(C)) and skin temperatures (five sites, T(Sk)) were continuously recorded. Subjects were studied during normothermia then at 38 degrees C, 50%RH within a climate chamber. T(C) and T(Sk) did not differ between HF and controls during normothermia and heating induced similar increases in both groups. During heating, CVC rose in both groups, but significantly less so in HF (HF 43.9+/-7.8 vs. controls 58.0+/-7.5% CVC(max), P<0.05). l-NAME attenuated SkBF responses in the control (58.0+/-7.5 vs. 34.6+/-5.1% CVC(max), P<0.001) and HF subjects (43.9+/-7.8 vs. 27.0+/-2.2% CVC(max), P<0.005), with a larger effect evident in the controls (P<0.05). CONCLUSION: HF patients exhibit impaired thermoregulatory responses to heat exposure. Lower SkBF in HF, which defends blood pressure during heat exposure, also predisposes these subjects to heat intolerance.     

Baroreflex control of the cutaneous active vasodilator system in humans

Cutaneous arterioles are controlled by vasoconstrictor and active vasodilator sympathetic nerves. To find out whether the active vasodilator system is under baroreceptor control, laser-Doppler velocimetry and the local iontophoresis of bretylium were combined to allow selective study of the active vasodilator system. Each of six subjects had two forearm sites (0.64 cm2) treated with bretylium to abolish adrenergic vasoconstrictor control. Laser-Doppler velocimetry was monitored at those sites and at two adjacent untreated sites. Subjects underwent 3 minutes of lower-body negative pressure (LBNP) and 3 minutes of cold stress to verify blockade of vasoconstrictor nerves. They were then subjected to whole-body heat stress (water-perfused suits), and the 3 minutes of LBNP was repeated. Finally, subjects were returned to normothermia, and LBNP and cold stress were repeated to verify the persistence of blockade. During the application of LBNP in normothermia, cutaneous vascular conductance (CVC) fell at untreated sites by 22.7 +/- 4.7% (p less than 0.01) but was unaffected at bretylium-treated sites (p greater than 0.20). During cold stress, CVC at untreated sites fell by 30.2 +/- 1.7% (p less than 0.01) and at treated sites rose by 0.7 +/- 4.6% (p greater than 0.10). Both control and bretylium-treated sites reflexly vasodilated in response to hyperthermia. With LBNP during hyperthermia, CVC at untreated sites fell by 23.3 +/- 7.1% (p less than 0.05) and at treated sites 17.9 +/- 9.2% (p less than 0.05) with no significant difference between sites (p greater than 0.10). After return to normothermia, neither LBNP application nor cold stress caused CVC to fall at treated sites (p greater than 0.10). Thus, the vasoconstrictor system was blocked by bretylium treatment throughtout the study, whereas the active vasodilator response to heat stress was intact. Because LBNP in hyperthermia induced similar falls in CVC at both sites, we conclude that baroreceptor unloading elicits a withdrawal of active vasodilator tone and that the baroreflex has control of the active vasodilator system.     

Maternal melatonin stimulates growth and prevents maturation of the capuchin monkey fetal adrenal gland

The primate fetal adrenal reaches a large size relative to body weight followed by a rapid decrease in size in the postnatal period. We tested the hypothesis that maternal melatonin stimulates growth and prevents maturation of the primate fetal adrenal gland. We suppressed maternal melatonin by exposing eight pregnant capuchin monkeys to constant light (LL) from 63% to 90% gestation (term 155 days). Three of these received daily oral melatonin replacement (LL + Mel). Five mothers remaining in light:dark cycle were used as controls. Fetuses were delivered at 90% gestation. The absence of maternal melatonin selectively decreased fetal adrenal weight (Control: 488.8 +/- 51.5; LL: 363.2 +/- 27.7 and LL + Mel 519 +/- 46 mg; P < 0.05 ANOVA) without effecting fetal weight, placental weight or the weight of other fetal tissues. Changes in fetal adrenal size were accompanied by an increase in the levels of Delta5-3beta-hydroxysteroid dehydrogenase (3beta-HSD) mRNA (Control: 0.8 +/- 0.2; LL: 5.2 +/- 0.6 and LL + Mel 0.8 +/- 0.1; 3beta-HSD/18S-rRNA; P < 0.05 ANOVA). In vitro we found that maternal melatonin suppression increased basal progesterone production to levels similar to those of the adult adrenal gland (Control: 0.36 +/- 0.09; LL 0.99 +/- 0.13; LL + Mel 0.18 +/- 0.06 and adult: 0.88 +/- 0.10 ng/mg of tissue; P < 0.05 ANOVA) but no change in cortisol production. We found an increased production of cortisone (Control: 1.65 +/- 0.60; LL: 5.44 +/- 0.63; LL + Mel: 2.90 +/- 0.38 and adult: 1.70 +/- 0.45 ng/mg of tissue; P < 0.05 ANOVA). Collectively, the effects of maternal melatonin suppression and their reversion by maternal melatonin replacement suggest that maternal melatonin stimulates growth and prevents maturation of the capuchin monkey fetal adrenal gland.     

Evaluation of a wireless ingestible temperature probe in cardiac surgery

OBJECTIVES: CorTemp is a wireless intestinal temperature monitoring system in the form of an ingestible pill and an external receiver. The aim of the study was to evaluate the system's accuracy and practicality during cardiac surgery. METHODS: A repeat measures design using simultaneous temperature readings from the pulmonary artery (T (pa)), a nasopharyngeal thermometer (T (np)), skin thermometers (T (sk)) and the CorTemp system (T (in)), was conducted in 15 patients undergoing elective cardiac surgery under hypothermic conditions. RESULTS: Only 67 % of patients' data was analysed and the statistical analysis of a total of 264 sets of readings showed a clinically significant temperature difference of T (in) compared to the other thermometers with limits of agreement between T (in) and T (pa), T (np) and T (sk) (+/- 0.35 to +/- 1.53 degrees C), (+/- 0.72 to +/- 1.63 degrees C) (+/- 0.40 to +/- 1.84 degrees C), respectively. The T (in) bias was significantly different from that of T (pa) ( P = 0.0023), T (np) ( P = 0.018) and T (sk) ( P = 0.0005) during rewarming. The T (in) rate of temperature change was also found to be significantly slower during the rewarming period. CONCLUSIONS: The significant temperature differences detected during rewarming urge caution regarding CorTemp use as an accurate estimator of brain temperature in cardiac surgery. Further studies are required to assess its potentially useful role as a body core and intestinal temperature monitoring system and as a useful adjunct in investigating bowel ischaemia aetiology in cardiac surgery.     

Effects of melatonin on the thermoregulatory responses to intermittent exercise

We examined the effects of a single 2.5-mg dose of melatonin on the thermoregulatory and circulatory responses to intermittent exercise at a room temperature of 27.2+/-0.4 degrees C (mean+/-S.D.), a relative humidity of 55+/-3% (mean+/-S.D.), and a light intensity of 200-300 lux. In a double-blind cross-over study, six male participants ingested either melatonin or placebo at 11:45 hr. Participants then rested in a semi-supine position for 75 min and completed an intermittent running protocol for 66 min at alternating intensities of 40, 60 and 80% of maximal oxygen uptake. Rectal and mean skin temperature, heart rate, blood pressure, skin blood flow, subjective alertness and sleepiness, ratings of perceived exertion (RPE) and thermal strain were recorded. No effects of melatonin were found on these variables measured during the resting period (P>0.10). During exercise, melatonin was found to moderate the increase in rectal temperature by approximately 0.25 degrees C (P=0.050) and magnify the increase in skin blood flow (P=0.047). Postexercise systolic blood pressure was 7.8+/-2.5 mmHg (mean+/-S.D.) lower than before the exercise in the melatonin trial; a change which differed significantly to that in the placebo trial (P=0.018). Melatonin did not influence subjective alertness and sleepiness before or after exercise and did not change the responses of mean skin temperature, RPE and thermal strain during the exercise (P>0.10). In summary it is apparent that a 2.5-mg dose of melatonin has hypothermic, but not soporific, effects during 66 min of intermittent exercise performed under moderate heat stress. Whether such effects improve endurance athletic performance in hot conditions remains to be confirmed. Our data also suggest that postexercise systolic hypotension is more marked after ingestion of melatonin.     

Effects of melatonin on peripheral reproductive function: regulation of testicular GnIH and testosterone

Study of seasonal reproduction has focused on the brain. Here, we show that the inhibition of sex steroid secretion can be seasonally mediated at the level of the gonad. We investigate the direct effects of melatonin on sex steroid secretion and gonadal neuropeptide expression in European starlings (Sturnus vulgaris). PCR reveals starling gonads express mRNA for gonadotropin inhibitory hormone (GnIH) and its receptor (GnIHR) and melatonin receptors 1B (Mel 1B) and 1C (Mel 1C). We demonstrate that the gonadal GnIH system is regulated seasonally, possibly via a mechanism involving melatonin. GnIH/ GnIHR expression in the testes is relatively low during breeding compared with outside the breeding season. The expression patterns of Mel 1B and Mel 1C are correlated with this expression, and melatonin up-regulates the expression of GnIH mRNA in starling gonads before breeding. In vitro, GnIH and melatonin significantly decrease testosterone secretion from LH/FSH-stimulated testes before, but not during, breeding. Thus local inhibition of sex steroid secretion appears to be regulated seasonally at the level of the gonad, by a mechanism involving melatonin and the gonadal GnIH system.     

Melatonin treatment protects against ischemia/reperfusion-induced functional and biochemical changes in rat urinary bladder

Reactive oxygen metabolites play important roles in ischemia/reperfusion (I/R) injury in several systems. The aim of this study was to investigate the role of melatonin against I/R injury of the rat urinary bladder. The abdominal aorta was clamped to induce ischemia for 30 min, then the animals were subjected to 60 min of reperfusion. Melatonin (10 mg/kg, i.p.) or the vehicle (control 1% alcohol i.p.) was administered before I/R. After decapitation, the bladder was removed and the tissue was either used for functional studies or stored for measurement of products of lipid peroxidation (LP), glutathione (GSH) levels and myeloperoxidase activity (MPO). Bladder strips were suspended in oxygenated Tyrode's buffer at 37 degrees C and isometric contractions to carbachol (CCh; 10(-8)-10(-4) m) were recorded. In the I/R group, the contractile responses of the bladder strips were lower than those of the control group (P < 0.01-0.001) and were reversed by treatment with melatonin (P < 0.05-0.001). LP which was higher in I/R group compared with control (27.68 +/- 1.69 and 10.59 +/- 1.27 nmol/g, respectively; P < 0.001) was partially reversed by melatonin (19.01 +/- 1.85 nmol/g; P < 0.01). Similarly, GSH showed a decrease in the I/R group compared with controls (0.27 +/- 0.03 and 0.43 +/- 0.04 micromol/g, respectively; P < 0.05) and melatonin prevented this effect completely (0.45 +/- 0.04 micromol/g; P < 0.05). MPO activity in the I/R group (4.19 +/- 0.08 U/g) was significantly higher than that of the control group (1.41 +/- 0.08 U/g; P < 0.001) and melatonin treatment reduced MPO levels compared with I/R alone (3.16 +/- 0.07; P < 0.001). Melatonin almost completely reversed the low contractile responses of rat urinary bladder strips to CCh and prevented oxidative tissue damage following I/R.     

mTOR信号介导的自噬在褪黑素减轻心脏缺血/再灌注损伤中的作用

目的 探讨mTOR信号介导的自噬在褪黑素（melatonin,Mel）减轻心脏缺血/再灌注损伤中的作用。方法 将60只8周龄C57BL/6小鼠随机分为假手术（Sham）组、单纯褪黑素10 mg/(kg·d)处理(Mel)组、缺血/再灌注（ischemia reperfusion,I/R）组和褪黑素10 mg/(kg·d)干预I/R（Mel+I/R）组。采用冠状动脉左前降支结扎术制备心肌I/R模型,HE染色观察心肌组织形态学变化,试剂盒检测各组血清中LDH的含量,TUNEL染色检测各组细胞凋亡情况,蛋白印迹法（Western blot）检测自噬相关蛋白微管相关蛋白1轻链3（microtubule-associated protein 1 light chain 3,LC3）I和II、Beclin1和mTOR磷酸化的表达,免疫荧光染色法检测LC3B的表达。结果 与Sham组相比,Mel组各项指标均无明显变化;I/R组心肌纤维断裂明显排列紊乱,血清中LDH含量明显增加（P<0.01）,TUNEL阳性细胞明显增多（P<0.01）,LC3II和Beclin1表达显著升高（P<0.01）,而磷酸化mTOR的表达降低（P<0.01）,免疫荧光结果显示LC3B表达增加（P<0.01）; Mel+I/R组可明显减轻心肌纤维的断裂,降低血清中LDH含量（P<0.01）,减少TUNEL阳性细胞数（P<0.01）,减少LC3II和Beclin1的表达（P<0.01）,降低免疫荧光染色中LC3B的表达（P<0.01）。结论 褪黑素通过调节mTOR信号介导的自噬减轻心脏I/R损伤。     

Attenuation of lipopolysaccharide-induced hyperreactivity of human internal mammary arteries by melatonin

Reactive oxygen species (ROS) are thought to be important mediators in ischaemia/reperfusion injury following coronary vasospasm. The most ubiquitous action of melatonin is that of a free radical scavenger. Therefore, we investigated the action of melatonin by monitoring changes in the tone on ring preparations from human internal mammary arteries (IMA). In quiescent IMA rings melatonin (0.1 nm-10 microm) never elicited any change in baseline tension but 1-100 nm melatonin enhanced significantly maximal responses to noradrenaline (NA) in arteries with endothelial function. In NA (1 microm) precontracted arteries inhibition of nitric oxide (NO(*)) formation by N(G)-monomethyl-L-arginine (l-NMMA, 100 and 400 microm) eliminated 43 +/- 7 and 61 +/- 7% of the acetylcholine (ACH) effect. Melatonin (100 and 400 nm) attenuated maximal endothelium-dependent relaxant responses to ACH slightly by 23 +/- 9 and 17 +/- 9% leaving responses to direct stimulation of soluble guanylate cyclase by sodium nitroprusside unchanged. Incubation of IMA for 20 hr at 37 degrees C with 1 microg/mL lipopolysaccharide (LPS) enhanced maximal NA effects to 147 +/- 18% (n = 22, P < 0.01) whereas 50 microg/mL LPS reduced the NA maxima to 68 +/- 9% (n = 10, P < 0.01) of the control effects. The LPS-induced potentiation was completely attenuated by coincubation with melatonin (400 nm) and significantly reduced by coincubation with the thromboxane synthase inhibitor dazoxiben (10 microm). It is suggested that the LPS-induced hyperreactivity of vascular smooth muscle is mediated through enhanced release of ROS and prostanoids and that melatonin inhibits the vascular hyperreactivity through selective scavenging of ROS.     

Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C beta inhibitor, ruboxistaurin

PURPOSE: This article aims to study the effects of ruboxistaurin (RBX) on skin microvascular blood flow (SkBF) and evaluate the relationship between endothelial and neural control of SkBF in patients with diabetic peripheral neuropathy (DPN). METHODS: We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression. RESULTS: No significant differences (RBX vs. placebo) were demonstrable for post-iontophoresis SkBF [fold increase from basal state (1 year): endothelium-dependent, 3.6 vs. 8.6; endothelium-independent, 3.7 vs. 2.0; C fiber-mediated, 1.7 vs. 2.0; P>.05] or sensory symptoms [NTSS-6 total score (1 year): 7.7 vs. 6.0 points; P=.4]. There were also no significant between-group differences in nerve conduction parameters, except for placebo peroneal nerve conduction velocity, which demonstrated a statistically significant improvement of unknown clinical importance (Z=2.1; P=.034). At baseline, C fiber-mediated vasodilatation correlated well with endothelium-dependent vasodilation (r=.7, P<.01) but not with endothelium-independent vasodilatation (r=-.1, P=.7). CONCLUSIONS: RBX demonstrated no effect on SkBF or sensory symptoms after 1 year in this cohort. The correlation between C fiber-mediated and endothelium-dependent SkBF at baseline suggests that improving endothelial function could affect the microcirculation not only locally but also via the neurovascular arcade.     

Fat oxidation after acipimox-induced reduction in plasma nonesterified fatty acids during exercise at 0 degrees C and 20 degrees C

The main aim of this study was to investigate if whole body fat oxidation, after acipimox administration, during submaximal exercise in the cold, is different from that at temperate environments. Seven healthy recreationally active male subjects cycled at 70% Vo(2peak) for 60 minutes; once at 0 degrees C and once at 20 degrees C. To exclude availability, and therefore oxidation of plasma-derived nonesterified fatty acids (NEFA), 90 minutes before each cycling bout, subjects ingested 250 mg of the antilipolytic drug, acipimox. Blood and expired gas measurements were obtained at rest, immediately before exercise, and at 15, 30, 45, and 60 minutes of exercise. In both trials, after the ingestion of acipimox, plasma NEFA concentrations fell dramatically and immediately before and during exercise were lower than 0.05 mmol. L(-1) in both trials. Pre-exercise and exercise values of glycerol, glucose, triacylglycerol (TG), and rectal temperature (T(re)) were not different between the 0 degrees C and 20 degrees C trials. During exercise at 0 degrees C, skin temperature (T(sk)) was significantly reduced from pre-exercise values (P <.05) and at all time points was significantly lower than during exercise at 20 degrees C. Muscle temperature did not differ between trials but in both trials was lower (P <.05) at 1 cm depth than at 3 cm and 2 cm. Gross energy expenditure of cycling (0 degrees C trial, 3.6 +/- 0.1 MJ; 20 degrees C trial, 3.6 +/- 0.1 MJ), the oxidation rates of carbohydrate (0 degrees C, 32.4 +/- 0.5 KJ. min(-1); 20 degrees C, 32.6 +/- 0.7 KJ. min(-1)) and fat (0 degrees C, 24.6 +/- 1.2 KJ. min(-1); 20 degrees C, 23.0 +/- 1.8 KJ. min(-1)), and the proportion of energy derived from fat (0 degrees C, 45 +/- 1 %; 20 degrees C, 40 +/- 4%) and carbohydrate (0 degrees C, 55 +/- 1%; 20 degrees C, 58 +/- 3%) were not different between the 2 trials. In conclusion, after acipimox administration, whole body fat oxidation during exercise, designed to avoid adjustment of core temperature or thermogenesis, is not different at 0 degrees C compared with 20 degrees C. This allows the inference that during submaximal exercise, cold has no effect on the utilization of intramuscular TG (IMTG).     

Reproductive effects of placing micro-implants of melatonin in the mediobasal hypothalamus and preoptic area in rams.

The reproductive effects of placing micro-implants of melatonin in the mediobasal hypothalamus (MBH) and preoptic area (POA) were monitored in Soay rams. Groups of animals were initially conditioned to alternating 16 weekly periods of long days (16 h light: 8 h darkness; 16L:8D) and short days (8L:16D) for at least 9 months to entrain the seasonal reproductive cycle. All experiments were then initiated at 10 weeks under long days when the animals were sexually inactive. In experiment 1, rams were exposed to short days for 14 weeks or maintained on long days to illustrate the photoperiodically induced re-activation and regression of the reproductive axis. In experiments 2-4, rams received micro-implants of melatonin in the MBH or POA, or received control treatments (sham-operated or no surgery) for 12-14 weeks while maintained on long days (total of 12 animals/treatment). The melatonin implants consisted of 22-gauge stainless-steel cannulae with melatonin fused inside the tip and were placed bilaterally in the brain. Incubation of the implants in Tricine-buffered saline (pH 8.0) at 37 degrees C showed that the release rate of melatonin was relatively constant after an initial peak in week 1 (means +/- S.E.M.: 3.42 +/- 0.43 micrograms/24 h). Rams with melatonin implants placed in the MBH, but not in the POA, showed a consistently earlier re-activation of the reproductive axis compared with the control animals in all three experiments (12/12 for MBH vs 2/12 for POA). The mean time to maximum testicular diameter was 12.2 +/- 0.9, 21.6 +/- 1.8 and 22.3 +/- 1.2 weeks for the MBH, POA and combined control groups respectively (MBH vs control, P less than 0.01; analysis of variance). The premature growth of the testes in the MBH group was associated with an earlier increase in the blood plasma concentrations of FSH and testosterone, and the appearance of the sexual skin coloration. Removal of the implants resulted in a decline in all reproductive parameters. The melatonin treatments did not cause a detectable increase in the peripheral concentrations of melatonin, or affect the diurnal rhythm in melatonin which reflected the long-day photoperiod. When implants containing 125I-labelled melatonin were introduced into the brain the associated radioactivity was localized to within 1 mm of the implants. The overall results demonstrate that the constant administration of melatonin into the MBH blocks the effect of the endogenous long-day melatonin signal and induces gonadal redevelopment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Potent therapeutic effect of melatonin on aging skin in pinealectomized rats

It is generally agreed that one of the major contributors to skin aging is reactive oxygen species. As organisms reach advanced age, free radical generation increases and the activity of tissue antioxidant enzyme system decreases. Melatonin is an antioxidant and free radical scavenger. The present study was first aimed to determine the morphometric and biochemical changes caused by long-term pinealectomy in order to investigate the role of melatonin as skin architecture. Secondly, the effect of exogenous melatonin administration on these changes was determined. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in important morphometric and biochemical changes in the back, abdominal and thoracic skin. The thickness of epidermis and dermis and the number of dermal papillae and hair follicles were reduced. Melatonin administration to pinealectomized rats significantly improved these alterations in all body areas (P < 0.005). On the contrary, in pinealectomized rats the levels of antioxidant enzymes, catalase and glutathione peroxidase were decreased. Melatonin restored the levels of these enzymes. The pinealectomy-induced increases in lipid peroxidation in the abdominal and thoracic skin were significantly reduced by melatonin treatment (P < 0.005 and 0.01 respectively). These results suggest that melatonin is highly efficient anti-aging factor and, as melatonin levels decrease with age, melatonin treatment may reduce age-related skin changes.     

Thermoregulatory responses in post-coronary artery bypass surgery and healthy males during moderate exercise in warm and cool environments

PURPOSE: The purpose of this study was to determine and compare the thermoregulatory and hemodynamic responses to moderate intensity exercise (60% of peak oxygen consumption [.VO(2peak)]) in warm (35 degrees C, 45% relative humidity) and cool (18 degrees C, 65% relative humidity) environments in men who had previously undergone coronary artery bypass graft (CABG) surgery and healthy control subjects, matched for age and body composition. METHODS: Fourteen post-CABG men and 16 healthy control subjects were recruited and walked 40 minutes at a moderate intensity, in randomized order, in warm and cool environments (on separate days). Measures of heart rate, systolic and diastolic blood pressures, rating of perceived exertion, core (rectal)(T(c)) and mean skin temperatures (T(sk)), oxygen consumption (.VO(2peak)), sweat rate, and blood lactate were taken. RESULTS: Both groups showed a larger increase (P <.05) in T(c) and rate-pressure product during exercise in the warm compared with the cool environment. However, T(c) and rate pressure product were significantly lower (P <.05), and systolic blood pressure decreased slightly with exercise duration (P <.05) in the CABG group compared with the control group in the warm environment. Heart rate, T(sk), percent .VO(2peak), blood lactate, sweat rate, and rating of perceived exertion did not differ significantly between the groups in either climate and no subject had ischemia or arrhythmia during test procedures. CONCLUSIONS: These results indicate that clinically stable men with revascularized coronary artery disease are able to cope as well as healthy controls with the thermoregulatory and cardiovascular demands of 40 minutes of moderate intensity exercise in warm and cool environments.     

Protective effects of melatonin against myocardial injury induced by isoproterenol in rats

This study was performed to determine whether melatonin could have a protective effect against myocardial injury (MI) induced by isoproterenol (ISO) in rats. Twenty-four rats were divided into three treatment groups: (1) control (n = 8): saline solution. (2) ISO (n = 8): ISO only. (3) melatonin + ISO (n = 8). Melatonin (10 mg/kg/day, i.p.) was administered 30 min before the initiation of ISO (150 mg/kg/day, s.c.). Drugs and saline were given at 14:00 hr for two consecutive days. At the end of the second day, blood samples were taken from the abdominal aorta shortly after the rats were anesthetized for the purpose of measuring cardiac troponins T (cTnT) and I (cTnI); hearts were removed, preserved and examined microscopically. Additionally, based on the histological changes in myocardial tissue, the rats were divided into three groups: no change, mild changes and moderate and/or marked changes. The mean cTnT and cTnI values were significantly increased in ISO group compared with control group [(1.29 +/- 0.22 ng/mL versus 0.46 +/- 0.07 ng/mL, P < 0.0001) and (0.56 +/- 0.11 ng/mL versus 0.21 +/- 0.01 ng/mL, P < 0.001)], respectively, and were significantly reduced in the ISO + melatonin group (0.65 +/- 0.06 ng/mL for cTnT and 0.25 +/- 0.01 ng/mL for cTnI) compared with the ISO only group (P < 0.01), respectively. cTnT and cTnI values were significantly increased in rats with moderate and/or marked cardiac changes compared with hearts where there were mild changes and no change (P < 0.05). ISO + melatonin group showed less histological changes than the ISO group (P < 0.01). In conclusion, this study revealed a protective effect of melatonin against ISO-induced MI in rats, and its potential clinical application in the treatment of MI.     

褪黑素对匹罗卡品致癫癎大鼠海马神经发生和突触重建的影响

目的探讨褪黑素(Mel)在匹罗卡品(PILO)致癫癎犬鼠模型中的抗癫癎作用机制。方法将45只Wistar大鼠按癫癎持续状态(SE)后6 h,14、28天分为PILO组(1 5只),PILO+Mel组(15只)和对照组(15只),采用PILO诱导大鼠慢性颞叶癫癎模型,用5溴-2-脱氧尿嘧啶核苷标记增殖细胞,Timms染色评价苔藓纤维发芽(MFS)等技术,动态观察MeI对癫癎大鼠海马神经发生和MFS的影响及其与反复自发性癫癎发作(SRS)发生的关系。结果与对照组比较,PILO组大鼠SE后6 h,14、28天细胞数明显增加,差异有统计学意义(P<0.01);与PILO组比较,PILO+Mel组大鼠在SE后6 h,14、28天,细胞数量明显减少(P<0.05),28天SRS数量明显减少,差异有统计学意义(P<0.05)。与PILO+Mel组比较,PILO组大鼠SE后14天,Timms染色密度开始增强,28天密度明显增强,差异有统计学意义(P<0.05)。结论Mel对SRS的预防作用可能与其对癫癎诱导的神经发生和MFS的抑制作用有关。     

Melatonin protects against ischemia/reperfusion injury in skeletal muscle

Abstract:  Melatonin has been shown to diminish ischemia-reperfusion (I/R) injury in many tissues. The main aim of this study was to evaluate the protective antioxidant effect of melatonin in skeletal muscle during I/R injury. Wistar albino rats were randomly divided into three groups. Hindlimb ischemia was achieved by clamping the common femoral artery in two groups but not in control group. Limbs were rendered ischemic for 1.5 hr; at the end of the reperfusion period of 1.5 hr muscle tissue samples were taken for the histological evaluation and biochemical analysis. Melatonin (10 mg/kg) was injected i.p. in the I/R + Mel group at the onset of ischemia whereas the vehicle solution was injected in the I/R group. In I/R + Mel group histological damage was significantly less than in the I/R group ( P  < 0.001). In the I/R + Mel group, the mean malonedialdehyde level was lower than in the I/R group ( P  < 0.01) and was quite near to the levels in the control group ( P  > 0.05). Glutathione levels were found to be reduced in the I/R group compared with the control ( P  < 0.01) and I/R + Mel group ( P  < 0.01). Melatonin has a protective effect against I/R injury in skeletal muscle and may reduce the incidence of compartment syndrome, especially after acute or chronic peripheral arterial occlusions.     

Cooling-induced contraction and protein tyrosine kinase activity of isolated arterioles in secondary Raynaud's phenomenon

OBJECTIVE: To investigate the response of skin arterioles from control subjects and patients with scleroderma and Raynaud's phenomenon (RP/SSc) to cooling and modulators of protein tyrosine kinase (PTK) activity. METHODS: We used the microvessel perfusion technique to characterize the response of isolated dermal arterioles (100-200 microm, outside diameter) from normal (n = 17) and RP/SSc (n = 17) subjects to cooling from 37 degrees to 31 degrees C. Fluorescent immunohistochemistry was used to measure tyrosine phosphorylation. RESULTS: Arterioles from control subjects exhibited dilation in response to cooling from 37 to 31 degrees C whereas those from RP/SSc subjects contracted (+4.3 +/- 1.7 vs -16.7 +/- 3.1%, P < 0.05, n = 6). In the presence of the protein tyrosine phosphatase inhibitor sodium orthovanadate (SOV, 10 microM), the response of arterioles from control subjects did not change; however, arterioles from RP/SSC subjects exhibited a significantly greater contraction (-72.6 +/- 19.7%; P < 0.05, n = 6). Tyrosine phosphorylation of arterioles at 37 degrees C from control and RP/SSc subjects was similar. In response to cooling to 31 degrees C, however, arterioles from RP/SSc subjects exhibited a significantly greater increase in tyrosine phosphorylation compared with those from control subjects (43 +/- 7.0% vs 10 +/- 3.8%; P < 0.01). SOV increased tyrosine phosphorylation in arterioles from both groups (73 +/- 11.6% vs 42 +/- 5.6%; P < 0.05, n = 5). Arterioles from RP/SSC subjects precontracted with norepinephrine exhibited greatly attenuated relaxation to acetylcholine compared with those from control subjects. CONCLUSION: The results of this study support the view that the hallmark of Raynaud's phenomenon associated with scleroderma, cooling-induced vasospasm, appears to be mediated by an increase in PTK activity possibly exacerbated by impaired endothelium-dependent vasodilation.     

支气管哮喘患者唾液褪黑素和皮质醇水平及其与病情的关系

目的　探讨基础状态与轻度、中 重度持续支气管哮喘 (简称哮喘 )患者唾液中褪黑素和皮质醇水平及其与病情严重程度的关系和临床意义。方法　收集哮喘患者 2 0例 ,其中轻度持续哮喘患者 10例 (A组 )、中 重度持续哮喘患者 10例 (B组 )和正常对照组 15名 (C组 )。采用放射免疫分析法检测受试者唾液中游离褪黑素和皮质醇含量。昼夜 2 4h按 8个时间点采集唾液标本 ,取样时白天为室内自然光 ,夜间光照强度控制在 50勒克司 (Lux)之内。结果　轻度和中 重度持续哮喘患者唾液中游离褪黑素水平分别为 (15 5± 5 3 ) μg/L和 (7 1± 2 5) μg/L ,与正常对照组 [(2 8 9± 8 7) μg/L]比较 ,差异有显著性 (F =4 47,P <0 0 5;F =7 61,P <0 0 1) ;轻度和中 重度持续哮喘患者唾液中游离皮质醇水平分别为 (3 1± 0 5) μg/L和 (4 2± 0 5) μg/L ,与正常对照组 [(5 9± 0 7) μg/L]比较 ,差异有显著性 (F =10 45,P <0 0 1;F =5 2 1,P <0 0 5) ,皮质醇振幅明显减小伴皮质醇分泌峰值相位显著后移 (P <0 0 5、<0 0 1) ;对照组和轻度持续哮喘患者唾液中褪黑素和皮质醇水平之间无相关性 (r=0 174,P =0 0 57;r =-0 13 8,P =0 2 2 1) ,中 重度持续哮喘患者的褪黑素和皮质醇水平之间呈显著负相关 (r =-0 2