neuropeptide-y and Chronic-Disease

Chronic heart failure (CHF) is a major health problem that carries a devastating prognosis. The prognosis worsens considerably once cardiac cachexia has been diagnosed. Neurohormonal, metabolic, hemodynamic and immunological alterations are involved in the initiation and progression of cardiac cachexia. Cachexia is characterized by a hypothalamic inappropriate response to the mechanisms controlling energy homeostasis. Levels of the anorexigenic hormone leptin are decreased whereas the orexigenic gherlin hormone levels are normal or elevated. Nevertheless, energy intake is not increased as expected due to a persistent activation of the proopiomelanocortin (POMC) system (anorexigenic) paralleled by a decreased activity of the neuropeptide Y (NPY, orexigenic) neurons. Cachexia is also characterized by an imbalance in anabolic (impairment in the growth hormone/insulin-like growth factor-I axis, insulin resistance) and catabolic (increased levels of catecholamines, increased cortisol/dehydroepiandrosterone ratio and activation of proinflammatory cytokines such as tumor necrosis factor-alpha, interleuchin-6, interleuchin-1') at the basis of the wasting process. This review discusses the complex role of the endocrine system in modulating energy balance, appetite and metabolism in patients with chronic heart failure. A joint multidisciplinary effort of the cardiologists, immunologists and endocrinologists might be useful to identify the precise mechanisms involved in the neuroendocrine alteration and to develop therapeutic strategies able to improve the prognosis of CHF patients.

Topics: Appetite; Biomarkers; Cachexia; Chronic Disease; Cytokines; Endocrine System; Ghrelin; Heart Failure; Humans; Hypothalamus; Leptin; Neuropeptide Y; Pro-Opiomelanocortin; Prognosis

Topics: Animals; Chronic Disease; Humans; Neurodegenerative Diseases; Neuropeptide Y

Pathogenic mechanisms of chronic systolic heart failure are constantly of great interest. In recent years the neurohumoral theory of heart failure has gained attraction. According to this theory, neurohumoral mechanisms play the main role in the pathogenesis of heart failure, especially in its progression. These mechanisms can be divided into 2 categories: vasoconstrictive, mitogenic and antinatriuretic on the one hand and vasodilative, antimitogenic and natriuretic on the other one. The former consists of sympathetic nervous system, renin-angiotensin-aldosterone system, vasopressin, endothelin, cytokines. The latter comprises natriuretic peptides, prostaglandins and nitric oxide. Undoubtedly unfavourable roles of sympathetic system and renin-angiotensin-aldosteron have been shown in the progression of heart failure. Data are being also gathered confirming harmful effects of endothelin and cytokines and possibly of neuropeptide Y and vasopressine. Extensive data exist that demonstrate beneficial influence of natriuretic peptide on heart failure. The roles of nitric oxide as well as recently discovered adrenomedullin and medullipin are far from clear.

Topics: Chronic Disease; Cytokines; Disease Progression; Endothelin-1; Heart Failure; Humans; Natriuretic Agents; Neuropeptide Y; Nitric Oxide; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

Topics: Atrial Natriuretic Factor; Bombesin; Chronic Disease; Glucagon; Heart Failure; Humans; Insulin; Neuropeptide Y; Neurosecretory Systems; Neurotensin; Renin-Angiotensin System

One of the causes of coronary artery spasm in patients with variant angina could be a disturbed interaction between the vasodilating action of endothelial derived relaxing factor and the vasospastic action of neuropeptide Y and thromboxane B2. The aim of this study was a verification of the participation of neuropeptide Y and thromboxane B2 in etiopathogenesis of the coronary artery spasm in patients with variant angina. The survey was made in 38 patients with variant angina and in 18 patients with chronic stable angina pectoris. The control group consisted of 20 healthy persons. Before the hyperventilation test, during which the person under test has been breathing with a frequency of 40/minute through 5 minutes, the Tris (tromethamol) of pH = 10.5 has been given in intravenous infusion lasting for 5 minutes. The neuropeptide Y and thromboxane B2 plasma levels have been determined just before the hyperventilation test, just after the termination of the test and 10 minutes after the termination of the test. Neuropeptide Y and thromboxane B2 plasma levels have been determined with a radioimmunologic method. It has been recorded that during the hyperventilation test in all of the 38 patients with variant angina the clinical and the electrocardiographic symptoms of the coronary artery spasm have appeared--but these have not appeared in patients with chronic stable angina pectoris and in healthy persons. The level of neuropeptide Y in patients with variant angina before the test, just at its end and as well as 10 min. after completing of the hyperventilation test, was significantly higher compared with the level in patients with chronic stable angina pectoris and controls. Contrary to chronic stable angina pectoris patients and controls, in variant angina group the level of neuropeptide Y increased rapidly at the end of the test and further elevation in neuropeptide Y level was observed 10 min. after the test. There was no difference in basal thromboxane B2 levels between angina patients and controls. At the end of hyperventilation test in variant angina group thromboxane B2 level significantly increased and remained on this level until 10 min. after the test. Significant increase of neuropeptide Y and thromboxane B2 plasma levels in variant angina patients during artery coronary spasm induced by hyperventilation test suggests the contribution of these humoral factors to the pathogenesis of vasospastic episodes in angina patients.

Topics: Adult; Angina Pectoris; Angina Pectoris, Variant; Chronic Disease; Female; Humans; Male; Middle Aged; Neuropeptide Y; Thromboxane B2

The mechanism of action of omalizumab in urticaria is still not literally known. This study examines the serum values of substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and interleukin-31 (IL-31) in patients using omalizumab. In this study, 30 patients with chronic spontaneous urticaria (CSU) who were going to be treated with omalizumab and 20 healthy volunteers took part. Demographic data, clinical data, and disease activity scores were noted. For serum SP, CGRP, NPY, and IL-31 values, 10 mL of blood were taken from the patients before starting the treatment, 3 months after the treatment, at the end of the 6th month, and from healthy volunteers all at once. The change in values measured at baseline, 3rd month, and 6th month was analyzed by the Friedman Test. The Mann-Whitney

Topics: Anti-Allergic Agents; Calcitonin Gene-Related Peptide; Chronic Disease; Chronic Urticaria; Humans; Immunoglobulin E; Interleukins; Neuropeptide Y; Omalizumab; Substance P; Treatment Outcome; Urticaria

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in mig

Topics: Adult; Blood Glucose; Chronic Disease; Cross-Sectional Studies; Female; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Migraine Disorders; Neuropeptide Y

Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). First, we found that ArcN NPY/AgRP fibers closely appose PVN and DMH presympathetic neurons. Second, nanoinjections of NPY or an NPY receptor Y1 (NPY1R) antagonist into PVN or DMH decreased or increased SSNA, respectively. Third, blockade of DMH NPY1R reversed the sympathoinhibition elicited by selective, DREADD-mediated activation of ArcN NPY/AgRP neurons. Finally, stimulation of ArcN NPY/AgRP terminal fields in the PVN and DMH decreased SSNA. Considering that chronic obesity decreases ArcN NPY content, we propose that the ArcN NPY neuropathway to the PVN and DMH is pivotal in obesity-induced elevations in SNA.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Blood Pressure; Chronic Disease; Gene Expression Regulation; Heart Rate; Mice; Mice, Transgenic; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Receptors, Neuropeptide Y; Sympathetic Nervous System

The visible burrow system (VBS) utilizes the natural social behavior of rodents to model chronic social stress. Classically, when male and female rats are housed together in the VBS a dominance hierarchy rapidly forms with one dominant (DOM) and three subordinate (SUB) males. SUB animals show signs of chronic social stress, including loss of body weight and elevated basal corticosterone. This study furthered examined differences among the SUB population. Quantitative observations across numerous VBS colonies within the Sakai Lab suggest that there is variability in the effects of stress on the SUB population, specifically that some animals may experience more severe effects of chronic social stress than others. To further examine this observation, SUB animals were classified as OMEGA if they received a disproportionate amount of their colonies' wounds. OMEGA animals received more wounds to their body compared to SUB (P<0.0001) and lost significantly more weight throughout the stress period compared to all other VBS-housed animals (group×time interaction P<0.0001). Following VBS housing it was determined the OMGEA also lost lean body mass (P<0.01 vs. controls and DOM), are hyporesponsive to an acute restraint challenge (P<0.01 vs all other groups) and show depressive-like behavior during a forced swim test. Furthermore, expression of neuropeptide Y within the amygdala, known for anxiolytic properties following chronic stress, was elevated among OMEGA (group×region interaction P<0.001). Together these observations suggest that an additional phenotype exists among the SUB animals within a VBS colony and represents the variability of the effects of chronic social stress.

Topics: Amygdala; Animals; Behavior, Animal; Body Composition; Body Weight; Chronic Disease; Depression; Dominance-Subordination; Feeding Behavior; Female; Housing, Animal; Male; Neuropeptide Y; Psychological Tests; Rats, Long-Evans; Stress, Psychological; Wounds and Injuries

The efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120mg/kg) and valproic acid (400mg/kg) could not prevent PTZ-induced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p=0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p<0.05), which were also more frequent than in the naïve group (p<0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY- and ΔFosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

Topics: Animals; Anticonvulsants; Brain; Callithrix; Carbamazepine; Chronic Disease; Disease Models, Animal; Electrocorticography; Epilepsy; Female; Immunohistochemistry; Male; Neuropeptide Y; Pentylenetetrazole; Phenobarbital; Pilocarpine; Proto-Oncogene Proteins c-fos; Seizures; Valproic Acid

H1-receptor inhibiting drugs, namely loratadine and cetirizine, were frequently used in treatment of chronic urticaria. Urticarial weal and flare reactions, a neurogenic reflex due to neuropeptides, were reported to be more effectively inhibited by cetirizine than loratadine. The aim of this study was to determine and compare the effects of systemic loratadine and cetirizine treatments on serum levels of selected neuropeptides in chronic urticaria. Treatment groups of either systemic loratadine or cetirizine (10 mg/d), consisting of 16 and 22 patients, respectively, were included. Serum levels of stem cell factor (SCF), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), and substance P (SP) were detected before and after one week of treatment with antihistamines. Serum NPY and VIP levels were significantly decreased when compared before and after treatment with antihistamines (P < 0.001 and P < 0.01, respectively). SCF and NGF values were also decreased after antihistamine treatment (P < 0.05). Post-treatment levels of CGRP were significantly higher compared with pretreatment values, while no significant difference was detected between pre and post treatment levels of SP. Cetirizine was significantly more effective than loratadine on lowering serum levels of SCF among the other neuropeptides. Systemic loratadine and cetirizine treatments in patients with chronic urticaria precisely caused variations in serum levels of neuropeptides. The predominant effect of cetirizine compared to loratadine on reducing serum SCF levels might be explained with anti-inflammatory properties of cetirizine.

Topics: Adolescent; Adult; Calcitonin Gene-Related Peptide; Cetirizine; Chronic Disease; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Middle Aged; Nerve Growth Factor; Neuropeptide Y; Neuropeptides; Stem Cell Factor; Substance P; Urticaria; Vasoactive Intestinal Peptide; Young Adult

Chronic stress has been shown to impair memory, however, the extent to which memory can be impaired is often variable across individuals. Predisposed differences in particular traits, such as anxiety, may reveal underlying neurobiological mechanisms that could be driving individual differences in sensitivity to stress and, thus, stress resiliency. Such pre-morbid characteristics may serve as early indicators of susceptibility to stress. Neuropeptide Y (NPY) and enkephalin (ENK) are neurochemical messengers of interest implicated in modulating anxiety and motivation circuitry; however, little is known about how these neuropeptides interact with stress resiliency and memory. In this experiment, adult male rats were appetitively trained to locate sugar rewards in a motivation-based spatial memory task before undergoing repeated immobilization stress and then being tested for memory retention. Anxiety-related behaviors, among other characteristics, were monitored longitudinally. Results indicated that stressed animals which showed little to no impairments in memory post-stress (i.e., the more stress-resilient individuals) exhibited lower anxiety levels prior to stress when compared to stressed animals that showed large deficits in memory (i.e., the more stress-susceptible individuals). Interestingly, all stressed animals, regardless of memory change, showed reduced body weight gain as well as thymic involution, suggesting that the effects of stress on metabolism and the immune system were dissociated from the effects of stress on higher cognition, and that stress resiliency seems to be domain-specific rather than a global characteristic within an individual. Neurochemical analyses revealed that NPY in the hypothalamus and amygdala and ENK in the nucleus accumbens were modulated differentially between stress-resilient and stress-susceptible individuals, with elevated expression of these neuropeptides fostering anxiolytic and pro-motivation function, thus driving cognitive resiliency in a domain-specific manner. Findings suggest that such neurochemical markers may be novel targets for pharmacological interventions that can serve to prevent or ameliorate the negative effects of stress on memory.

Topics: Amygdala; Animals; Chronic Disease; Enkephalins; Hippocampus; Hypothalamus; Individuality; Male; Memory; Motivation; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Resilience, Psychological; RNA, Messenger; Stress, Psychological

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-β (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.

Topics: Animals; Apoptosis; Cell Membrane; Cell Proliferation; Cell Survival; Chronic Disease; Coronary Angiography; Disease Models, Animal; Fatty Acids; Fibrosis; Gene Expression Regulation; Glucose Transporter Type 4; Heart Ventricles; Hypercholesterolemia; Hypertrophy; Male; Myocardial Ischemia; Myocytes, Cardiac; Neovascularization, Pathologic; Neuropeptide Y; Oxidative Stress; Swine

The dorsomedial hypothalamus (DMH) has long been implicated in feeding behavior and thermogenesis. The DMH contains orexigenic neuropeptide Y (NPY) neurons, but the role of these neurons in the control of energy homeostasis is not well understood. NPY expression in the DMH is low under normal conditions in adult rodents but is significantly increased during chronic hyperphagic conditions such as lactation and diet-induced obesity (DIO). To understand better the role of DMH-NPY neurons, we characterized the efferent projections of DMH-NPY neurons using the anterograde tracer biotinylated dextran amine (BDA) in lactating rats and DIO mice. In both models, BDA- and NPY-colabeled fibers were limited mainly to the hypothalamus, including the paraventricular nucleus of the hypothalamus (PVH), lateral hypothalamus/perifornical area (LH/PFA), and anteroventral periventricular nucleus (AVPV). Specifically in lactating rats, BDA-and NPY-colabeled axonal swellings were in close apposition to cocaine- and amphetamine-regulated transcript (CART)-expressing neurons in the PVH and AVPV. Although the DMH neurons project to the rostral raphe pallidus (rRPa), these projections did not contain NPY immunoreactivity in either the lactating rat or the DIO mouse. Instead, the majority of BDA-labeled fibers in the rRPa were orexin positive. Furthermore, DMH-NPY projections were not observed within the nucleus of the solitary tract (NTS), another brainstem site critical for the regulation of sympathetic outflow. The present data suggest that NPY expression in the DMH during chronic hyperphagic conditions plays important roles in feeding behavior and thermogenesis by modulating neuronal functions within the hypothalamus, but not in the brainstem.

Topics: Age Factors; Animals; Animals, Newborn; Biotin; Chronic Disease; Dextrans; Disease Models, Animal; Efferent Pathways; Female; Gonadotropin-Releasing Hormone; Hyperphagia; Hypothalamic Hormones; Hypothalamus; Intracellular Signaling Peptides and Proteins; Lactic Acid; Male; Melanins; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Obesity; Orexins; Peptide Fragments; Pituitary Hormones; Pregnancy; Rats; Rats, Wistar; Tryptophan Hydroxylase

The primary purpose of this study was to investigate the sympathetic innervation of the long head of the biceps brachii tendon LHB via immunohistochemical staining for protein S-100 and neuropeptide Y (NPY) in patients with complex proximal humerus fractures, in individuals with chronic biceps tendinosis in the setting of large rotator cuff tears (RC), and in cadaveric samples with no previously reported shoulder pathology.. We investigated the presence of sympathetic innervation and α1-adrenergic receptors of the long head of the biceps brachii tendon (LHB) in patients with complex proximal humerus fractures and individuals with chronic biceps tendinosis in the setting of large rotator cuff tears (RC). The correlation of morphological features with immunohistochemical evidence of neural element presence was also investigated. Forty-one LHB tendon specimens were examined. Seventeen were harvested from patients who underwent hemiarthroplasty for proximal humerus fractures, 14 were from individuals with biceps tendinosis in the context of a large RC tear, and ten were from cadaveric controls with no previous shoulder pathology. Histologic examination was performed using hematoxylin and eosin. Immunohistochemistry was used to detect the expression of the protein S-100, neuropeptide Y, and α1-adrenergic receptors, as well as to characterize the potential neural differentiation of tendon cells.. A strong correlation between the expression of NPY/S-100, α1-adrenergic/S-100, and α1-adrenergic/NPY was found. The LHB tendon has sympathetic innervation and α1-adrenergic receptors in acute and chronic pathological conditions.. Our results provide useful guidance on the management of tendinosis and the handling of the LHB in hemiarthroplasties for fractures.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Arthroplasty; Biopsy; Chronic Disease; Female; Humans; Humeral Fractures; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Receptors, Adrenergic, alpha-1; Regression Analysis; S100 Proteins; Tendinopathy; Tendons

Chronic stress, as seen in post-traumatic stress disorder, can exacerbate existing diseases. Electroacupuncture (EA) has been proposed to treat chronic stress, although information on its efficacy or mechanism(s) of action is limited. While many factors contribute to the chronic stress response, the sympathetic peptide, neuropeptide Y (NPY), has been shown to be elevated in chronic stress and is hypothesized to contribute to the physiological stress response. Our objective was to determine if EA at acupuncture point stomach 36 (ST(36)) is effective in mitigating cold stress-induced increase in NPY in rats. Both pretreatment and concomitant treatment with EA ST(36) effectively suppressed peripheral and central NPY after 14 d of cold stress (P < 0.05). The effect was specific, as NPY in Sham-EA rats was not different than observed in stress-only rats. Additionally, the effect of EA ST(36) was long-lasting, as NPY levels remained suppressed despite early cessation of EA ST(36), while exposure to cold stress was continued. In the paraventricular nucleus (PVN), it was notable that changes in NPY mirrored plasma NPY levels, and that the significant elevation in PVN Y1 receptor observed with stress was also prevented with EA ST(36). The findings indicate that EA ST(36) is effective in preventing one of the sympathetic pathways stimulated during chronic stress, and thus may be a useful adjunct therapy in stress-related disorders.

Topics: Acupuncture Points; Animals; Chronic Disease; Electroacupuncture; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Random Allocation; Rats; Rats, Sprague-Dawley; Stomach; Stress, Psychological; Sympathetic Nervous System

Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npy(tet/tet)) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity. Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown or intrathecal administration of Y1 or Y2 receptor antagonists. In addition, Y2 antagonism increased dorsal horn expression of Fos and phosphorylated form of extracellular signal-related kinase. Taken together, these data establish spinal NPY receptor systems as an endogenous braking mechanism that exerts a tonic, long-lasting, broad-spectrum inhibitory control of spinal nociceptive transmission, thus impeding the transition from acute to chronic pain. NPY and its receptors appear to be part of a mechanism whereby mammals naturally recover from the hyperalgesia associated with inflammation or nerve injury.

Topics: Animals; Arginine; Behavior, Animal; Benzazepines; Chronic Disease; Gene Expression Regulation; Mice; Mice, Knockout; Neuropeptide Y; Nociceptors; Pain; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Receptors, Neuropeptide Y; Synaptic Transmission

Inflammation and stress are regarded as two important atherogenic factors. Because stress can affect leukocyte distribution, we hypothesized that stress-mediated leukocyte extravasation can modify the inflammatory environment of the arterial wall possibly contributing to atherogenesis. To test this hypothesis we evaluated the inflammatory environment of the aorta in C57Bl/6 mice subjected to 3 and 12 months of chronic stress and compared it to age matched non-stressed animals. Experiments were carried out in mice fed regular chow or atherogenic diets. Both treatments increased the expression of vascular and leukocyte adhesion molecules and leukocyte accumulation. At 3 months, stress but not an atherogenic diet elevated the number of CD4 cells, CD8 cells, macrophages, dendritic cells and neutrophils. These changes were associated with elevation of transcripts for ICAM-1 and VCAM-1, E-selectin and neuropeptide Y. At 12 months, stress or high cholesterol acted similarly to elevate the number of CD8 and macrophages, and synergistically on the number of all cell types investigated. At this time-point, strong synergism was also observed on the level of E-selectin and NPY in the aorta, but not in the circulation. Despite these effects, histological and morphological alterations of the arterial wall were severe in the atherogenic diet, but not in the stress groups. Thus, although stress and an atherogenic diet may both affect leukocyte accumulation in the aorta, they may contribute differently to atherogenesis.

Topics: Animals; Aorta; Atherosclerosis; Biomarkers; Chronic Disease; Diet; Diet, Atherogenic; E-Selectin; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Immunoenzyme Techniques; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Plaque, Atherosclerotic; Real-Time Polymerase Chain Reaction; Stress, Psychological; Vascular Cell Adhesion Molecule-1

Unilateral constrictive sciatic nerve injury (uCCI) is a common neuropathic pain model. However, the bilateral constrictive injury (bCCI) model is less well studied, and shows unique characteristics. In the present study, we sought to correlate effects of bCCI on nocifensive responses to cold and mechanical stimuli with selected dorsal horn anatomic markers. bCCI or sham ligation of both rat sciatic nerves were followed up to 90 days of behavioural testing. Additional rats sacrificed at 15, 30 and 90 days were used for anatomic analyses. Behavioural tests included hindpaw withdrawal responses to topical acetone, cold plate testing, an operant thermal preference task and hindpaw withdrawal thresholds to mechanical probing.. All nocifensive responses to cold increased and remained enhanced for >45 days. Mechanical withdrawal thresholds decreased for 25 days only. Densitometric analyses of immunoperoxidase staining in the superficial dorsal horn at L4-5 revealed decreased cholecystokinin (CCK) staining at all times after bCCI, decreased mu opiate receptor (MOR) staining, maximal at 15 days, increased neuropeptide Y (NPY) staining only at days 15 and 30, and increased neurokinin-1 receptor (NK-1R) staining at all time points, maximal at 15 days. Correlation analyses at 45 days post-bCCI, were significant for individual rat nocifensive responses in each cold test and CCK and NK-1R, but not for MOR or NPY.. These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain.

Topics: Acetone; Analgesics; Animals; Biomarkers; Cholecystokinin; Chronic Disease; Cold Temperature; Disease Models, Animal; Female; Functional Laterality; Hyperalgesia; Immunohistochemistry; Ligation; Neuropeptide Y; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Posterior Horn Cells; Predictive Value of Tests; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Receptors, Opioid, mu; Reflex; Sciatic Neuropathy

We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia. Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After 3 weeks, an osmotic pump was placed to deliver either placebo (control, n=8) or NPY(3-36) (NPY, n=8) to the collateral dependent region. Five weeks after pump placement, after cardiac catheterization and hemodynamic assessment, the heart was harvested for analysis. NPY treated animals demonstrated increased mean arterial pressures and improved left ventricular function (+dP/dt). Cardiac catheterization demonstrated a significant increase in the blush score in the NPY group (p<0.001). Blood flow to the ischemic myocardium was not different between groups at rest or during ventricular pacing. Immunohistochemical double staining for CD-31 and smooth muscle actin demonstrated an increase in capillary and arteriole formation in NPY treated animals (p=0.02 and p<0.001). Immunoblotting showed a significant upregulation of DPPIV (p=0.009) and NPY receptors 1 (p=0.008), 2 (p=0.02) and 5 (p=0.03) in the NPY treated group. Additionally, there was significant upregulation of VEGF (p=0.04), eNOS (p=0.014), phospho-eNOS (ser1177) (p=0.02), and PDGF (p<0.001) in NPY treated group. The anti-angiogenic factors endostatin and angiostatin were significantly decreased in NPY treated animals (endostatin, p=0.03; angiostatin, p=0.04). Exogenous NPY(3-36) resulted in improved myocardial function and increased angiogenesis and arteriogenesis by stimulating growth factor, pro-angiogenic receptor upregulation, and decreasing anti-angiogenic expression, but did not increase blood flow to the ischemic myocardium. NPY may act as a good adjunct to primary agents of therapeutic angiogenesis.

Topics: Animals; Chronic Disease; Collateral Circulation; Coronary Angiography; Disease Models, Animal; Heart Function Tests; Immunoblotting; Immunohistochemistry; Microvessels; Models, Biological; Myocardial Ischemia; Neuropeptide Y; Perfusion; Sus scrofa

Repeated injection of corticosterone (CORT) induces dysregulation in the HPA axis, resulting in depression and anxiety. Many studies have shown that acupuncture, which is widely used for the treatment of stress and mental illness, in East Asian countries, is an effective therapeutic intervention for psychosomatic disorders. We investigated the influence of acupuncture therapy on chronic CORT-induced behavioral responses to the forced swimming test (FST) and elevated plus maze (EPM) and expression of neuropeptide Y (NPY) in the rat brain using immunohistochemistry. Male Sprague-Dawley rats were injected with CORT (40 mg/kg, i.p.) once daily for 19 consecutive days. The dysregulation of HPA axis by external injection of CORT was confirmed by measuring the CORT concentration in plasma and the expression level of CRF in hypothalamus. Acupuncture was performed at the PC6 acupoint for 5 min before CORT injection. Acupuncture significantly reduced depression- and anxiety-like behavior and increased NPY expression in the hypothalamus. These results demonstrated that stimulation of the PC6 acupoint suppresses the symptopathology of the hypoactivated HPA axis in chronic CORT-induced rat model of depression.

Topics: Acupuncture Therapy; Animals; Anxiety; Behavior, Animal; Chronic Disease; Corticosterone; Depression; Hypothalamo-Hypophyseal System; Male; Maze Learning; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley

This study sought to investigate the effects of injury-induced neuropeptide Y (NPY) on c-Fos expression in the cuneate neurons and neuropathic pain after median nerve injury. Four weeks after median nerve transection (MNT), the injured nerves stimulated at low intensity (0.1 mA) expressed significantly less NPY-like immunoreactive (NPY-LI) fibers in the cuneate nucleus (CN) than those stimulated at high intensities (1.0 mA and 10 mA). Conversely, a significantly higher number of c-Fos-LI cells were observed in the CN in rats stimulated with 0.1 mA compared to those stimulated with 1.0 mA or 10 mA. These results suggest that more NPY was released following low-intensity stimulation, and consequently fewer NPY-LI fibers and more c-Fos-LI cells were identified in the CN. Furthermore, the number of c-Fos-LI cells as well as the percentage of c-Fos-LI cuneothalamic projection neurons (CTNs) in the CN was markedly decreased after injection of NPY receptor antagonist along with retrograde tract-tracing method, indicating that NPY regulated c-Fos expression. In rats with median nerve chronic constriction injury (CCI), intracerebroventricular injection of NPY aggravated mechanical allodynia and low-intensity stimulus-evoked c-Fos expression, both of which were reversed by injection of NPY receptor antagonist. However, thermal hyperalgesia was not affected by injection of these two reagents. Taken together, these findings suggest that more NPY release, following low-intensity electrical stimulation of the injured nerve, significantly induces c-Fos expression in the CTNs, which possibly provide the ascending thalamic transmission of neuropathic pain signals.

Topics: Animals; Behavior, Animal; Chronic Disease; Constriction, Pathologic; Electric Stimulation; Enzyme-Linked Immunosorbent Assay; Hyperalgesia; Injections, Intraventricular; Male; Median Nerve; Median Neuropathy; Medulla Oblongata; Neuropeptide Y; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y

Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) and neuropeptide Y (NPY) in the response to stress and modulation of depression, but it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression. Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of depression-like behavioral changes, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test. These CUMS-induced behavioral changes were suppressed or blocked by intra-hippocampal injection of 5-HT (31.25 microg/microl) or NPY (10 microg/microl). These data suggest a critical role of reduced hippocampal 5-HT and NPY neurotransmission in CUMS-induced depression.

Topics: Animals; Behavior, Animal; Body Weight; Chronic Disease; Depressive Disorder; Disease Models, Animal; Exploratory Behavior; Food Preferences; Grooming; Hippocampus; Immobilization; Male; Microinjections; Motor Activity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Serotonin; Stress, Psychological; Swimming

The amygdala modulates memory consolidation with the storage of emotionally relevant information and plays a critical role in fear and anxiety. We examined changes in neuronal morphology and neurotransmitter content in the amygdala of rats exposed to a single prolonged stress (SPS) as a putative animal model for human post-traumatic stress disorder (PTSD). Rats were perfused 7 days after SPS, and intracellular injections of Lucifer Yellow were administered to neurons of the basolateral (BLA) and central amygdala (CeA) to analyze morphological changes at the cellular level. A significant increase of dendritic arborization in BLA pyramidal neurons was observed, but there was no effect on CeA neurons. Neuropeptide Y (NPY) was abundant in BLA under normal conditions. The local concentration and number of immunoreactive fibers of NPY in the BLA of SPS-exposed rats were increased compared with the control. No differences were observed in this regard in the CeA. Double immunostaining by fluorescence and electron microscopy revealed that NPY immunoreactive terminals were closely associated with calcium/calmodulin II-dependent protein kinase (CaMKII: a marker for pyramidal neurons)-positive neurons in the BLA, which were immunopositive to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). SPS had no significant effect on the expression of CaMKII and MR/GR expression in the BLA. Based on these findings, we suggest that changes in the morphology of pyramidal neurons in the BLA by SPS could be mediated through the enhancement of NPY functions, and this structural plasticity in the amygdala provides a cellular and molecular basis to understand for affective disorders.

Topics: Afferent Pathways; Amygdala; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Shape; Chronic Disease; Dendrites; Disease Models, Animal; Fluorescent Antibody Technique; Isoquinolines; Male; Microscopy, Electron, Transmission; Neuronal Plasticity; Neurons; Neuropeptide Y; Neurotransmitter Agents; Presynaptic Terminals; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Stress Disorders, Post-Traumatic; Stress, Psychological; Time Factors

Temporal lobe epilepsy remains amongst the most common and drug refractory of neurological disorders. Gene therapy may provide a realistic therapeutic approach alternative to surgery for intractable focal epilepsies. To test this hypothesis, we applied here a gene therapy approach, using a recombinant adeno-associated viral (rAAV) vector expressing the human neuropeptide Y (NPY) gene, to a progressive and spontaneous seizure model of temporal lobe epilepsy induced by electrical stimulation of the temporal pole of the hippocampus, which replicates many features of the human condition. rAAV-NPY or a control vector lacking the expression cassette (rAAV-Empty) was delivered into the epileptic rat hippocampi at an early progressive stage of the disease. Chronic epileptic rats were video-EEG monitored to establish pre-injection baseline recordings of spontaneous seizures and the effect of rAAV-NPY versus rAAV-Empty vector injection. Both non-injected stimulated controls and rAAV-empty injected rats showed a similar progressive increase of spontaneous seizure frequency consistent with epileptogenesis. The delivery of rAAV-NPY in epileptic rat brain leads to a remarkable decrease in the progression of seizures as compared to both control groups and this effect was correlated with the NPY over-expression in the hippocampus. Moreover, spontaneous seizure frequency was significantly reduced in 40% of treated animals as compared to their pre-injection baseline. Our data show that this gene therapy strategy decreases spontaneous seizures and suppresses their progression in chronic epileptic rats, thus representing a promising new therapeutic strategy.

Topics: Animals; Chronic Disease; Dependovirus; Electroencephalography; Epilepsy, Temporal Lobe; Gene Expression; Genetic Engineering; Genetic Therapy; Genetic Vectors; Hippocampus; Injections; Male; Neurons; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Transduction, Genetic; Video Recording

Topics: Acclimatization; Animals; Calcitonin Gene-Related Peptide; Carotid Body; Chronic Disease; Hypoxia; Neuropeptide Y; Rats; Substance P; Time Factors; Vasoactive Intestinal Peptide

Topics: Animals; Calcitonin Gene-Related Peptide; Carbon Dioxide; Carotid Body; Chronic Disease; Hypercapnia; Hypocapnia; Hypoxia; Neuropeptide Y; Rats; Substance P; Time Factors; Vasoactive Intestinal Peptide; Vasodilation

To investigate a possible link between some neuropeptides and depression, we analyzed their mRNA levels in brains of rats exposed to chronic mild stresses (CMS; a stress-induced anhedonia model), a commonly used model of depression. Rats exposed for 3 weeks to repeated, unpredictable, mild stressors exhibited an increased self-stimulation threshold, reflecting the development of an anhedonic state, which is regarded as an animal model of major depression. In situ hybridization was employed to monitor mRNA levels of neuropeptide Y (NPY), substance P and galanin in several brain regions. In the CMS rats, NPY mRNA expression levels were significantly decreased in the hippocampal dentate gyrus but increased in the arcuate nucleus. The substance P mRNA levels were increased in the anterodorsal part of the medial amygdaloid nucleus, in the ventromedial and dorsomedial hypothalamic nuclei and the lateral hypothalamic area, whereas galanin mRNA levels were decreased in the latter two regions. These findings suggest a possible involvement of these three peptides in mechanisms underlying depressive disorders and show that similar peptide changes previously demonstrated in genetic rat models also occur in the present stress-induced anhedonia model.

Topics: Amygdala; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Mapping; Chronic Disease; Dentate Gyrus; Depressive Disorder, Major; Disease Models, Animal; Galanin; Gene Expression Regulation; Hypothalamus; Male; Neuropeptide Y; Neuropeptides; Rats; Rats, Wistar; RNA, Messenger; Self Stimulation; Stress, Psychological; Substance P

Major aspects of temporal lobe epilepsy (TLE) can be reproduced in mice following a unilateral injection of kainic acid into the dorsal hippocampus. This treatment induces a non-convulsive status epilepticus and acute lesion of CA1, CA3c and hilar neurons, followed by a latent phase with ongoing ipsilateral neuronal degeneration. Spontaneous focal seizures mark the onset of the chronic phase. In striking contrast, the ventral hippocampus and the contralateral side remain structurally unaffected and seizure-free. In this study, functional and neurochemical alterations of the contralateral side were studied to find candidate mechanisms underlying the lack of a mirror focus in this model of TLE. A quantitative analysis of simultaneous, bilateral EEG recordings revealed a significant decrease of theta oscillations ipsilaterally during the latent phase and bilaterally during the chronic phase. Furthermore, the synchronization of bilateral activity, which is very high in control, was strongly reduced already during the latent phase and the decrease was independent of recurrent seizures. Immunohistochemical analysis performed in the contralateral hippocampus of kainate-treated mice revealed reduced calbindin-labeling of CA1 pyramidal cells; down-regulation of CCK-8 and up-regulation of NPY-labeling in mossy fibers; and a redistribution of galanin immunoreactivity. These changes collectively might limit neuronal excitability in CA1 and dentate gyrus, as well as glutamate release from mossy fiber terminals. Although these functional and neurochemical alterations might not be causally related, they likely reflect long-ranging network alterations underlying the independent evolution of the two hippocampal formations during the development of an epileptic focus in this model of TLE.

Topics: Action Potentials; Animals; Brain Chemistry; Calbindins; Chronic Disease; Disease Models, Animal; Down-Regulation; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Functional Laterality; Galanin; Hippocampus; Kainic Acid; Mice; Mossy Fibers, Hippocampal; Nerve Degeneration; Neural Pathways; Neuropeptide Y; Neurotoxins; Pyramidal Cells; S100 Calcium Binding Protein G; Sincalide; Status Epilepticus; Theta Rhythm; Up-Regulation

We reported previously that neuropeptide Y (NPY) induces an atherosclerotic-like lesion that is significantly reduced by NPY-Y1 and NPY-Y5 receptor (R) inhibitors. Because antagonists also inhibit neointima induced by angioplasty alone, we now test whether stress-induced endogenous NPY release mimic these changes.. Rats were nonstressed or stressed (4 degrees C water; 2 hours per day for 14 days) starting immediately before and continuing after carotid artery angioplasty. Stress acutely and chronically increased blood pressure and doubled plasma NPY levels. After 14 days, angioplasty-induced neointima was markedly greater in stressed (than nonstressed) rats, in which most of the vessels became occluded with an atherosclerotic-like lesion containing macrophages, lipids, thrombus, and microvessels that was similar but more inflammatory than the injury in the NPY-treated vessels. Fourteen days after angioplasty combined with stress or NPY, Y1R and Y5R (mRNA and protein) became upregulated in areas of neointima, microvessels, and macrophages in injured carotid arteries. Stress- and NPY-induced changes were completely prevented by a selective Y1R antagonist (0.02 micromol/kg per minute for 14 days), whereas neointima induced by angioplasty alone was reduced by 60%.. Because of sympathetic NPY release, stress may be a less-than-appreciated risk factor for restenosis/atherosclerosis, and Y1R antagonists a potential therapy for these conditions.

Topics: Angioplasty, Balloon; Animals; Blood Pressure; Carotid Artery Diseases; Carotid Artery Injuries; Carotid Stenosis; Chronic Disease; Cold Temperature; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Recurrence; Risk Factors; RNA, Messenger; Stress, Physiological; Sympathetic Nervous System; Tunica Intima; Tunica Media

Morphological changes in the rat carotid bodies 1, 2, 4, and 8 weeks after the termination of chronically hypocapnic hypoxia (10% O2 for 8 weeks) were examined by means of morphometry and immunohistochemistry. The rat carotid bodies after 8 weeks of hypoxic exposure were enlarged several fold with vascular expansion. The carotid bodies 1 and 2 weeks after the termination of 8 weeks of hypoxic exposure were diminished in size, although their diameter remained larger than the normoxic controls. The expanded vasculature in chronically hypoxic carotid bodies returned to the normoxic control state. In the carotid bodies 1 week after the termination of chronic hypoxia, the density of NPY fibers was remarkably increased and that of VIP fibers was dramatically decreased in comparison with the density in chronically hypoxic carotid bodies. In the carotid bodies 2 and 4 weeks after the termination of hypoxia, the density of SP and CGRP fibers was gradually increased. In the carotid bodies 8 weeks after the termination of hypoxia, the appearance of the carotid body returned to a nearly normoxic state, and the density of SP, CGRP, VIP, and NPY fibers also recovered to that of normoxic controls. These results suggest that the morphological changes in the recovering carotid bodies start at a relatively early period after the termination of chronic hypoxia, and a part of these processes may be under the control of peptidergic innervation.

Topics: Animals; Calcitonin Gene-Related Peptide; Carotid Body; Chronic Disease; Hypocapnia; Hypoxia; Immunohistochemistry; Nerve Fibers; Neuropeptide Y; Peptide Fragments; Rats; Rats, Wistar; Substance P; Time Factors; Vasoactive Intestinal Peptide

Expression of C-terminal flanking peptide of neuropeptide Y (CPON) in DRG and cell proliferation (incorporation of BrdU) in sciatic nerve of rats following chronic nerve compression (silicone tubes with different internal diameters) was studied by immunocytochemistry. An increased number of CPON-positive neurons and cells incorporating BrdU was induced on the compressed side, most pronounced when a tight tube was used, while no cells expressed CPON or BrdU in intact nerves. The increase was transient and declined with time. Nerve compression induces transient cell proliferation in the nerve and expression of CPON in nerve cell bodies, but this is of a lesser magnitude than those following nerve transection.

Topics: Animals; Axons; Bromodeoxyuridine; Cell Count; Cell Division; Chronic Disease; Denervation; Disease Models, Animal; Female; Ganglia, Spinal; Immunohistochemistry; Nerve Compression Syndromes; Nerve Degeneration; Neurons, Afferent; Neuropeptide Y; Pain; Peptide Fragments; Rats; Rats, Wistar; Schwann Cells; Sciatic Nerve; Up-Regulation

Chronic heart failure is associated with increased sympathetic nerve activity and elevated plasma neuropeptide Y levels. The aim of this study was to investigate whether increased neuropeptide Y release altered vascular neuropeptide Y responses in the dorsal hand veins in patients with chronic heart failure.. Neuropeptide Y responsiveness was studied in vivo with use of a hand vein tonometry technique in 14 patients with chronic heart failure and left ventricular ejection fraction (LVEF) values <20%, 16 patients with LVEF values from 20% to 35%, and 16 age-similar healthy control subjects. Plasma norepinephrine and neuropeptide Y levels were significantly elevated in patients with chronic heart failure and LVEF values <20% compared with control subjects (P < .01). Plasma neuropeptide Y but not norepinephrine levels were significantly elevated in patients with chronic heart failure and LVEF values from 20% to 35% compared with control subjects (P < .01). Increasing doses of neuropeptide Y (25 to 2,000 pmol/min) were infused into a dorsal hand vein of each subject. Dose-dependent venoconstriction to neuropeptide Y was observed in all subjects studied. The neuropeptide Y dose-response curve in patients with LVEF values from 20% to 35% was significantly shifted to the left compared with patients with LVEF values <20% and control subjects (P < .01), whereas no significant difference was observed between the control subjects and the patients with LVEF values <20%. No significant difference in neuropeptide Y dose responses was observed between patients with chronic heart failure with plasma neuropeptide Y levels above the median and patients with chronic heart failure with plasma neuropeptide Y levels below the median.. In vivo venous neuropeptide Y receptor responsiveness is increased in patients with chronic heart failure and LVEF values from 20% to 35%. This increased neuropeptide Y responsiveness may contribute to venoconstriction at this stage of heart failure.

Topics: Cardiac Output, Low; Case-Control Studies; Chronic Disease; Dose-Response Relationship, Drug; Female; Hand; Humans; Male; Middle Aged; Neuropeptide Y; Radioimmunoassay; Receptors, Neuropeptide Y; Stroke Volume; Tonometry, Ocular; Veins

Topics: Animals; Calcitonin Gene-Related Peptide; Carotid Body; Chronic Disease; Hypoxia; Immunohistochemistry; Neuropeptide Y; Neuropeptides; Rats; Substance P; Time Factors; Vasoactive Intestinal Peptide

Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides.. We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant.. Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery.. The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

Topics: Aged; Calcitonin Gene-Related Peptide; Chronic Disease; Endothelin-1; Femoral Artery; Heart Failure; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Pulmonary Artery; Radioimmunoassay; Vasoactive Intestinal Peptide; Veins

The peripheral nervous system was analysed in the oral mucosa of eight patients with oral lichen planus (OLP), five with a lichenoid reaction (LR) and three with mild chronic inflammation (MCI), by morphometric analysis of nerve fibres containing immunoreactive PGP 9.5, substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), or C-flanking peptide of neuropeptide Y (CPON). Overall nerve fibre density was higher in OLP (P=0.039) and LR (P=0.026) compared with healthy oral mucosa and was compatible with sprouting and collateral formation. In contrast to the innervation visualized with structural nerve fibre-marker PGP 9.5, the densities of neuropeptide-immunoreactive nerves were low in inflamed tissue. This is consistent with depletion via local release. Retraction and local loss of innervation were found in areas coinciding with the most severe inflammation and basal membrane (BM) damage. Interestingly, LR showed a twenty-eight-fold loss of post-ganglionic CPON-ir sympathetic nerve fibres (P=0.044). In LR, CPON-ir innervation was markedly lower than in OLP. Finally, the pattern of innervation in relation to inflammatory cell infiltrates and tissue structures differed between OLP and LR. In conclusion, the peripheral nervous system is implicated in the immunopathogenesis of lichen planus and lichenoid reactions, with a disorder-specific difference in this involvement.

Topics: Adult; Aged; Analysis of Variance; Basement Membrane; Calcitonin Gene-Related Peptide; Chronic Disease; Humans; Lichen Planus, Oral; Lichenoid Eruptions; Middle Aged; Mouth Diseases; Mouth Mucosa; Nerve Fibers; Nerve Tissue Proteins; Neuropeptide Y; Statistics, Nonparametric; Stomatitis; Substance P; Sympathetic Nervous System; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Inflammatory processes may play a critical role in the degeneration of basal forebrain cholinergic cells that underlies some of the cognitive impairments associated with Alzheimer's disease. In the present study, the proinflammagen lipopolysaccharide, from the cell wall of Gram-negative bacteria, was used to produce inflammation within the basal forebrain of rats. The effects of acute, high-dose injections of lipopolysaccharide (2, 20 or 40 microg) upon basal forebrain chemistry and neuronal integrity were compared with the effects of chronic, low-dose lipopolysaccharide infusions (0.18, 0.25, 1.8 or 5.0 microg/h) for either 14, 37, 74 or 112 days. Acute exposure to lipopolysaccharide decreased cortical choline acetyltransferase activity and the number of immunoreactive choline acetyltransferase-positive cells within a small region of the basal forebrain. Regional levels of five different neuropeptides were unchanged by acute, high-dose lipopolysaccharide injections. Chronic lipopolysaccharide infusions produced (i) a time-dependent, but not dose-dependent, decrease in cortical choline acetyltransferase activity that paralleled a decline in the number of choline acetyltransferase- and p75-immunoreactive cells within the basal forebrain, and (ii) a dense distribution of reactive astrocytes and microglia within the basal forebrain. Chronic neuroinflammation might underlie the genesis of some neuropathological changes associated with normal ageing or Alzheimer's disease.

Topics: Acute Disease; Animals; Cerebral Cortex; Choline O-Acetyltransferase; Chronic Disease; Escherichia coli; Galanin; Inflammation; Lipopolysaccharides; Male; Neurokinin B; Neuropeptide Y; Neuropeptides; Neurotensin; Prosencephalon; Rats; Rats, Inbred F344; Somatostatin; Time Factors

Neuropeptide plasticity in the gracile nucleus is thought to play a role in the development of neuropathic pain following nerve injury. Two weeks after chronic constriction injury of adult rat sciatic nerve, galanin, neuropeptide Y and calcitonin gene-related peptide immunoreactivities were increased in fibers and cells in the gracile nucleus ipsilateral to injury. At the electron microscopic level, this increased neuropeptide immunoreactivity was localized in myelinated axons, boutons, dendrites, neurons and glial cells. Galanin-, neuropeptide Y- and calcitonin gene-related peptide-immunoreactive boutons were frequently presynaptic to dendrites of both immunoreactive and non-immunoreactive neurons. However, no neuropeptide Y, galanin and calcitonin gene-related peptide messenger RNA was detected in the injured side gracile nuclei by in situ hybridization. These results show that partial nerve injury to the sciatic nerve induces increases in the content of galanin, neuropeptide Y and calcitonin gene-related peptide immunoreactivities in synaptic terminals within the gracile nucleus, which suggests that there may be increased release of these neuropeptides following sensory or spontaneous stimulation of large-diameter primary afferents following partial nerve injury, perhaps one mechanism involved in neuropathic pain. We also show an apparent transfer of these neuropeptides to the cells of the gracile nucleus, both neurons and glial cells, an intriguing phenomenon of unknown functional significance.

Topics: Animals; Axons; Calcitonin Gene-Related Peptide; Chronic Disease; Constriction, Pathologic; Galanin; Immunohistochemistry; In Situ Hybridization; Male; Medulla Oblongata; Microscopy, Immunoelectron; Neurons; Neuropeptide Y; Neuropeptides; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sciatic Nerve

Neuropathic pain resulting from peripheral nerve injury can often be relieved by administration of alpha-adrenergic receptor antagonists. Tonic activation of alpha-adrenergic receptors may therefore facilitate the hyperalgesia and allodynia associated with neuropathic pain. It is currently unclear whether alpha2A- or alpha2c-adrenergic receptor subtypes are involved in the pro-nociceptive actions of alpha-adrenergic receptors under neuropathic conditions. We therefore investigated the effects of peripheral nerve injury on the expression of these subtypes in rat spinal cord using immunohistochemical techniques. In addition, neuropeptide Y immunoreactivity was examined as an internal control because it has previously been shown to be up-regulated following nerve injury. We observed a decrease in alpha2A-adrenergic receptor immunoreactivity in the spinal cord ipsilateral to three models of neuropathic pain: complete sciatic nerve transection, chronic constriction injury of the sciatic nerve and L5/L6 spinal nerve ligation. The extent of this down-regulation was significantly correlated with the magnitude of injury-induced changes in mechanical sensitivity. In contrast, alpha2c-adrenergic receptor immunoreactivity was only increased in the spinal nerve ligation model; these increases did not correlate with changes in mechanical sensitivity. Neuropeptide Y immunoreactivity was up-regulated in all models examined. Increased expression of neuropeptide Y correlated with changes in mechanical sensitivity. The decrease in alpha2A-adrenergic receptor immunoreactivity and the lack of consistent changes in alpha2C-adrenergic receptor immunoreactivity suggest that neither of these receptor subtypes is likely to be responsible for the abnormal adrenergic sensitivity observed following nerve injury. On the contrary, the decrease in alpha2A-adrenergic receptor immunoreactivity following nerve injury may result in an attenuation of the influence of descending inhibitory noradrenergic input into the spinal cord resulting in increased excitatory transmitter release following peripheral stimuli.

Topics: Animals; Chronic Disease; Hyperalgesia; Immunohistochemistry; Ligation; Male; Nerve Compression Syndromes; Neuropeptide Y; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2; Sciatic Nerve; Spinal Cord; Spinal Nerves

An immunohistochemical study of the nasal mucosa was done in pediatric patients attending an otorhinolaringology (ORL) clinic. The goal was a comparison between vascular innervation in patients with or without symptoms of chronic rhinitis. All patients had an indication for tonsillectomy prior to their inclusion in this study. Samples were obtained under general anesthesia at the time of programmed surgery and fixed in a paraformaldehyde-picric acid mixture. Cryostat sections were immunostained for the following neuronal markers: protein-gene product 9.5 (PGP), calcitonin gene- related peptide (CGRP), substance P (SP), and C-terminal peptide of neuropeptide Y (CPON). The following classes of vessels were identified: arteries, sinusoids, veins, and arteriovenous anastomoses (AVAs). As shown by immunostaining with the general neuronal marker PGP, each vessel type had a characteristic innervation pattern, differing in the amount of fibers and their distribution within the adventitial and muscle layers. Evaluation of PGP, CPON, and CGRP immunoreactivity patterns indicated that rhinitic arteries and AVAs displayed a richer innervation than did nonrhinitic blood vessels. Quantification of vascular PGP immunostaining confirmed the difference of vascular innervation between nonrhinitic and rhinitic patients. Fibers immunostained by CPON partially accounted for the rhinitic arterial hyperinnervation.

Topics: Arteries; Arteriovenous Anastomosis; Blood Vessels; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Chronic Disease; Humans; Immunohistochemistry; Nasal Mucosa; Nerve Fibers; Nerve Tissue Proteins; Neuropeptide Y; Peptide Fragments; Rhinitis; Substance P; Thiolester Hydrolases; Turbinates; Ubiquitin Thiolesterase

Neuropeptides act on most of the components of the bronchial environment. They influence bronchomotor tone and bronchial vascular caliber and permeability. To investigate the nonadrenergic, noncholinergic system within the airways in asthma and chronic bronchitis, we performed endobronchial biopsies in 16 normal human volunteers, 49 patients with asthma of varying severity, including 16 patients treated with oral corticosteroids, and 13 patients with chronic bronchitis. Frozen sections of biopsies stained with specific antibodies against the neural marker PGP 9.5, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were analyzed for the presence of nerves through indirect immunofluorescence. Nerves were present in most of the biopsies and were found within and below the epithelium and adjacent to smooth muscle, glands, and blood vessels. By comparison with those in normal subjects, the numbers of VIP-immunoreactive nerves were not significantly decreased in patients with asthma and chronic bronchitis, but NPY-immunoreactive nerves were significantly decreased in the smooth muscle of these latter two groups of patients (p < 0.005). There was no correlation between disease severity and the number of nerves found in the biopsies. This study does not confirm previous findings in autopsy material of some defects in sensory and VIP-containing nerves in severe asthma.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Beclomethasone; Biomarkers; Biopsy; Bronchi; Bronchitis; Bronchoconstriction; Calcitonin Gene-Related Peptide; Capillary Permeability; Chronic Disease; Epithelium; Female; Fluorescent Antibody Technique, Direct; Glucocorticoids; Humans; Male; Middle Aged; Mucous Membrane; Muscle, Smooth; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Prednisone; Substance P; Thiolester Hydrolases; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide; Vasomotor System

Hypoglycemia causes hyperphagia and weight gain, through unknown peripheral and central signals. We investigated the effect of hypoglycemia on NPY and leptin expression and the ability of leptin to inhibit hypoglycemia-induced hyperphagia. Acute hypoglycemia (60 U/kg SC insulin; n = 8) increased food intake (p < 0.01) compared with controls (n = 8). Insulin- and leptin-treated rats (300 microg/kg IP leptin; n = 8) had reduced hyperphagia (p < 0.05 vs. controls; p < 0.05 vs. insulin alone) and a 15% fall in NPY mRNA levels compared with controls (p < 0.01). Chronic hypoglycemia, (20-60 U/kg/day insulin; n = 8) increased food intake compared with vehicle-treated controls (p < 0.01). Leptin and insulin administration (300 microg/kg/day IP leptin; n = 8) reduced hyperphagia (p < 0.01 vs. controls, p < 0.05 vs. insulin alone), and NPY mRNA fell by 18% vs. controls (p < 0.01). We conclude that hypoglycemia-induced hyperphagia is not mediated by either a fall in leptin or an increase in hypothalamic NPY mRNA. Leptin can inhibit feeding in hyperphagic hypoglycemic rats, and this may partly be attributable to its inhibition of the NPY neurons.

Topics: Acute Disease; Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Chronic Disease; Eating; Hyperphagia; Hypoglycemia; Insulin; Leptin; Male; Models, Biological; Neuropeptide Y; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; RNA, Messenger

The influence of long-term hypoxia on substance P (SP) and neuropeptide Y (NPY)-like immunoreactivity (LI) in discrete brain areas and peripheral structures was assessed by radioimmunoassay. Rats were exposed to normobaric hypoxia (10% O2 in nitrogen) for 14 days. In the carotid bodies of hypoxic animals, NPY-LI was significantly increased (56% vs. normoxic controls) while SP-LI was unchanged. In the brain, NPY-LI was increased in the ventrolateral medulla oblongata (23%) and in the striatum (53%); however, SP-LI was unaltered in these two regions. In the anterior pituitary, NPY-LI was increased (99%), while SP-LI was decreased (37%). No significant alteration in NPY-LI and SP-LI was observed in other discrete brain areas or peripheral structures studied. These results show that, in the rat, long-term hypoxia induces changes in NPY-LI or SP-LI in a few central and peripheral structures; these biochemical alterations may be linked to adaptative mechanisms involving morphological changes in carotid bodies or alterations in sympathetic control and neuroendocrine function.

Topics: Adrenal Glands; Animals; Antibodies; Brain Chemistry; Carotid Body; Chronic Disease; Ganglia, Sympathetic; Hypoxia; Male; Neuropeptide Y; Pituitary Gland, Anterior; Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains; Substance P

Somatostatin-, neuropeptide Y-, neurokinin B- and cholecystokinin-containing neurons were investigated in the rat hippocampus in two chronic models of temporal lobe epilepsy, i.e. 30 days after rapid kindling or electrically induced status epilepticus (post-status epilepticus). After rapid kindling, somatostatin immunoreactivity was strongly increased in interneurons and in the outer and middle molecular layer of the dentate gyrus. In four of six post-status epilepticus rats (status epilepticus I rats), somatostatin immunoreactivity was slightly increased in the dorsal but decreased in the ventral dentate gyrus and molecular layer. Somatostatin immunoreactivity decreased in neurons of the dorsal hilus in the two other post-status epilepticus rats investigated, while a complete loss was found in the respective ventral extension (status epilepticus-II rats). These changes were associated with a different extent of neurodegeneration as assessed by Nissl staining. Similarly, neuropeptide Y immunoreactivity was enhanced in neurons of the hilus and in the middle and outer molecular layer of the dentate gyrus in the dorsal hippocampus of rapidly kindled and status epilepticus-I rats. Neuropeptide Y and neurokinin B immunoreactivity was enhanced in the mossy fibers of all post-status epilepticus rats, but not in the rapidly kindled rats. In status epilepticus-II rats, neuropeptide Y-and neurokinin B-positive fibers were also detected in the infrapyramidal region of the stratum oriens of CA3 and in the inner molecular layer of the dentate gyrus in the dorsal and ventral hippocampus respectively, labeling presumably sprouted mossy fibers. Increased staining of neuropeptide Y and neurokinin B was found in the alveus after rapid kindling. Cholecystokinin immunoreactivity was markedly increased in the cerebral cortex, Ammon's horn and the molecular layer of the dentate gyrus in the ventral hippocampus of rapidly kindled and post-status epilepticus rats. The lasting changes in the immunoreactive pattern of various peptides in the hippocampus may reflect functional modifications in the corresponding peptide-containing neurons. These changes may be involved in chronic epileptogenesis, which evolves in response to limbic seizures.

Topics: Animals; Brain; Cholecystokinin; Chronic Disease; Epilepsy, Temporal Lobe; Immunohistochemistry; Male; Nerve Degeneration; Neurokinin B; Neuropeptide Y; Neuropeptides; Rats; Rats, Sprague-Dawley; Somatostatin; Tissue Distribution

We measured the release of neuropeptide Y (NPY) from hippocampal slices of rats at various times after limbic seizures induced by a subcutaneous injection of 12 mg/kg kainic acid (KA). Two days after KA, 100 mM KCl induced a 1.6 +/- 0.2-fold increase in NPY release compared to saline-injected rats (P < 0.05), while spontaneous and 50 mM KCl-induced release were unchanged. Thirty days after KA, the spontaneous and 100 mM KCl-induced efflux of NPY was enhanced 2-fold on average (P < 0.01) compared to controls, while no significant differences were found using 50 mM KCl. Tissue concentration of NPY was raised 2.2 +/- 0.2 times (P < 0.01) 30 days after KA. Thirty days after KA, the rats showed enhanced susceptibility to tonic-clonic seizures, assessed using a normally subconvulsive dose of pentylenetetrazol (PTZ; 30 mg/kg). A selective antibody (Ab) raised against NPY in a rabbit was infused bilaterally for three days in the CA3 area and dentate gyrus (DG) of the dorsal hippocampus of rats treated 30 days before with KA. This significantly reduced (P < 0.05) the number of animals with tonic-clonic seizures induced by 30 mg/kg PTZ, compared to KA treated rats which received the inactivated Ab. The Ab was ineffective in naive rats injected with a full convulsive dose of PTZ (55 mg/kg). The present results show that neuronal release of NPY is enhanced in the hippocampus after limbic seizures induced in rats by KA. This effect persists for at least 30 days and may contribute to the chronically enhanced susceptibility to seizures after injection of this toxin.

Topics: Animals; Antibodies; Chronic Disease; Disease Susceptibility; Dose-Response Relationship, Drug; Electrophysiology; Hippocampus; In Vitro Techniques; Kainic Acid; Male; Neurons; Neuropeptide Y; Pentylenetetrazole; Potassium Chloride; Rats; Rats, Sprague-Dawley; Seizures

Effects of surgical sympathectomy on the cutaneous temperature abnormalities of plantar surface evoked by the chronic constriction injury (CCI) of the sciatic nerve were investigated in the rat. In normal animals, there were very small temperature differences between both plantar surfaces. There were also very small temperature differences in plantar surfaces following the sympathectomy prior to CCI. In rats with CCI, the cutaneous temperature of the nerve-injured plantar surface was significantly higher (warmer) than that of the contralateral plantar surface during the first week following CCI, and then became lower (cooler). Surgical sympathectomy prior to and just after CCI significant suppressed the temperature abnormalities during the first week, but no effect was observed after 2 weeks following CCI. These observations indicate that sympathetic vasoconstriction may contribute to the cutaneous temperature abnormalities evoked by CCI during the early stage, but does not affect the abnormalities at later stages.

Topics: Animals; Body Temperature Regulation; Chronic Disease; Fluorescent Antibody Technique; Immunohistochemistry; Lumbosacral Region; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Skin Temperature; Sympathectomy; Tyrosine 3-Monooxygenase

The distribution and concentration of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), and gastrin-releasing peptide (GRP) immunoreactivities in the pancreas of cats with experimentally induced chronic pancreatitis and of age- and sex-matched controls were investigated. By narrowing the main pancreatic duct between the head and the body to approximately 25% of its normal diameter, we induced within 5 weeks chronic pancreatitis restricted to the body and tail. In control animals, peptide immunoreactive nerves were distributed to the islets, acini, and ducts; the latter were predominantly innervated by fibers immunoreactive for NPY, VIP, or CGRP. The vasculature received an abundant supply of NPY-, CGRP-, and, to a lesser extent, SP-containing axons. Within intrapancreatic ganglia, peptide immunoreactivities were identified in fibers and ganglion cells, with the exception of CGRP and SP immunostaining, which could be visualized only in fibers. In animals with chronic pancreatitis, the innervation pattern of each peptidergic system was comparable to that described in controls. However, there was a remarkable increase in the density and staining intensity of VIP and NPY immunoreactive fibers in the exocrine parenchyma and fibrous septa of the body and tail, where chronic pancreatitis developed. Fibers immunoreactive for CGRP and SP also were moderately denser than in controls, whereas those containing GRP immunoreactivity did not show any detectable changes. In addition, a marked increase of the immunostaining for VIP and, to a much lesser extent, for NPY and GRP, was observed in neurites supplying the head of the pancreas, which appeared devoid of histologically detectable pathological alterations. Radioimmunoassay analysis confirmed the immunohistochemical observations. The increased density of distinct peptidergic nerves in the pancreas with induced chronic pancreatitis might be the result of compensatory phenomena in response to the inflammatory process.

Topics: Animals; Calcitonin Gene-Related Peptide; Cats; Chronic Disease; Constriction; Female; Gastrin-Releasing Peptide; Immunohistochemistry; Male; Neuropeptide Y; Neuropeptides; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Substance P; Tachykinins; Vasoactive Intestinal Peptide

Neuropeptide Y (NPY) is a peptide released together with noradrenaline (NA) from sympathetic nerve endings. Elevated plasma levels of NA and NPY-like immunoreactivity (LI) are found in patients with congestive heart failure. In order to assess any relationship found between plasma NPY-LI and haemodynamic data 12 patients with mild to moderate chronic congestive heart failure were studied during cardiac catheterization. All patients were treated with diuretics but not ACE inhibitors and were in New York Heart Association functional class II or III. Mean left ventricular ejection fraction determined by echocardiography was 34%. Plasma NPY-LI from mixed venous blood was elevated in five patients and NA in nine. Mean plasma NPY-LI was 29 +/- 3 pmoll-1 (mean +/- standard error of the mean) and NA 2.6 +/- 0.3 nmoll-1. Heart rate was 70 +/- 3 beats min-1, systolic blood pressure (SBP) 131 +/- 7 mmHg, stroke volume index (SVI) 29 +/- 1.9 ml m-2 and cardiac index (CI) 2.0 +/- 0.13 l min-1 m-2. Elevated levels of plasma NPY-LI (> 30 pmol l-1) were associated with lower SVI, CI, and SBP and a higher pulmonary vascular resistance. Elevated plasma NA (> 2 nmol l-1) did not correlate with haemodynamic data. Log NPY-LI correlated inversely with SVI (P < 0.01) and CI (P < 0.05) but not with plasma NA. It is concluded that log NPY-LI in mixed venous blood correlates inversely with SVI and CI in patients with mild to moderate chronic congestive heart failure.

Topics: Aged; Cardiac Catheterization; Chronic Disease; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Regression Analysis; Ventricular Function, Left

We sought to identify characteristics of peptidergic innervation that altered in patients with chronic pancreatitis. Pancreatic tissue removed from patients with chronic pancreatitis was analyzed by immunohistochemistry using antisera against neuropeptide Y, tyrosine hydroxylase, vasoactive intestinal polypeptide, peptide histidine isoleucine, calcitonin gene-related peptide, and substance P, respectively. In accordance with recent findings, the number and diameter of intralobular and interlobular nerve bundles were found to be increased as compared with control pancreas from organ donors. The striking change in the peptidergic innervation pattern in chronic pancreatitis concerned these altered nerves. It consisted of an intensification of the immunostaining for calcitonin gene-related peptide and substance P in numerous fibers contained in these nerves. Adjacent sections showed that immunoreactive substance P and immunoreactive calcitonin gene-related peptide coexisted in these fibers. Because both of these peptides are generally regarded as pain transmitter candidates, our findings provide further evidence that changes in pancreatic nerves themselves might be responsible for the long-lasting pain syndrome in chronic pancreatitis.

Topics: Adult; Calcitonin Gene-Related Peptide; Chronic Disease; Female; Humans; Male; Nerve Fibers; Neuropeptide Y; Neuropeptides; Pain; Pancreas; Pancreatitis; Peptide PHI; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

The relationship among neuropeptide Y (NPY), catecholamines and haemodynamics was assessed both at baseline and during inotropic intervention in patients with congestive heart failure. Eighteen patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction (LVEF) = 26 +/- 10%) underwent both right and left catheterization. Haemodynamic parameters were recorded at baseline and during dobutamine infusion. To measure norepinephrine (NE), epinephrine (E) (nmol.l-1: radioenzymatic assay) and NPY (pmol.l-1: immunoradiometric assay) plasma concentrations, blood samples were drawn from the femoral artery and from the coronary sinus, both at baseline and during dobutamine infusion. At baseline, NPY concentration were 2.15 +/- 0.97 pmol.l-1 in the femoral artery and 1.97 +/- 0.63 pmol.l-1 in the coronary sinus. Peripheral concentrations of NPY were, however, no different from those of patients without congestive heart failure: 2.4 +/- 2.7 pmol.l-1. Peripheral NE concentration was correlated to haemodynamic parameters: LVEF (r = -0.65; P less than 0.01), cardiac index (r = -0.54; P less than 0.05), LV end-diastolic pressure (r = +0.59; P less than 0.05), while peripheral NPY and E concentrations were not. Dobutamine improved haemodynamics, since cardiac index increased by 30% and LV end-diastolic pressure decreased by 40% (P less than 0.01). Peripheral NE concentration decreased from 6.48 +/- 4.5 to 4.82 +/- 2.69 nmol.l-1 (P less than 0.05) but there was no change in E (0.99 +/- 0.61 vs 1.04 +/- 0.74 nmol.l-1) or NPY concentrations (2.41 +/- 0.99 pmol.l-1). In the coronary sinus, neither NE nor NPY concentrations changed during dobutamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Cardiac Output; Cardiomyopathy, Dilated; Chronic Disease; Coronary Vessels; Dobutamine; Dose-Response Relationship, Drug; Epinephrine; Female; Heart Failure; Hemodynamics; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Sympathetic Nervous System

A possible role of platelet-derived 5-HT was examined concerning the pathogenesis of cerebral vasospasm. Intracisternal injection of 5 ml of platelet-rich plasma (PRP; approximately 7.5 x 10(8) platelets) induced not only acute (1 h) but also chronic (7 days) angiographically evident cerebral vasospasm in dogs. Sympathetic perivascular nerves on cerebral arteries showed no remarkable change following repeated injections of PRP, as the dense distribution of catecholamine-fluorescence and neuropeptide Y-like immunoreactive nerve fibers on Day 7 was comparable to findings in the preinjection controls. While there were no 5-HT-immunoreactive fibers in the cerebral arteries of control animals, numerous 5-HT-immunoreactive fibers were present in the PRP-injected animals. These results suggest that 5-HT, presumably released from extravasated platelets, may be taken up by nerve endings and act as a vasoconstrictor transmitter in the pathogenesis of chronic vasospasm.

Topics: Acute Disease; Animals; Basilar Artery; Blood Platelets; Catecholamines; Chronic Disease; Dogs; Female; Immunohistochemistry; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Neurons; Neuropeptide Y; Serotonin; Subarachnoid Hemorrhage

The regional distribution of neuropeptide Y-like immunoreactivity (NPY-IR) in the human hypothalamus has been determined using a highly specific immunoradiometric assay. Hypothalami were removed during postmortem examination from 19 subjects. The pituitary stalk and 11 anatomically defined nuclei and areas were microdissected from one or both sides of each hypothalamus. NPY-IR was detectable in the acid extracts of tissue samples prepared from all the hypothalamic regions studied, with the highest concentrations being found in the infundibular nucleus (325 +/- 53 fmol/mg wet weight of tissue) and the ventromedial nucleus (217 +/- 22 fmol/mg). For the 11 subjects where both sides of the hypothalamus were dissected, values obtained for the areas in one half showed a good degree of symmetry with the corresponding areas on the contralateral side. The infundibular nucleus exhibited the greatest range of values (72-1,137 fmol/mg). Interestingly, variations in other parts of the hypothalamus were observed to parallel those of this nucleus. Expressed as correlation coefficients (r), levels in the infundibular nucleus appeared to be most closely related to those of the ventromedial nucleus (VM; r = 0.89) and paraventricular nucleus (PV; r = 0.84). In addition, retrospective analysis of the clinical histories showed that all patients with very high NPY levels in the infundibular nucleus (621.0 +/- 107.7 fmol/mg; n = 8) had suffered from respiratory failure or severe dyspnea of at least 10 days duration prior to death. The remaining patients (166.7 +/- 17.1 fmol/mg; n = 11) had either died 48 h from the onset of cardiorespiratory difficulties or of unrelated causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aged, 80 and over; Chronic Disease; Female; Humans; Hypothalamus; Immunoradiometric Assay; Male; Middle Aged; Neuropeptide Y; Respiratory Insufficiency