Intermedin/adrenomedullin-2 (IMD/AM2), a member of the calcitonin gene-related peptide/AM family, plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus (PVN) of the hypothalamus on sympathetic nerve activity (SNA), and lipopolysaccharide (LPS)-induced sympathetic activation in obesity-related hypertensive (OH) rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure (MAP) in response to specific drugs. Male rats were fed a control diet (12% kcal as fat) or a high-fat diet (42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4 (TLR4) and plasma norepinephrine (NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS (0.5 µg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD (50 pmol) caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympathetic activation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However, IMD in the PVN decreased the LPS-induced ERK activation, which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover, IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.
Adrenomedullin ; metabolism ; Animals ; Blood Pressure ; drug effects ; physiology ; Hypertension ; etiology ; Lipopolysaccharides ; pharmacology ; Male ; Neuropeptides ; metabolism ; Obesity ; complications ; Rats, Sprague-Dawley ; Receptors, Adrenomedullin ; drug effects ; metabolism ; Sympathetic Nervous System ; drug effects ; metabolism ; Toll-Like Receptor 4 ; metabolism

Neurological injury is a frequent and important complication of coronary artery bypass grafting (CABG). Several risk factors for this type of sequela have been identified, among them aortic arch atherosclerosis. Our previous study indicated that atherosclerotic burden in coronary arteries may likewise predict postoperative neurological complications (Pawliszak et al., 2016b). We assessed the severity of this condition by using the SYNTAX score calculator. However, diagnosing angiographic three-vessel coronary artery disease (3VD) could be an even simpler method of achieving this goal.
Aged ; Coronary Angiography ; Coronary Artery Bypass, Off-Pump/adverse effects* ; Coronary Artery Disease/surgery* ; Female ; Glial Fibrillary Acidic Protein/blood* ; Humans ; Male ; Middle Aged ; Neurofilament Proteins/blood* ; Neuropeptides/blood* ; Phosphorylation ; Prospective Studies ; Serpins/blood* ; Neuroserpin

In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
Blood Glucose ; Brain ; Comorbidity ; Diabetes Mellitus, Type 2 ; Glucagon ; Glucose* ; Hand ; Homeostasis* ; Human Body ; Insulin ; Intestines ; Liver ; Neuropeptides ; Pancreas ; Peptides ; Prevalence

PURPOSE: The aim of this study was to compare serum leptin, neuropeptide Y (NPY), and islet amyloid polypeptide (amylin) levels in obese and normal weight children, and to investigate their correlations with anthropometric parameters and metabolic bio-marker levels. METHODS: Body mass index (BMI), waist and hip circumference, blood pressure (systolic/diastolic), lipid profile, fasting glucose, and serum insulin, leptin, NPY, and amylin levels were measured in 56 children (24 obese children and 32 non-obese controls). Homeostatic model assessment-insulin resistance (HOMA-IR) values were calculated and the relationships between anthropometric variables, metabolic biomarkers, and diet-regulating factors (leptin, NPY, and amylin levels) were examined. RESULTS: BMI, hip circumference, waist circumference, and systolic and diastolic pressure were significantly higher in the obese group than in the non-obese group (p<0.0001). Total cholesterol, triglyceride, low-density lipoprotein-cholesterol, glucose, and insulin levels were also significantly higher in the obese group (p<0.05). On the other hand, high-density lipoprotein-cholesterol levels were higher in the non-obese group , but this was not significant. Serum leptin, NPY, and amylin levels were significantly higher in the obese group (p<0.05). Furthermore, in the obese group, leptin levels were found to be significantly correlated with BMI (r=0.379, p=0.043), and NPY levels (r=0.377, p=0.044), and amylin levels were found to be significantly correlated with insulin levels (r=0.400, p=0.048), and HOMA-IR (r=0.459, p=0.028). CONCLUSION: Metabolic risk factor alterations are present in obese children, and these children show abnormalities in the diet regulatory system caused by leptin, NPY, and amylin resistance. Of particular note, amylin was found to be positively correlated with insulin resistance.
Biomarkers ; Blood Pressure ; Body Mass Index ; Child ; Cholesterol ; Diet ; Fasting ; Glucose ; Hand ; Hip ; Humans ; Insulin ; Insulin Resistance ; Islet Amyloid Polypeptide ; Leptin ; Neuropeptide Y ; Neuropeptides ; Risk Factors ; Waist Circumference

Arginine vasopressin (AVP) is a neuropeptide with vasoconstrictive, antidiuretic, cardiovascular regulative and hepatic glycogenolysis effects, that also affects other behaviors including modulating learning. A number of studies on AVP regulation have been conducted in various metabolic diseases (disorders). In this study, the immunoreactivities of AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and mRNA expressions in the hypothalamus were investigated by immunohistochemistry and quantitative real-time PCR (RT-qPCR) in stroke-prone spontaneously hypertensive rats at different ages (i.e., at postnatal months [PM] 1, 8, and 12). Blood glucose levels in the PM 8 group were higher than in the other groups. However, cresyl violet positive neurons were detected in the PVN and SON of all animals, and numbers of cresyl violet positive neurons were similar in all aged groups. In addition, AVP immunoreactivity was detected in the PVN and SON of all age groups, and AVP immunoreactivity and mRNA expression levels were found to be increased in proportion to age by immunohistochemistry and RT-qPCR. These results suggest that the diabetic condition is temporally generated after hypertension has developed. Furthermore, our findings suggest that increased AVP expressions in the hypothalamic PVN and SON are associated with hypertension by age.
Aged ; Animals ; Arginine ; Arginine Vasopressin ; Benzoxazines ; Blood Glucose ; Glycogenolysis ; Humans ; Hypertension ; Hypothalamus ; Immunohistochemistry ; Learning ; Metabolic Diseases ; Molybdenum ; Neurons ; Neuropeptides ; Oxides ; Paraventricular Hypothalamic Nucleus ; Rats, Inbred SHR ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Supraoptic Nucleus ; Viola

Narcolepsy is a sleep disorder, which is characterized by excessive daytime sleepiness (EDS) that is typically associated with cataplexy, sleep fragmentation and other REM sleep-related phenomenon such as sleep paralysis and hypnagogic hallucination. Narcoleptic symptoms can be developed from various medical or neurological disorders. A 17-year-old male patient admitted for the evaluation of EDS which started three-month ago. He slept more than 18 hours a day with cataplexy and hypnagogic hallucination. He was obese with body mass index (BMI) of 30.4 kg/m2. After admission he was newly diagnosed to the thyrotoxicosis. T3 391.2 ng/dL (60-181), free T4 4.38 ng/dL (0.89-1.76), TSH <0.01 microIU/mL (0.35-5.5) were measured. His pulse rate ranged 70-90 beats per minute and blood pressure ranged 150/100-120/70 mmHg. Polysomnography revealed many fragmentations in sleep with many positional changes (81 times/h). Sleep onset latency was 33.5 min, sleep efficiency was 47.9%, and REM latency from sleep onset was delayed to 153.6 min. REM sleep percent was increased to 27.1%. Periodic limb movement index was 13.4/h. In the multiple sleep latency test (MSLT), average sleep latency was 0.4 min and there were noted 3 SOREMPs (Sleep Onset REM sleep period) on 5 trials. We couldn't discriminate the obvious sleep-wake pattern in the actigraph and his HLA DQB1 *0602 type was negative. His thyroid function improved following treatment with methimazole and propranolol. Vital sign maintained within normal range. Cataplexy was controlled with venlafaxine 75 mg. Subjective night sleep continuity and PLMS were improved with clonazepam 0.5 mg, but the EDS were partially improved with modafinil 200-400 mg. Thyrotoxicosis might give confounding role when we were evaluating the EDS, though sleep fragmentation was one of the major symptoms of narcolepsy, but enormous amount of it made us think of the influence of thyroid hormone. The loss of sleep-wake cycle, limited improvement of EDS to the stimulant treatment, and the cataplexy not supported by HLA DQB1 *0602 should be answered further. We still should rule out idiopathic hypersomnia and measuring CSF hypocretin level would be helpful.
Adolescent ; Benzhydryl Compounds ; Blood Pressure ; Body Mass Index ; Cataplexy ; Clonazepam ; Cyclohexanols ; Extremities ; Hallucinations ; Heart Rate ; HLA-DQ beta-Chains ; Humans ; Hypersomnolence, Idiopathic ; Intracellular Signaling Peptides and Proteins ; Male ; Methimazole ; Narcolepsy ; Nervous System Diseases ; Neuropeptides ; Polysomnography ; Propranolol ; Reference Values ; Sleep Deprivation ; Sleep Paralysis ; Sleep, REM ; Thyroid Gland ; Thyrotoxicosis ; Vital Signs ; Orexins ; Venlafaxine Hydrochloride

AIMThe present study was designed to determined the cardiovascular effects of IMD1-53 in rats and its possible mechanism.

METHODSIsolated rat hearts were perfused by Iangendorff mode, and ventricular function was measured after IMD1-53 perfusion. Meanwhere, we investigated the effects of IMDI) on arterial pressure after intravenous administration of IMD. And cAMP content was detected in rat ventricular and aortic tissues.

RESULTSThe results showed that perfusion with IMD significantly enhanced cardiac function and resulted in higher LVSP, +dp/dt(max) and -dp/dt(max) by 45%, 51% and 37%, respectively, compared with control and increased coronary infusion flow. The effects of IMD1-53 on cardiac function were antagonized by H-89, an inhibitor of PKA. The content of cAMP in the ventricular tissues after IMD perfusion was 131% higher than control. In addition, intravenous administration of IMD induced a potent decrease in arterial pressureand heart rate, and in aortic tissues, IMD incubation resulted in a 236% increase in cAMP content compared with control group.

CONCLUSIONThe study reveals that IMD can increase cardiac function and decrease arterial pressure in rat and the effects may be related to cAMP pathway.

Adrenomedullin ; metabolism ; pharmacology ; Animals ; Blood Pressure ; drug effects ; Cardiovascular Physiological Phenomena ; drug effects ; Cyclic AMP ; metabolism ; Heart ; drug effects ; In Vitro Techniques ; Male ; Neuropeptides ; metabolism ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Ventricular Function ; drug effects

AIMTo study the effect and significances of two-week hypoxia on the expression of intermedin/adrenomedullin2 (IMD/ADM2) in plasma and the tissues of heart and lung in rats.

METHODSTwenty male SD rats were randomly divided into normal control group and hypoxia group. The concentrations of IMD/ADM2 and adrenomedullin (ADM) in plasma, right ventricle and lung tissue were measured by radioimmunoassay. RT-PCR was used to detect the mRNA levels of IMD/ADM2 and ADM in right ventricle and lung tissue.

RESULTS(1) The mean pulmonary arterial pressure (mPAP) and the weight ratio of right ventricle (RV) to left ventricle plus septum (LV + S) of hypoxia group were significantly higher than those of normal control group (P < 0.01). (2) The concentrations of IMD/ADM2 and ADM in plasma were significantly higher in hypoxia group, compared with normal control group (P < 0.01). (3) The concentration of ADM in right ventricle and lung tissue in hypoxia group was significantly higher than that in normal control group (P < 0.01), while there was no significant difference in IMD/ADM2 between the two groups. (4) The mRNA levels of IMD/ADM2 and ADM in right ventricle and lung tissues were significantly up-regulated in hypoxia group (P < 0.05).

CONCLUSIONThe expressions of IMD/ADM2 peptides and gene in plasma, right ventricular and pulmonary tissues are different in the early-middle pathological proceeding of pulmonary hypertension induced by two-week hypoxia in rats.

Adrenomedullin ; blood ; genetics ; metabolism ; Animals ; Hypertension, Pulmonary ; etiology ; metabolism ; Hypoxia ; complications ; metabolism ; Lung ; metabolism ; Male ; Myocardium ; metabolism ; Neuropeptides ; blood ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To explore the change of orexin-A expression in hepatic reperfusion and their association with liver injury, and to find out the role of orexin-A in traumatic stress responses. METHODS: A 70% hepatic reperfusion model of rats was established, setting groups of sham-operation and injury ones with different reperfusion time. A self-produced radioimmunoassay and relevant kits were used to detect the protein level of orexin-A in the plasma and the hypothalamus, serum glucose, total anti-oxidation capacity and alanine transaminase, HE staining and immunohistochemistry were used to investigate the pathological variation and protein expression of orexin-A in the liver, while RT-PCR was applied to observe mRNA expression of orexin-A in the hypothalamus and the liver. RESULTS: Both the shape of standard curve and metrical results of the self-produced orexin-A radioimmunoassay were good. Protein levels of orexin-A in the plasma and the hypothalamus in each reperfusion group showed no significant change. Serum glucose and total anti-oxidation capacity increased significantly at the later phase of injury. There was significant and positive linear correlation between the plasma orexin-A and serum glucose and total anti-oxidation capacity; serum alanine transaminase in each reperfusion group was significantly higher, and liver damage was significantly alleviated at the later phase of the injury. Different extents of variation were observed in protein expression of orexin-A in the liver and its mRNA expression in the hypothalamus and the liver. CONCLUSION Orexin-A undergoes significant changes during hepatic reperfusion, indicating that orexin-A participates in the modulation of hepatic reperfusion-induced liver injury and internal disorders.
Animals ; Hypothalamus ; metabolism ; Intracellular Signaling Peptides and Proteins ; genetics ; metabolism ; Liver ; blood supply ; metabolism ; Male ; Neuropeptides ; genetics ; metabolism ; Orexins ; RNA, Messenger ; genetics ; metabolism ; Radioimmunoassay ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; metabolism

OBJECTIVECurrently people regard polysomnography (PSG) monitoring as the golden standard for diagnosis of obstructive sleep apnea-hypopnea syndrome (OSAHS) in children. However, due to the high cost, time and manpower consuming, PSG is not applicable to epidemiological investigation and clinical screening, especially not suitable for child patients and remote hospitals in Xinjiang. Therefore, it is of important clinical significance to find out a simple method (e.g. a kind of serum index) to primarily screen out suspicious patients for early diagnosis and treatment. The present study was conducted to assess the clinical usefulness of the measurement of orexin-A concentration in serum as a diagnostic predictor to screen patients with OSAHS in children.

METHODSSerum orexin-A concentration was measured with enzyme immunoassay (EIA) kit in 60 patient with snoring before performing polysomnography (PSG). Subsequently all the subjects underwent PSG test. Forty subjects were diagnosed as having OSAHS, and twenty subjects had no OSAHS. These 20 non-OSAHS subjects served as controls. Compared with the PSG results the clinical usefulness of the measurement of orexin-A concentration in serum was assessed as a diagnostic predictor to screen patients with OSAHS. Correlation between orexin-A levels and apnea hypoventilation index (AHI), micro-arousal index (MAI) and lowest SaO2 (LSaO2) were analyzed.

RESULTSThe serum orexin-A levels in the OSAHS group [(0.49 +/- 0.10) microg/L] was significantly higher than that of the control group [(0.28 +/- 0.11) microg/L, P < 0.01]. If a patient's level of orexin-A was higher than 0.36 microg/L, the patient more likely to have OSAHS. The sensitivity rate was 85.0% and the specificity was 80.0%. Serum orexin-A levels in children with OSAHS correlated positively with the AHI (r = 0.427, P < 0.05) and MAI (r = 0.468, P < 0.05), but correlated negatively with the LSaO2 (r = -0.527, P < 0.01) and the mean oxygen saturation (MSaO2) (r = -0.541, P < 0.01), not correlated significantly with the BMI (r = -0.212, P > 0.05). The serum orexin-A levels in the OSAHS children after who under went tonsillectomy and adenoidectomy significantly decreased (P < 0.05) 3 months after surgery as compared with pre-operation level.

CONCLUSIONThese findings suggest that the serum level of orexin-A could be used as a predictor in screening for OSAHS children and a biological marker of the severity of OSAHS children.

Case-Control Studies ; Child ; Female ; Humans ; Intracellular Signaling Peptides and Proteins ; blood ; Male ; Neuropeptides ; blood ; Orexins ; Sleep Apnea, Obstructive ; blood ; diagnosis