Plasma Neuropeptide Y Levels Research Articles

Neuropeptide Y receptor Y2 gene polymorphism interacts with plasma neuropeptide Y levels in predicting left ventricular hypertrophy in dialysis patients

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors involved in cardiovascular remodelling and angiogenesis. Plasma levels of NPY are increased in patients with end-stage renal disease (ESRD) and are independently related to left ventricular hypertrophy (LVH) and incident cardiovascular events in these patients. To investigate the relationship between NPY receptor Y2 gene polymorphism and left ventricular mass index (LVMI) as well as the interaction between this polymorphism and plasma NPY in determining LVH in 189 ESRD patients. LVMI was significantly higher (+12%, P = 0.03) in patients carrying the C allele than in those without C allele and was linearly associated with plasma NPY (P = 0.01). Interaction analysis showed a significant NPY-LVMI relationship in patients with the C allele, both at univariate (r = 0.27, P = 0.001) and multivariate (r = 0.21, P = 0.01) analyses, whereas no such relationship existed in patients without this allele. In fully adjusted analyses, a 10 pmol/l increase in plasma NPY entailed a 4.9 g/m increase in LVMI in patients with C allele, whereas the same change in NPY levels did not modify the NPY-LVMI link in patients without such allele (P = 0.009). NPY receptor Y2 polymorphism is independently associated with LVMI and interacts with plasma levels of NPY in explaining the variability of LVH in ESRD. These results offer a genetic basis to the hypothesis that NPY is causally implicated in the pathogenetic pathway leading to LVH in ESRD patients.

Effects of Panax notoginseng saponins on immune-neuroendocrinenetwork of SD rats in experimental navigation and intensive exercise

The present study aims to study the influences experimental navigation and intensive exercise on immune-neuroendocrine network of the male rats and the effects of PNS to this influence. Thirty 6-week Sprague-Dawley male rats (SD rats) were randomly located into three groups: Quiescent control (QC) group, training control (TC) group and Panax notoginseng saponins (PNS) group. Rats from QC group were not given any stimuli, and samples were taken after 7-day intragastric administration of saline. Rats from TC group underwent 10-day run training of increasing load on treadmill and received 7-day intragastric administration of saline. PNS group were subjected to the same procedure of run training as group TC, and received intragastric administration of PNS at the dose of 0.2 g x kg(-1). Blood samples were immediately obtained at the end of the tests to determine the serum levels of corticosterone (Cort), adrenocorticotropic hormone (ACTH), beta-endorphin (beta-EP), Neuropeptide Y (NPY) and interleukin-1beta (IL-1beta), interleukin-6 (IL-6) by RIA. Expressions of Pituitary ACTH, NPY were observed use the immunohistochemistry method and correlation analyses conducted. And the ultrastructural changes of the pituitaries and the adrenal cortex cells were examined by electron microscope meanwhile. The serum beta-EP and Cort levels in TC group were significantly increased compared to the QC group; whereas Expression levels of pituitary ACTH, NPY were markedly higher after experimental navigation and intensive exercise. In Group PNS, the plasma Cort, ACTH and NPY levels decreased significantly compared to Group TC. Meanwhile we found expression levels of pituitary ACTH, NPY also lower than group TC. There was no significant difference about the ultrastructure of anterior pituitary and adrenal cortex of QC and PNS group. However, a obvious change of ultrastructure occurred to TC group rats. These results suggest that immune-neuroendocrine network function of rats were confused by negative psychological stresses and intensive exercise. PNS therapy may exert regulation effects to the network.

Higher Levels of Plasma TNF-α and Neuropeptide Y in Hypertensive Patients with Obstructive Sleep Apnea Syndrome

Resistant hypertension is always fount to be accompanied with obstructive sleep apnea syndrome (OSAS). Previous studies assumed inflammation participated in OSAS and hypertension. The fact that tumor necrosis factor a (TNF-α) was related to OSAS, while neuropeptide Y (NPY) was related to hypertension, was widely reported separately. To investigate the involvement of TNF-α and NPY simultaneously in hypertension accompanied with OSAS, 417 subjects who underwent the polymonograph and blood pressure measurement were consecutively selected. Plasma TNF-α and NPY levels were determined in normotensive with OSAS (n = 113), hypertensive without OSAS (n = 73), hypertensive with OSAS (n = 134), and those of controls (n = 97), respectively. A significant increase of plasma TNF-α and NPY were both observed in hypertensive subjects with or without OSAS, the highest level of TNF-α and NPY were in hypertension with the OSAS group. TNK-α, NPY, and neck circumference contributed to OSAS and hypertension as risk factors in the logistic regression model. Neck circumference was impacted by apnea/hyponea index, mean diastolic blood pressure, and TNF-α level, which was indicated via the multiple linear model. The present study indicated a positive interplay between plasma TNF-α, NPY, hypertension, and OSAS in the Han population of Xinjiang. Although there is evidence that inflammation plays a role in the pathophysiology of hypertension and OSAS, clear evidence is still lacking, and raises the dilemma of the hen and the egg. Further studies are needed to clarify the role of inflammation in the pathogenesis of hypertension with OSAS, in which neck size should be considered as a linked independent factor.

Expression of Neuropeptide Y, Omentin and Visfatin in Visceral and Subcutaneous Adipose Tissues in Humans: Relation to Endocrine and Clinical Parameters

Objective: We aimed at exploring the expression of neuropeptide Y (NPY), omentin and visfatin in adipose tissues of adults along with clinical parameters and hormones. Methods: We included 168 adult patients (31 surgical obese patients and 31 surgical controls, 76 non-surgical obese patients, 30 non-surgical controls). We measured plasma NPY (by radioimmunoassay), cortisol (with an electrochemiluminescence immunoassay) and urinary cortisol metabolites (by gas chromatography/mass spectrometry). Expression of NPY, omentin and visfatin in subcutaneous and visceral adipose tissue specimens of the surgical patients was quantified using real-time PCR. Results: NPY was detectable in adipose tissue specimens and, like plasma NPY concentrations, comparable between groups. Omentin gene expression was higher in visceral than in subcutaneous adipose tissues (p < 0.0001). Visfatin expression was lower in the subcutaneous tissue of obese patients compared with controls (p < 0.05). Cortisol was lower in obese adults compared with controls (136.5 ± 74.1 vs. 162.2 ± 56.1 ng/ml; p < 0.05), cortisol metabolites were comparable between groups. Conclusion: In our obese adults, plasma NPY levels and the glucocorticoid measures were not elevated. Even though the expression of NPY, omentin and visfatin was comparable between obese individuals and controls, we have to consider differences in the total production rate of adipose tissue-derived factors.

Higher levels of plasma TNF-α and neuropeptide Y in hypertensive patients with obstructive sleep apnea syndrome

Previous studies assumed inflammation participated in obstructive sleep apnea syndrome (OSAS) and hypertension. The fact that tumor necrosis factor α (TNF-α) was related to OSAS while neuropeptide Y (NPY) was related to hypertension was widely reported separately. To investigate the involvement of TNF-α and NPY simultaneously in hypertension accompanied with OSAS, 417 subjects who underwent the polysomnography and blood pressure measurement were consecutively selected. Plasma TNF-α and NPY levels were determined in normotensive with OSAS (n=113), hypertensive without OSAS (n=73), hypertensive with OSAS (n=134) and those of controls (n=97) respectively. Significant increase in TNF-α and NPY was observed simultaneously in hypertensive subjects with or without OSAS in the present cross-sectional study. Both of TNF-α and NPY besides neck circumference (NC) contributed to OSAS and hypertension as risk factors in logistic regression model. NC was impacted by apnea/hypopnea index, mean diastolic blood pressure and TNF-α level, which was indicated via multiple linear regression model. These data suggested that complex interactions existed in TNF-α, NPY and hypertension and OSAS in Han population of Xinjiang. The highest levels of TNF-α and NPY were observed in OSAS with hypertension. Elevated concentration of plasma TNF-α and NPY potentiate the hypertension combined with OSAS. However, whether raised plasma TNF-α and NPY levels were the cause or the results of hypertension overlapping OSAS was not been determined. Further studies are needed to clarify the role of inflammation in the pathogenesis of OSAS with hypertension, in which NC should be entered as an independent factor.

Association of the C-399T promoter polymorphism of neuropeptide Y with susceptibility to ischemic stroke

Objectives The common sequence variants of neuropeptide Y (NPY) were known to be associated with some kinds of diseases including stroke. This study investigated the association of NPY promoter polymorphism, C-399T, with ischemic stroke and its underlying mechanism using in vitro systems. Design and methods Study subjects consisted of 444 ischemic stroke patients and 326 controls without stroke. C-399T genotyping was conducted by a primer extension-based method. Plasma NPY was quantified with an enzyme immunoassay, and transcription characteristics were investigated by a reporter gene assay and an enzyme mobility shift assay. Results A significantly lower frequency of TT genotype was observed in a stroke group (OR[95% CI], 0.399[0.187–0.854], p = 0.0180). The C-399T polymorphism affected the transcription efficiency of NPY gene and its genotypes were related to the changes in plasma NPY levels. Conclusion This study suggests that NPY promoter polymorphism, C-399T, should be considered a genetic risk factor for ischemic stroke.

Zhou et al. reply

Replying to: C. H. Cotton, J. Flint & T. G. Campbell , 10.1038/nature07927 (2009) The inability of Cotton 1 to detect an effect of a functional haplotype (and locus) of neuropeptide Y (NPY), a stress regulatory neuropeptide, on neuroticism is interesting. Although it is important to measure effects of functional loci on complex behaviours, the strength of our study2, and primary basis of its conclusions, was the larger and convergent effects of NPY on intermediate phenotypes, including regional brain responses to emotional stimuli and pain, and brain NPY messenger RNA and plasma NPY levels. Eysenck Neuroticism is a trait that we did not directly investigate. We reported modest association of NPY with two Harm Avoidance subscales from the Tridimensional Personality Questionnaire. Association of NPY with the complex trait of anxiety, especially when measured differently, is not the first place we would look to validate our results.

Platelet neuropeptide Y (NPY) and the collateral and capillary networks in skeletal muscle ischemia

Previously, we showed that sympathetically‐derived or exogenous NPY promotes ischemic revascularization after femoral artery ligation (FAL) in rodents by activating Y2 receptors and dipeptidyl peptidase IV (DPPIV), which forms a Y2/Y5‐preferring agonist. FAL also induced early up‐regulation of Y2 and DPPIV mRNA in adductor (collateral zone, CZ) and gastrocnemius (capillary angiogenesis zone, AZ) muscles and elevated plasma NPY levels, followed by increased platelet NPY levels at 7 and 14 days post‐ligation. The latter findings suggested platelet NPY may play a role in angiogenesis/collateralization after FAL, which is evaluated in this study. In 129/SvlmJ/NPY+/+ mice, FAL induced an increase in capillary density (CD31+ vessels) in the AZ by 14 days (vs. sham), which in NPY‐/‐ remained unchanged (no difference in basal capillary density between NPY+/+ and NPY‐/‐ mice.). Transfer of NPY‐/‐ platelets into platelet‐depleted (Busulfan 25 mg/kg, i.p.) NPY+/+ mice attenuated the angiogenic response in the AZ, while NPY+/+ platelet transfer into NPY‐/‐ mice significantly increased the density of CD31+ vessels in this region. In a separate group of mice, adductor and plantar perfusion were decreased in NPY‐/‐ mice after FAL. These data suggest that NPY's effect on both the collateral and capillary networks promote ischemic revascularization and is, at least in part, mediated by platelet NPY.

Neuropeptide Y Gene Polymorphisms Confer Risk of Early-Onset Atherosclerosis

Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58–2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46–1.65, p = 0.01–0.05), showing stronger association in youngest cases (OR 1.84–2.20, p = 0.0004–0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79–2.06, p = 0.003–0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor–antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.

Stress-Induced Hypertension and Increased Sympathetic Activity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

Background and Aims: Neuropeptide Y (NPY) is a sympathetic neurotransmitter co-stored and co-released with noradrenaline and adrenaline. We have constructed a novel NPY transgenic mouse model (OE-NPY^DBH mouse) where targeted overexpression results in increased levels of NPY in the brainstem and adrenal glands. The present study was aimed to understand the role of NPY released from sympathetic nerves and brain noradrenergic neurons in regulation of blood pressure, and behavioral responses to stress. Methods: Blood pressure was measured by radiotelemetry in conscious male OE-NPY^DBH and wild-type mice during surgical stress and in baseline conditions. Plasma and adrenal gland catecholamine levels were measured at baseline. Acute immobilization and cold exposure were used to study the plasma levels of NPY and corticosterone in stress, and brown adipose tissue thermogenic activity was measured with [³H]GDP binding after cold. Results: Here, we demonstrate that sympathoadrenal activity is enhanced in the OE-NPY^DBH mice. Blood pressure during surgical stress was significantly increased in comparison with wild-type controls. Furthermore, OE-NPY^DBH mice showed sexually dimorphic NPY responses to stress, and an anxiolytic-like behavior in elevated plus-maze and light-dark tests. Conclusion: This study shows that the overactive noradrenergic NPY system plays a role in regulation of blood pressure and adaptive responses to stress, and may be a link between chronic stress and adiposity-associated disturbances in metabolism.

Correlation of Gut Hormones with Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is a functional bowel disorder which is characterized by abdominal pain and disturbed bowel habits. The pathophysiological mechanism is complex and still remains incompletely clear. Alterations at both the central and the peripheral level are thought to contribute to the symptoms of IBS, including psychosocial factors, visceral hypersensitivity and abnormal gastrointestinal motility and secretion. Several gut peptides contribute to the regulation of gastrointestinal function, but little is known about gut hormone secretion in IBS. Methods: We evaluated the concentrations of cholecystokinin (CCK), vasoactive intestinal peptide (VIP), somatostatin, substance P, neuropeptide Y (NPY) in plasma and in sigmoid tissue in 40 patients with IBS and 15 age- and gender-matched controls by using radioimmunoassay. Results: IBS patients had higher plasma level of CCK (p < 0.01), and the level of CCK in the sigmoid was also increased compared with controls (p < 0.05). The levels of somatostatin and substance P in fasting plasma and in the sigmoid were not different between IBS patients and control subjects (p > 0.05), but the levels of VIP in sigmoid tissue or in plasma were higher in IBS patients than in control group (p < 0.01). The NPY levels in both plasma and the sigmoid were significantly lower in IBS patients than in controls (p < 0.05). Plasma NPY level in patients with IBS with diarrhea as a predominant bowel pattern was lower than in patients with IBS with constipation as a predominant bowel pattern. Conclusion: IBS patients have increased levels of CCK and VIP and decreased NPY levels in fasting plasma and sigmoid tissue. These alterations of VIP, CCK and NPY may play a role in the pathogenesis of IBS.

Transcutaneous electroacupuncture improves dyspeptic symptoms and increases high frequency heart rate variability in patients with functional dyspepsia

The aim of the study was to evaluate the therapeutic value and possible mechanisms of transcutaneous electroacupuncture (TEA) in a double-blind and cross-over study in patients with functional dyspepsia (FD). Twenty-seven patients with FD were enrolled and the study consisted of two parts: (i) acute effects of TEA at PC6 and ST36 on gastric slow waves and heart rate variability and (ii) chronic (2 weeks) effects of TEA at PC6 and ST36 on dyspepsia symptoms, gastric slow waves, heart rate variability and neuropeptide Y (NPY) and motilin. The results of this study are: (i) The dyspepsia symptom score was decreased by 55% at the end of chronic TEA and the improvement was significant (P < 0.01); (ii) the high frequency (HF) assessed from the spectral analysis of heart rate variability was markedly increased with both acute TEA (76% increase, P = 0.01) and chronic TEA (75% increase, P = 0.025); (iii) gastric slow waves were not altered by either acute or chronic TEA; and (iv) the plasma level of NPY but not motilin was increased after chronic TEA. Non-invasive and needleless transcutaenous electroacupuncture at ST36 and PC6 markedly improves dyspepsia symptoms and the improvement may be associated with the increase in HF heart rate variability and the modulation of NPY.

Influence of short- and long-term treadmill exercises on levels of ghrelin, obestatin and NPY in plasma and brain extraction of obese rats

This study aims to clarify the effects of exercise on levels of appetite regulatory hormones in plasma and hypothalamus of obese rats. Diet-induced obese rats undergo short- (40 min) and long-term (40 min, 5 days/week for 8 weeks) exercises. The rats ran at a speed of 20 m/min on a 5 degrees slope treadmill. Rats undergoing short-term exercise were divided into C, E0, E1, E3, E12, and E24. Rats undergoing long-term exercise (LE) were compared to long-term control (LC). Concentrations of ghrelin, obestatin, and neuropeptide Y (NPY) were measured using radio immuno-assay. Expression of ghrelin receptor (GHSR-1a), putative obestatin receptor (GPR-39), and NPY in the hypothalamus was measured by quantitative RT-PCR. After short-term exercise, the plasma concentrations of ghrelin and obestatin were not changed, but NPY decreased. Ghrelin and obestatin in the hypothalamus decreased, and recovered 12 until 24 h. NPY increased and recovered after 24 h. Expression of GHSR-1a and NPY was not changed and GPR-39 was not observed. In LE, these changes are different in plasma and hypothalamus. It would be concluded appetite and body weight of obese rats are decreased by exercise through reduced level of ghrelin in the hypothalamus. Obestatin seems to have no effect in exercise-induced change in appetite.

Chronic cold stress exacerbates early diabetic kidney damage

Chronic stress is considered a co‐morbid factor in diabetic complications, but evidence is anecdotal, and without potential mechanisms. Since neuropeptide Y (NPY) is implicated in other stress‐induced pathophysiology, we hypothesize that stress will activate the NPY system and exacerbate early diabetic kidney disease. Diabetes (D) was induced with STZ in adult rats, and after 6 wks rats were placed in 4° water for 2h/day/14 days, then sacrificed. Chronic stress had no effect on plasma NPY levels in female rats. In contrast, stress increased platelet levels of NPY in both non‐diabetic (ND) (23.2±3.9 v 12.2±2.1 ng/ml in control, P&lt;0.01) and D males (18.2±.9 ng/ml, P&lt;0.05 vs cont). Of potential importance is the finding that ND females had 30% greater renal DPPIV/protease activity (which cleaves NPY to NPY 3–36) than ND male kidneys (P&lt;0.05). This activity was decreased to male levels +/− STZ, suggesting that the diabetic female kidney may be exposed to excessive amount of NPY 1–36. Stress significantly increased the tubulointerstitial fibrotic index (in AU) in both sexes in ND rats [Male: 0.72±.06 v 0.54±.02 in cont, P&lt;0.05); Female: 0.68±.04 vs 0.44±.07, P&lt;0.05] and diabetic rats [Male: 1.61±.06 v 1.37±.03 non‐stress, P&lt;0.05; Female: 1.51±.08 v 1.21±.06, P&lt;0.05]. Thus, for the first time we show that chronic stress initiates renal fibrosis in both ND and D kidneys, and sex differences in the stress‐induced NPY system.

Megakaryocyte/platelet‐derived Neuropeptide Y (NPY), in addition to neuronal, is essential for ischemic revascularization in rodents

Previously, we showed that sympathetically‐derived NPY promotes ischemic revascularization after femoral artery occlusion (FAO) in rodents by activating Y2 receptors (Rs) and dipeptidyl peptidase IV (DPPIV), which forms a Y2/Y5‐preferring agonist. The role of other NPY sources (platelets), Rs and temporal relationship to ischemic revascularization was unknown and is studied here. A critical role for NPY but not Y5R was shown in NPY−/− and Y5−/− mice whose post‐FAO limb revascularization was markedly impaired and unchanged, respectively. Within 5 days, FAO in rats (expressing platelet NPY) elevated plasma NPY levels (neuronal) and Y1, Y2, DPPIV and NPY mRNA (vs. non‐ischemic contralateral limb) in adductor (arteriogenesis zone) and gastrocnemius (angiogenesis zone) muscles; while density of CD31+‐capillaries fell. Vascular density, CD31+‐ and smooth muscle α‐actin+‐vessels, was restored by 14 days, when platelet levels doubled, and accelerated to 5 days by NPY slow‐release pellet (below FAO, 1 μg/14 days). Platelet NPY and bone marrow NPY mRNA were increased after FAO in platelet NPY‐expressing Sv129 WT mice, which were then used in a platelet depletion/transfer experiment [found (KA) to restore NPY atherosclerotic effects in resistant NPY−/−] with NPY−/−mice. Thus, early activation of neuronal and later activation of megakaryocyte/platelet‐derived NPY is essential for ischemic revascularization. NIH grants HL067357 and HL055310 to Z.Z.

Neuropeptide Y Gene Polymorphism and Plasma Neuropeptide Y Level in Febrile Seizure Patients in Taiwan

Neuropeptide Y (NPY) has been shown to depress the hyperexcitability of neurons. In the present study, we investigated the association between the nucleotide (nt) 5671 C/T polymorphism of the NPY gene and the plasma NPY level in patients with febrile seizures (FS). Fifty-six patients with FS and 55 control subjects were enrolled. Genotype and allele frequencies were compared. The frequencies of genotypes TT, TC and CC for the NPY gene nt 5671 C/T polymorphism were 21.4%, 28.6% and 50.0%, respectively, in patients with FS, and 14.6%, 40.0% and 45.4%, respectively, in control subjects. The frequencies of alleles T and C were 35.7% and 64.3%, respectively, in patients with FS, while those in the control group were 34.5% and 65.5%, respectively. We found no significant relationship between the NPY gene nt 5671 C/T polymorphism and FS. The plasma NPY concentrations of the FS group, the age-matched non-FS group, and subjects aged > 6 years in the non-FS group were 48.23 +/- 32.49, 55.36 +/- 23.12, and 70.10 +/- 60.31 pg/mL, respectively. These results indicate no statistical difference in plasma NPY concentration between FS patients and the non-FS group. However, plasma NPY concentration was found to increase significantly with age.

Renal and cardiac neuropeptide Y and NPY receptors in a rat model of congestive heart failure

Neuropeptide Y (NPY) is coreleased with norepinephrine and stimulates vasoconstriction, vascular and cardiomyocyte hypertrophy via Y1 receptors (R) and angiogenesis via Y2R. Although circulating NPY is elevated in heart failure, NPY's role remains unclear. Activation of the NPY system was determined in Wistar rats with the aortocaval (A-V) fistula model of high-output heart failure. Plasma NPY levels were elevated in A-V fistula animals (115.7 +/- 15.3 vs. 63.1 +/- 17.4 pM in sham, P < 0.04). Animals either compensated [urinary Na(+) excretion returning to normal with moderate disease (COMP)] or remained decompensated with severe cardiac and renal failure (urinary Na(+) excretion <0.5 meq/day), increased heart weight, decreased mean arterial pressure and renal blood flow (RBF), and death within 5-7 days (DECOMP). Cardiac and renal tissue NPY decreased with heart failure, proportionate to the severity of renal complications. Cardiac and renal Y1R mRNA expression also decreased (1.5-fold, P < 0.005) in rats with heart failure. In contrast, Y2R expression increased up to 72-fold in the heart and 5.7-fold in the kidney (P < 0.001) proportionate to severity of heart failure and cardiac hypertrophy. Changes in receptor expression were confirmed since the Y1R agonist, [Leu31, Pro34]-NPY, had no effect on RBF, whereas the Y2R agonist (13-36)-NPY increased RBF to compensate for disease. Thus, in this model of heart failure, cardiac and renal NPY Y1 receptors decrease and Y2 receptors increase, suggesting an increased effect of NPY on the receptors involved in cardiac remodeling and angiogenesis, and highlighting an important regulatory role of NPY in congestive heart failure.

NPY and Cardiac Diseases

Hypertension-induced left ventricular hypertrophy (LVH), along with ischemic heart disease, result in LV remodeling as part of a continuum that often leads to congestive heart failure. The neurohormonal model has been used to underpin many treatment strategies, but optimal outcomes have not been achieved. Neuropeptide Y (NPY) has emerged as an additional therapeutic target, ever since it was recognised as an important mediator released from sympathetic nerves in the heart, affecting coronary artery constriction and myocardial contraction. More recent interest has focused on the mitogenic and hypertrophic effects that are observed in endothelial and vascular smooth muscle cells, and cardiac myocytes. Of the six identified NPY receptor subtypes, Y(1), Y(2) and Y(5) appear to mediate the main functional responses in the heart. Plasma levels of NPY become elevated due to the increased sympathetic activation present in stress-related cardiac conditions. Also, NPY and Y receptor polymorphisms have been identified that may predispose individuals to increased risk of hypertension and cardiac complications. This review examines what understanding exists regarding the likely contribution of NPY to cardiac pathology. It appears that NPY may play a part in compensatory or detrimental remodeling of myocardial tissue subsequent to hemodynamic overload or myocardial infarction, and in angiogenic processes to regenerate myocardium after ischemic injury. However, greater mechanistic information is required in order to truly assess the potential for treatment of cardiac diseases using NPY-based drugs.

The Dynamic Changes of Plasma Neuropeptide Y and Neurotensin and Their Role in Regulating Cerebral Hemodynamics in Neonatal Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is a common cause of neonatal encephalopathy and is one of the most important causes of neonatal death and disabilities, especially those infants with moderate to severe encephalopathy. However, the pathogenesis of HIE still remains unclear. The purpose of this study was to explore the dynamic changes in plasma neuropeptide Y (NPY) and neurotensin (NT) as well as their role in regulating cerebral hemodynamics in HIE patients. The plasma levels of NPY and NT in the umbilical artery and peripheral blood on the first, third, and seventh days after birth in 40 term infants with HIE and 40 healthy controls were measured using radioimmunoassay. On the first day of life, the blood samples were collected immediately when ultrasound examinations were finished. The ultrasound transducer was placed on the temporal fontanelle to detect the hemodynamic parameters of the middle cerebral artery, including peak systolic flow velocity, end-diastolic flow velocity, time-average mean velocity, pulsatility index, and resistance index (RI) in both groups were measured by pulse Doppler ultrasound in the first day after birth. The relationship between RI and NPY or NT was analyzed by linear regression analysis. NPY levels in umbilical blood ([mean +/- standard deviation] 615.5 +/- 130.7 ng/L) and first-day peripheral blood (355.9 +/- 57.4 ng/L) in neonates with HIE were significantly higher than those in normal newborns' blood (199.1 +/- 63.2 and 214.4 +/- 58.0 ng/L, respectively; P < 0.01). NPY levels in HIE neonates then declined to control levels on the third day after birth ( P > 0.05). However, the levels of plasma NT in umbilical blood and peripheral blood were much higher in the HIE group than those in normal newborns during the first week ( P < 0.01). The results of Doppler ultrasound examinations showed that cerebral blood flow velocity significantly decreased, whereas RI increased markedly in HIE patients compared with healthy controls ( P < 0.01). Linear regression analysis revealed that the RI was positively correlated with NPY levels ( R = 0.614; P < 0.01) and negatively correlated with NT levels ( R = -0.579; P < 0.01). The results of this study showed that there was a significant increase in plasma NPY and NT levels in HIE patients and this was strongly related to the severity of HIE, and the hemodynamic parameter RI was significantly correlated with NPY and NT. Therefore, we believe that the dynamic changes in plasma NPY or NT levels participate in the mechanisms of HIE by regulating cerebral hemodynamic changes after neonatal asphyxia occurs.

Impact of the Leu7Pro Polymorphism of preproNPY on Diurnal NPY and Hormone Secretion in Type 2 Diabetes

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that plays a role in e.g. circulation, hormone release and angiogenesis. Earlier studies have shown that the Leucine 7 to Proline 7 (Leu7Pro) polymorphism of preproNPY is associated with increased risk for vascular complications in type 2 diabetes. The mechanism for this maybe altered transmitter and hormone levels or altered cardiovascular functions, which have been observed in healthy subjects having the Leu7Pro polymorphism. The current study was undertaken to explore if the Leu7Pro polymorphism has an impact on these functions in subjects with type 2 diabetes. Diurnal measurements were performed for Finnish Caucasian type 2 diabetes patients of two preproNPY genotypes (matched by sex, age, BMI, duration of diabetes and HbA1c) in resting position to prevent sympathetic stimulation. Standard meals were offered during the 24-hour study period. Nine subjects with the Leu7Pro polymorphism and ten subjects without this polymorphism were studied. Plasma concentrations of NPY, glucose, insulin, cortisol, prolactin and leptin were measured by taking blood samples at 20 time points (from 8 a.m. to 8 a.m.). Heart rate and blood pressure were measured at the same time points. The results show that NPY concentrations were similar in both preproNPY genotypes. Glucose, insulin, cortisol and leptin concentrations as well as heart rate and blood pressure were also similar. However, a significant difference between genotypes was found in the association of NPY concentrations with cortisol concentrations (p for difference=0.002). Also a statistically significant negative association of plasma NPY levels with plasma glucose levels was found in both genotypes. Since no impact of preproNPY genotype on mean NPY or hormone levels were detected in subjects with type 2 diabetes, the mechanisms for the increased risk for diabetic complications in the subjects with the Leu7Pro polymorphism need to be further explored.