Anti-Inflammatory Effects of Melatonin in Obesity and Hypertension

Purpose of Review

Here, we review the known relations between hypertension and obesity to inflammation and postulate the endogenous protective effect of melatonin and its potential as a therapeutic agent. We will describe the multiple effects of melatonin on blood pressure, adiposity, body weight, and focus on mitochondrial-related anti-inflammatory and antioxidant protective effects.

Recent Findings

Hypertension and obesity are usually associated with systemic and tissular inflammation. The progressive affection of target-organs involves multiple mediators of inflammation, most of them redundant, which make anti-inflammatory strategies ineffective. Melatonin reduces blood pressure, body weight, and inflammation. The mechanisms of action of this ancient molecule of protection involve multiple levels of action, from subcellular to intercellular. Mitochondria is a key inflammatory element in vascular and adipose tissue and a potential pharmacological target. Melatonin protects against mitochondrial dysfunction.

Summary

Melatonin reduces blood pressure and adipose tissue dysfunction by multiple anti-inflammatory/antioxidant actions and provides potent protection against mitochondria-mediated injury in hypertension and obesity. This inexpensive and multitarget molecule has great therapeutic potential against both epidemic diseases.

     

Male <Emphasis Type="Italic">Drosophila melanogaster</Emphasis> flies exposed to hypergravity at young age are protected against a non-lethal heat shock at middle age but not against behavioral impairments due to this shock

Previous studies have shown that exposing flies to hypergravity (3 or 5g) for two weeks at young age slightly increases longevity of male flies and survival time at 37 °C of both sexes, and delays an age-linked behavioral change. The present experiments tested whether hypergravity could also protect flies from a non-lethal 37 °C heat shock applied at young, middle or old age (2, 4 or 6weeks of age). Various durations of exposure at 37 °C had similar deleterious effects on climbing activity, spontaneous locomotor activity and learning in flies that lived or not in hypergravity at young age. Therefore, hypergravity does not protect the behavior of flies from a deleterious non-lethal heat shock. Hypergravity increased longevity of virgin males and decreased that of mated ones; it also increased longevity of virgins at 25 °C, the usual rearing temperature, but not at 30 °C. Thus, the positive effect of hypergravity on longevity is observed only if flies are not subjected to living conditions decreasing longevity, like mating and high temperature. Finally, 4 weeks-old males that lived in hypergravity at young age lived slightly longer (+ 15%) after a non-lethal heat shock (60 or 90 min at 37 °C) than flies that always lived at 1 g, but this positive effect of hypergravity was not observed in females or in older males. Therefore, all these results show that hypergravity exposure can help male middle-aged flies recovering from a heat shock, but does not protect them from behavioral impairments linked to this shock: a mild stress occurring at young age can partially protect from a moderate stress at middle age.     

The effect of different preparations of human growth hormone on plasma renin activity in normal males.

The effect of acute administration of 2 preparations of growth hormone (hGH) on plasma renin activity (PRA) was studied in normal volunteers. 4 IU of standard, commercially available hGH II, Kabi, Sweden) were injected im into each of four normal subjects, and the PRA was determined in the basal state and at 30, 60, 120, 180, and 240 min after injection. Free fatty acid (FFA) was determined basally and at 15 and 210 min post-injection. The study was repeated on a different day in the same group using highly purified hGH (hGH I, 4 IU) virtually free of arginine-vasopressin. Four other normal subjects received 12 IU standard hGH (hGH II, Kabi, Sweden). There was no significant difference in PRA values with 4 IU of either preparation or with 12 IU of hGH II in any of the groups, although mean PRA was elevated in two of the patients receiving 12 IU hGH II. A rise in FFA occurred in all subjects, indicating the biological activity of hGH preparations. The possible significance of these findings to the renin-angiotensin system found in acromegaly is considered.     

Growth hormone and somatostatin gene expression in pituitary adenomas with active acromegaly and minimal plasma growth hormone elevation.

Some patients with active acromegaly have elevated plasma IGF-I concentrations with only minimal elevation of plasma GH. We compared adenomatous GH and SRIH expression in 3 such patients (patients No. 1, 2 and 3; basal plasma GH level less than 4 micrograms/l) and in 3 acromegalic patients with high basal plasma GH level (patients No. 4, 5 and 6; 51.7 +/- 16.1 micrograms/l, mean +/- SEM). By immunocytochemistry, all the tumours proved to be somatotropic adenomas. At the ultrastructural level, signs of low secretory activity were observed in adenomas from patients No. 2 and 3. Perifused adenoma cells of patients No. 1, 2 and 3 released very little GH compared with those of patients No. 4, 5 and 6 (1 +/- 0.37 vs 51.5 +/- 34.1 micrograms x (10(-6) cells) x min-1, p less than 0.001). Adenoma SRIH content was 65.7 and 30.6 pg/mg proteins in patients No. 1 and 2, whereas it was undetectable in the others (patients No. 4, 5 and 6). Northern blot analysis showed that the GH gene was poorly expressed in the adenomas from patients No. 1, 2 and 3 compared with the adenomas from patients No. 4, 5 and 6. SRIH mRNA was detected in all 6 adenomas. However, the signal was more intense in the adenomas from patients No. 1, 2 and 3 than in those from patients No. 4, 5 and 6.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon

BACKGROUND & AIMS: The notion that specific receptors account for the ability of natural and synthetic cannabinoids to alter physiological functions, prompted this study aimed at assessing their functional presence in the human gut. METHODS: The effects have been studied of cannabinoids and selective antagonists of their receptors on chemically or electrically evoked contractions in preparations of human intestinal smooth muscle in vitro. RESULTS: Atropine prevented the contractions of longitudinal and circular muscle strips of ileum and colon induced by carbachol or electrical field stimulation; tetrodotoxin abolished only the latter which suggests they do involve activation of cholinergic neurons. The synthetic cannabinoid (+)WIN 55,212-2 had no effect on carbachol contractions, but in a concentration-dependent fashion prevented those elicited by electrical field stimulation - which were insensitive to the putative endogenous cannabinoid anandamide - more potently in longitudinal than in circular strips. The selective CB1 receptor antagonist SR141716, which had no effect in the absence of (+)WIN 55,212-2, competitively antagonised its inhibition of electrical field stimulation contractions, unlike the selective CB2 antagonist SR144528. CONCLUSIONS: Cannabinoid CB1 receptors are functionally present in the human ileum and colon; their pharmacological activation apparently results in inhibition of excitatory cholinergic pathways subserving smooth muscle contraction.     

The effect of delipidated deglycolipidated (DDMV) and heat-killed Mycobacterium vaccae in asthma

Experimental and epidemiological evidence supports the hypothesis that exposure to mycobacteria has the potential to suppress the development of asthma and/or atopy and there are reports in the Chinese medical literature of repeated vaccination with inactivated BCG being effective in the management of asthma. Forty-three patients with stable moderately severe asthma who were skin prick test positive to house dust mite were randomized to receive two intradermal injections of either phosphate-buffered saline (placebo), heat-killed Mycobacterium vaccae (0.5 mg), or delipidated deglycolipidated Mycobacterium vaccae (DDMV) (0.05 mg). Markers of asthma severity were measured for 3 mo and blood eosinophil, IgE levels, and the T cell proliferative and cytokine responses were monitored. There were no significant differences between either treatment group and the placebo group for any of the outcome variables. There was also no difference between the treatment groups and placebo for eosinophil, IgE levels, or the T cell proliferative and cytokine response. The results indicate no effect of low dose intradermal DDMV or M. vaccae on asthma severity in patients with established asthma.     

Effects of acute angiotensin converting enzyme inhibition on renal blood flow in patients with stable congestive heart failure

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.     

Treatment of common bile duct stones with laparoscopy. Retrospective multicenter study with 612 patients

OBJECTIVE: To analyse retrospectively the results of one-stage laparoscopic treatment for common bile duct stones in 19 surgical centers in France. PATIENTS: From January 1991 to July 1996, 612 patients with choledocholithiasis underwent laparoscopic treatment. RESULTS: Overall duct clearance was obtained in 489 of the 612 patients (80%): through the cystic duct in 222 of 380 patients (58.4%), by secondary choledochotomy (after unsuccessful transcystic duct extraction) in 77 of 96 (80%), and in 190 of 232 (82 %) by primary choledochotomy. The overall duct clearance rate increased from 65% in 1991 to 84% in 1996. The use of the choledochotomy approach increased from 43% in 1991 to 69% in 1996 (P<0.01), due to a substantial increase in primary choledochotomy. In contrast, the use of the transcystic approach decreased from 57% to 31% (P<0.01). The mean time for surgery was shorter for cystic duct exploration than for primary choledochotomy (101+/-51 vs. 155+/-62 min, P<0.0001). The mean hospital stay decreased from 7.7+/-3.6 days in 1991 to 4.1+/-2 days in 1996 (P<0.001). The main biliary complications were related to biliary drainage (2,8%) and retained stones (3.1%). CONCLUSION: This study confirms that laparoscopy is a good alternative with a low complication rate, a short hospital stay, and is an effective and safe option for the management of common bile duct stones.