neuropeptide-y and Heart-Failure

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; Heart; Heart Failure; Humans; Myocardial Infarction; Neuropeptide Y

Neuropeptide Y (NPY) family of hormones exhibits a wide spectrum of central and peripheral activities mediated by six G-protein coupled receptor subtypes denoted as Y1, Y2, Y3, Y4, Y5, and y6. Investigations to date have implicated NPY in the pathophysiology of a number of diseases including feeding disorders, seizures, anxiety, diabetes, hypertension, congestive heart failure and intestinal disorders. These observations suggest that long-acting, potent NPY receptor selective agonists and antagonists developed could be used to treat a variety of diseases. These possibilities are discussed in this paper.

Topics: Feeding and Eating Disorders; Heart Failure; Humans; Malabsorption Syndromes; Neuropeptide Y; Receptors, Neuropeptide Y; Seizures

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

This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 microg/kg of clonidine resulted in a fall in cardiac (326+/-73 to 160+/-40 pmol/min, P<0.001), renal (2.5+/-0.6 to 1.5+/-0.3 nmol/min, P=0.01), and global norepinephrine spillover (4.0+/-0.6 to 3.1+/-0.5 nmol/min, P<0.01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity (P<0.05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.

Topics: Aged; Brain; Clonidine; Dose-Response Relationship, Drug; Heart; Heart Failure; Hemodynamics; Humans; Kidney; Male; Middle Aged; Myocardium; Neuropeptide Y; Norepinephrine; Organ Specificity; Sympathetic Nervous System; Sympatholytics

Few studies have described how neurohormonal activation is influenced by treatment with beta-receptor antagonists in patients with heart failure after acute myocardial infarction. The aims were to describe neurohormonal activity in relation to other variables and to investigate treatment effects of a beta(1) receptor-antagonist compared to a partial beta(1) receptor-agonist.. Double-blind, randomized comparison of metoprolol 50-100 mg b.i.d. (n=74), and xamoterol 100-200 mg b.i.d (n=67). Catecholamines, neuropeptide Y-like immunoreactivity (NPY-LI), renin activity, and N-terminal pro-atrial natriuretic factor (N-ANF) were measured in venous plasma before discharge and after 3 months. Clinical and echocardiographic variables were assessed.. N-ANF showed the closest correlations to clinical and echocardiographic measures of heart failure severity, e.g. NYHA functional class, furosemide dose, exercise tolerance, systolic and diastolic function. Plasma norepinephrine, dopamine and renin activity decreased after 3 months on both treatments, in contrast to a small increase in NPY-LI which was greater (by 3.9 pmol/l, 95% CI 1.2-6.6) in the metoprolol group. N-ANF increased on metoprolol, and decreased on xamoterol (difference: 408 pmol/l, 95% CI 209-607). Increase above median of NPY-LI (>25.2 pmol/l, odds ratio 2.8, P=0.0050) and N-ANF (>1043 pmol/l, odds ratio 2.8, P=0.0055) were related to long term (mean follow-up 6.8 years) cardiovascular mortality.. Decreased neurohormonal activity, reflecting both the sympathetic nervous system and the renin-angiotensin system, was found 3 months after an acute myocardial infarction with heart failure treated with beta-receptor antagonists. The small increase in NPY-LI may suggest increased sympathetic activity or reduced clearance from plasma. The observed changes of N-ANF may be explained by changes in cardiac preload, renal function, and differences in beta-receptor mediated inhibition of atrial release of N-ANF. NPY-LI, and N-ANF at discharge were related to long term cardiovascular mortality.

Topics: Acute Disease; Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Chi-Square Distribution; Dopamine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography, Doppler; Epinephrine; Female; Follow-Up Studies; Heart Failure; Humans; Male; Metoprolol; Middle Aged; Myocardial Infarction; Neuropeptide Y; Norepinephrine; Probability; Proportional Hazards Models; Prospective Studies; Survival Rate; Treatment Outcome; Xamoterol

To investigate the effect of Shenmai injection (SMI) on neuroendocrine function in the patients with heart failure (HF).. Sixty patients with HF were randomly divided into the treated group administered with SMI combined with western medicine, and the control group administered with western medicine alone. The change of cardiac function was observed, and plasma neuropeptide Y (NPY), endothelin (ET) and atrial natriuretic polypeptide (ANP) were determined by immunoradiometric assay.. The total effective rate and markedly effective rate were higher in the treated group than that of the control group, the level of NPY, ET and ANP of both groups were higher than healthy subjects. The plasma NPY, ET and ANP of both groups were significantly reduced after treatment, the effect of treated group was better than that of control group.. SMI could improve the HF patient's cardiac function, reduce the level of plasma NPY, ET and ANP, their neuroendocrine activity was affected at the same time.

Topics: Aged; Atrial Natriuretic Factor; Coronary Disease; Drugs, Chinese Herbal; Endothelins; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Neuropeptide Y

Previous studies have demonstrated that continuous infusion of furosemide results in increased diuresis and natriuresis compared with bolus administration of the drug in patients with severe heart failure. We reasoned that continuous infusion of furosemide caused less activation of neurohumoral mechanisms, since other studies have shown that bolus administration of furosemide may activate this system. We therefore tested the hypothesis that continuous administration of furosemide would increase water and sodium excretion due to less activation of neurohormones. Eight patients with severe heart failure were studied during continuous infusion over 24 h and bolus injections of furosemide twice daily in a randomized cross-over study. Bolus administration of furosemide increased diuresis and natriuresis significantly in the first 4 h after administration compared with continuous administration, but this was later reversed, resulting in similar 24 h total output. The neurohormones measured at baseline were all markedly elevated. Neither regimens of furosemide caused any further significant changes in neurohumoral response except that pro-ANF decreased more during the first 8 h after bolus administration compared to continuous infusion. This study has demonstrated that bolus administration of furosemide in conventional doses is equally effective as continuous intravenous infusion in patients with severe heart failure. This may be due to maximal neurohormonal activation in severe heart failure (NYHA III-IV) which could not be further activated by bolus administration.

Topics: Atrial Natriuretic Factor; Blood Pressure; Brain; Catecholamines; Cross-Over Studies; Diuresis; Diuretics; Endothelin-1; Endothelins; Female; Furosemide; Heart Failure; Heart Rate; Hormones; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Natriuresis; Neuropeptide Y; Protein Precursors; Vasopressins

The purpose of the study was to measure plasma concentrations of neuropeptide Y (NPY), endothelin-1,2 (ET-1,2), alpha atrial natriuretic polypeptide (ANP) and noradrenaline (NA) in relation to cardiac index (CI) and left ventricular ejection fraction (LVEF) in patients with congestive heart failure (CHF). There were significant increases in venous blood concentrations of NPY, Na, ET-1,2, ANP in the patients with CHF. Plasma concentrations of NPY correlated with plasma NA concentrations but plasma noradrenaline concentrations alone correlated with CI and LVEF. In patients with CHF plasma NA concentrations seems to be more sensitive index of cardiac dysfunction then the concentrations of neuropeptide Y.

Topics: Atrial Natriuretic Factor; Endothelins; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Stroke Volume

Forty-two patients with congestive heart failure were studied in order to clarify whether the plasma level of neuropeptide Y-like immunoreactivity (NPY-LI) rises in parallel with plasma noradrenaline (NA) during physical exercise in congestive heart failure (CHF). All patients were studied in a randomized placebo-controlled trial with the ACE-inhibitor ramipril during 12 weeks to determine whether ACE-inhibition alters the response of plasma NPY-LI to exercise. The patients were treated with diuretics and had stable congestive heart failure (NYHA classes II-III). Plasma NPY-LI was 50 +/- 5 pmol l-1 (mean +/- standard error of the mean) at rest and 60 +/- 6 pmol l-1 at the end of exercise at baseline (P < 0.01). The corresponding values for plasma NA were 2.8 +/- 0.2 nmol l-1 and 15.3 +/- 1.2 nmol l-1 (P < 0.001). Before ACE-inhibition, there was a correlation between high NPY-LI and NA values after exercise. After treatment with ramipril or placebo for 12 weeks, there was no difference in plasma NPY-LI and NA at rest or after exercise between the two treatment groups. The maximal exercise time was unchanged. It is concluded that plasma NPY-LI and NA were elevated at rest in CHF. The additional rise of plasma NPY-LI and NA after exercise was attenuated in CHF compared to healthy individuals. ACE-inhibition with ramipril did not alter plasma NPY-LI or NA at rest or after exercise compared to placebo.

Topics: Aged; Double-Blind Method; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Ramipril

Topics: Coronary Sinus; Heart; Heart Failure; Humans; Neuropeptide Y; Renin-Angiotensin System

Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons.. To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF.. Prospective observational cohort study conducted at a single-center, tertiary care hospital. Stable patients with heart failure undergoing elective cardiac resynchronization therapy device implantation between 2013 and 2015.. Chronic heart failure hospitalization, death, orthotopic heart transplantation, and ventricular assist device placement.. Coronary sinus (CS) blood samples were obtained during cardiac resynchronization therapy (CRT) device implantation in 105 patients (mean [SD] age 68 [12] years; 82 men [78%]; mean [SD] left ventricular ejection fraction [LVEF] 26% [7%]). Clinical, laboratory, and outcome data were collected prospectively. Stellate ganglia (SG) were collected from patients with CHF and control organ donors for molecular analysis. Mean (SD) CS NPY levels were 85.1 (31) pg/mL. On bivariate analyses, CS NPY levels were associated with estimated glomerular filtration rate (eGFR; rs = -0.36, P < .001); N-terminal-pro hormone brain natriuretic peptide (rs = 0.33; P = .004), and LV diastolic dimension (rs = -0.35; P < .001), but not age, LVEF, functional status, or CRT response. Adjusting for GFR, age, and LVEF, the hazard ratio for event-free (death, cardiac transplant, or left ventricular assist device) survival for CS NPY ≥ 130 pg/mL was 9.5 (95% CI, 2.92-30.5; P < .001). Immunohistochemistry demonstrated significantly reduced NPY protein (mean [SD], 13.7 [7.6] in the cardiomyopathy group vs 31.4 [3.7] in the control group; P < .001) in SG neurons from patients with CHF while quantitative polymerase chain reaction demonstrated similar mRNA levels compared with control individuals, suggesting increased release from SG neurons in patients with CHF.. The CS levels of NPY may be associated with outcomes in patients with stable CHF undergoing CRT irrespective of CRT response. Increased neuronal traffic and release may be the mechanism for elevated CS NPY levels in patients with CHF. Further studies are warranted to confirm these findings.. ClinicalTrials.gov identifier: NCT01949246.

Topics: Aged; Biomarkers; Cardiac Resynchronization Therapy; Cohort Studies; Coronary Sinus; Female; Heart Failure; Heart Transplantation; Heart-Assist Devices; Hospitalization; Humans; Male; Neuropeptide Y

Thromboembolic complications are a significant cause of mortality and re-hospitalization in heart failure (HF) patients. One source of thrombi is the ventricular endocardial surface that becomes increasingly pro-thrombotic as HF progresses. Anticoagulation comes with bleeding risks so identifying therapeutic agents for improving cardiac endothelial health are of critical clinical importance. Endocardial endothelial cells are closely apposed to cardiac sympathetic nerves. In HF, cardiac sympathetic nerves are dysregulated and promote disease progression. Whether endocardial endothelial health and function is impacted by sympathetic dysregulation in HF is unknown. Also unexplored is the impact of neuropeptides, such as galanin and neuropeptide Y (NPY), co-released from sympathetic nerve terminals, on endothelial health. In this study we examined the effect of sympathetic nerve-released neurotransmitters and neuropeptides on the procoagulant phenotype of cultured human endocardial endothelial cells from HF patients. As a functional readout of procoagulant state we examined thrombin-mediated von Willebrand factor (vWF) extrusion and multimer expression. We demonstrate that vWF extrusion and multimer expression is promoted by thrombin, that isoproterenol (a beta-adrenergic receptor agonist) augments this effect, whereas co-treatment with the beta-blockers propranolol and carvedilol blocks this effect. We also show that vWF extrusion and multimer expression is attenuated by treatment with the neuropeptide galanin, but not with NPY. Our results are consistent with a protective role of beta-blockers and galanin on endocardial endothelial health in heart failure. Improving endothelial health through galanin therapy is a future clinical application of this study.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Adult; Aged; Antithrombins; Carbazoles; Carvedilol; Cells, Cultured; Endothelial Cells; Galanin; Heart Failure; Heart Ventricles; Humans; Isoproterenol; Male; Middle Aged; Neuropeptide Y; Phenotype; Propanolamines; Propranolol; Protein Multimerization; Thrombin

Galanin, a cotransmitter similar to neuropeptide Y (NPY), aggravates autonomic imbalance in systolic heart failure (HF) by attenuating vagal tonus after burst sympathetic activity. In animal HF models, galanin antagonists have improved cardiac function. To determine whether galanin is a promising therapeutic target in HF, we studied its concentrations in HF patients and evaluated its correlation with NPY, markers of humoral activity such as pro-BNP and copeptin, and echocardiographic parameters of HF severity.. After recording demographic and echocardiographic characteristics of 87 individuals (57 HF patients and 30 control subjects), fasting serum concentrations of galanin, NPY, copeptin, and pro-BNP were determined.. Unlike pro-BNP, copeptin, and NPY, which were significantly elevated in HF patients (p<0.001, p<0.001, and p=0.001, respectively), galanin was similar in HF patients and control subjects (p=0.9). NPY correlated with the echocardiographic parameters of HF severity (r=-0.22, p=0.03 for EF; r=0.3, p=0.005 for Tei index of RV; r=-0.23, p=0.03 for TAPSE; and r=0.24, p=0.024 for E/e') and pro-BNP (r=0.22, p=0.046). NPY levels were also associated with beta blocker (BB) use, wherein BB significantly decreased NPY in both HF patients and control subjects. Galanin correlated with humoral biomarkers, pro-BNP and copeptin (r=0.39, p<0.001 and r=0.41, p<0.001, respectively). Although current smoking, BB therapy, pro-BNP, copeptin, and body mass index were associated with galanin in univariate analyses, the multiple linear regression model revealed that pro-BNP was the only significant determinant of galanin levels in HF patients.. Our findings confirmed the role of NPY in autonomic balance and suggest that galanin is associated with the proadrenergic state, but its role in HF in humans remains unclear.

Topics: Biomarkers; Case-Control Studies; Demography; Echocardiography; Female; Galanin; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Prospective Studies; Sensitivity and Specificity; Systole; Turkey

Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [AB]) and the loss of female sex hormones (ovariectomy [OVX]) impairs cerebrovascular control and spatial memory.. Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB, (3) OVX, and (4) AB-OVX. Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole-board task) were lower in the OVX groups (. Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y-induced vasoconstriction along with reduced vasodilation associated with decreased Ca

Topics: Animals; Aorta; Arterial Pressure; Behavior, Animal; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognition; Cognition Disorders; Disease Models, Animal; Female; Gonadal Steroid Hormones; Heart Failure; Ligation; Neuropeptide Y; Nitric Oxide; Ovariectomy; Pia Mater; Potassium Channels, Calcium-Activated; Signal Transduction; Spatial Memory; Swine; Swine, Miniature; Time Factors; Vasoconstriction; Vasodilation

Congestive heart failure and other cardiac diseases are characterized by increased activity of the sympathetic nervous system, whereas at the same time parasympathetic activity is often suppressed. Such imbalance may be a result of or at least enhanced by presynaptic inhibitory effects of sympathetic neurotransmitters on acetylcholine release. We investigated whether the sympathetic cotransmitters neuropeptide Y (NPY), norepinephrine (NE), and ATP are capable of modulating acetylcholine release in human heart atrium. Human atrial appendages were incubated with [(3)H]-choline to label cholinergic transmitter stores and placed in superfusion chambers. Electrical field stimulations (S1, S2) induced a tetrodotoxin-dependent [(3)H]-release, which was taken as an index of endogenous acetylcholine release. NE, NPY, ATP, and a P2-receptor analogue were added before S2. NPY (0.05-1.0 micromol/l) concentration dependently inhibited acetylcholine release. This effect was prevented by the NPY-Y(2)-receptor antagonist BIIE 0246 (0.1 micromol/l) but not by the NPY-Y(1)-receptor antagonist BIBP 3226 (10 micromol/l). ATP (10 micromol/l), a stable analogue ADP-beta S (3 micromol/l), and NE (1 micromol/l) had no effect on acetylcholine release. m-RNA for the NPY-receptor subtypes Y(1), Y(2), Y(4), Y(5), and y(6) was demonstrated by reverse transcription-polymerase chain reaction (RT-PCR). The results suggest that the sympathetic neurotransmitter NPY inhibits parasympathetic neurotransmission in the human heart through activation of presynaptic Y(2)-receptors. NE and ATP seem not to play a role. Since NPY plasma levels are high in chronic heart failure patients, NPY may be one component leading to impaired parasympathetic neurotransmission in those patients.

Topics: Acetylcholine; Aged; Aged, 80 and over; Arginine; Atrial Appendage; Benzazepines; Electric Stimulation; Female; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Presynaptic Terminals; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; Vasodilator Agents

We reported recently that inhibition of neuronal reuptake of norepinephrine (NE) by desipramine prevented the reduction of sympathetic neurotransmitters in the failing right ventricle of right heart failure animals. In this study, we studied whether desipramine also reduced the sympathetic neurotransmitter loss in animals with left heart failure induced by rapid ventricular pacing (225 beats/min) or after chronic NE infusion (0.5 microg. kg(-1). min(-1)). Desipramine was given to the animals for 8 wk beginning with rapid ventricular pacing or NE infusion. Animals receiving no desipramine were studied as controls. We measured myocardial NE content, NE uptake activity, and sympathetic NE, tyrosine hydroxylase, and neuropeptide Y profiles by histofluorescence and immunocytochemical techniques. Effects of desipramine on NE uptake inhibition were evidenced by potentiation of the pressor response to exogenous NE and reduction of myocardial NE uptake activity. Desipramine treatment had no effect in sham or saline control animals but attenuated the reduction of sympathetic neurotransmitter profiles in the left ventricles of animals with rapid cardiac pacing and NE infusion. In contrast, the panneuronal marker protein gene product 9.5 profile was not affected by either rapid pacing or NE infusion, nor was it changed by desipramine treatment in the heart failure animals. The study confirms that excess NE contributes to the reduction of cardiac sympathetic neurotransmitters in heart failure. In addition, it shows that the anatomic integrity of the sympathetic nerves is relatively intact and that the neuronal damaging effect of NE involves the uptake of NE or its metabolites into the sympathetic nerves.

Topics: Adrenergic alpha-Agonists; Adrenergic Fibers; Adrenergic Uptake Inhibitors; Animals; Blood Pressure; Desipramine; Dogs; Heart; Heart Failure; Heart Rate; Immunohistochemistry; Microscopy, Fluorescence; Neuropeptide Y; Norepinephrine; Thiolester Hydrolases; Ubiquitin Thiolesterase

Recent studies showed higher plasma levels of several cytokines, such as interleukines or tumour necrosis factor in patients with congestive heart failure. Cytokines play a very important role in pathogenesis of congestive heart failure, because they impair contractility of heart muscle and cause damage of endothelium and myocytes due to their proinflammatory effects. One of the treatment modalities of heart failure might be administration of drugs inhibiting production of cytokines. The study was undertaken to evaluate whether beneficial effects of amlodipine in congestive heart failure are due to inhibition of synthesis of cytokines. The plasma levels of interleukine 6 (IL-6), tumour necrosis factor (TNF-alpha), neuropeptide Y (NPY) and endothelin-1 (ET-1) were determined in patients with congestive heart failure (NYHA II and III) before and after 30 days of treatment with amlodipine. 40 patients with congestive heart failure (CHF) treated in the Department of Cardiology of Medical University in Wrocław participated in this study. In all patients CHF developed in the course of ischaemic heart disease and coexisting hypertension. Patients were divided into 2 groups dependingly on the NYHA classification. The first group consisted of 24 patients in II NYHA class, the other one--of 16 patients in III NYHA class. At 8 am, on the second day after admission and before treatment with amlodipine blood samples were taken from examined patients to determine plasma levels of IL-6, TNF-alpha, NPY and ET-1. Then patients were administered amlodipine at the dose of 5-10 mg per day. The next blood samples were taken on 5th and 30th day of treatment. Plasma levels of TNF-alpha, IL-6, NPY and ET-1 were estimated with radioimmunoassay using Medgerix kits. Our findings showed that plasma levels of TNF-alpha, IL-6, NPY and ET-1 in patients with CHF are increased. 30-days treatment with amlodipine caused significant decrease of TNF-alpha and IL-6 levels, but did not influence the plasma levels of NPY and ET-1. Amlodipine causes improvement of circulatory efficiency assessed according to NYHA classification. Treatment with amlodipine may be an additional way of therapy in CHF.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Endothelin-1; Female; Heart Failure; Humans; Interleukin-6; Male; Middle Aged; Neuropeptide Y; Tumor Necrosis Factor-alpha

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, beta-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [(3)H]NE, beta-receptor density by [(125)I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial beta-adrenoceptor density and beta-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial beta-adrenoceptor density and beta-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.

Topics: Adrenergic alpha-Agonists; Adrenergic Uptake Inhibitors; Animals; Blood Pressure; Cardiotonic Agents; Desipramine; Dobutamine; Dogs; Heart Failure; Immunohistochemistry; Myocardial Contraction; Myocardium; Neuropeptide Y; Norepinephrine; Organ Size; Presynaptic Terminals; Receptors, Adrenergic, beta; Sympathetic Nervous System; Tyrosine 3-Monooxygenase; Ventricular Dysfunction, Right

Sympathetic nerve activity, including that in the kidney, is increased in heart failure with increased plasma concentrations of norepinephrine and the vasoconstrictor cotransmitter neuropeptide Y (NPY). We examined the contribution of NPY to sympathetically mediated alterations in kidney function in normal and heart failure rats. Heart failure rats were created by left coronary ligation and myocardial infarction. In anesthetized normal rats, the NPY Y(1) receptor antagonist, H 409/22, at two doses, had no effect on heart rate, arterial pressure, or renal hemodynamic and excretory function. In conscious severe heart failure rats, high-dose H 409/22 decreased mean arterial pressure by 8 +/- 2 mm Hg but had no effect in normal and mild heart failure rats. During graded frequency renal sympathetic nerve stimulation (0 to 10 Hz), high-dose H 409/22 attenuated the decreases in renal blood flow only at 10 Hz (-36% +/- 5%, P <.05) in normal rats but did so at both 4 (-29% +/- 4%, P <.05) and 10 Hz (-33% +/- 5%, P <.05) in heart failure rats. The glomerular filtration rate, urinary flow rate, and sodium excretion responses to renal sympathetic nerve stimulation were not affected by high-dose H 409/22 in either normal or heart failure rats. NPY does not participate in the regulation of kidney function and arterial pressure in normal conscious or anesthetized rats. When sympathetic nervous system activity is increased, as in heart failure and intense renal sympathetic nerve stimulation, respectively, a small contribution of NPY to maintenance of arterial pressure and to sympathetic renal vasoconstrictor responses may be identified.

Topics: Amides; Anesthesia; Animals; Blood Pressure; Electric Stimulation; Heart Failure; Heart Rate; Kidney; Kidney Function Tests; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Renal Circulation; Sympathetic Nervous System; Vasoconstriction

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

Topics: Animals; Blood Pressure; Exercise Test; Exocytosis; Guinea Pigs; Heart; Heart Failure; Heart Rate; Humans; Middle Aged; Neuropeptide Y; Norepinephrine

The aim of the present study was to elucidate if the potentiating effect of neuropeptide Y on various vasoactive agents in vitro is (1) altered in mesenteric arteries from rats with congestive heart failure and (2) mediated by the neuropeptide Y Y1 receptor. The direct vascular effects of neuropeptide Y and its modulating effects on the contractions induced by endothelin-1-, noradrenaline-, 5-hydroxytryptamine (5-HT)-, U46619-(9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F2alpha) and ATP, and acetylcholine-induced dilatations were studied in the presence and absence of the neuropeptide Y Y1 antagonist, BIBP3226 (BIBP3226¿(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl ]-D-arginine-amide¿). Neuropeptide Y, per se, had no vasoactive effect in the arteries. The potency of endothelin-1 was significantly decreased in congestive heart failure rats. Neuropeptide Y and neuropeptide Y-(13-36) potentiated the endothelin-1-induced contraction in congestive heart failure mesenteric arteries. In 20% of the congestive heart failure rats, sarafotoxin 6c induced a contraction of 31+/-4%. Neuropeptide Y also potentiated U46619- and noradrenaline-induced contractions but not 5-HT-induced contractions in congestive heart failure arteries. In sham-operated animals neuropeptide Y potentiated noradrenaline- and 5-HT-induced contractions. These potentiations were inhibited by BIBP3226. Acetylcholine induced an equipotent relaxation in both groups which was unaffected by neuropeptide Y. In conclusion, neuropeptide Y responses are altered in congestive heart failure rats. The potentiating effect differs between vasoactive substances. Neuropeptide Y Y1 and non-neuropeptide Y1 receptors are involved.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Triphosphate; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Endothelins; Heart Failure; Male; Mesenteric Arteries; Muscle Relaxation; Myocardial Contraction; Neuropeptide Y; Norepinephrine; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Serotonin; Sympathetic Nervous System; Vasoconstrictor Agents

1. Hormones involved in cardiovascular regulation are influenced by drug treatment. It is therefore difficult to study endocrine mechanisms in heart failure as most patients are already on treatment by the time they reach hospital. 2. We studied nine hospital in-patients before and after treatment of acute New York Heart Association class IV heart failure. 3. Before treatment, plasma brain and atrial natriuretic peptides were markedly elevated (BNP 121 +/- 26 pg/ml, ANP 163 +/- 33 pg/ml; normal range: BNP 3.9 +/- 0.3 pg/ml, ANP 8.6 +/- 0.8 pg/ml) and correlated positively with serum creatinine and left ventricular end-diastolic diameter and negatively with ejection fraction. Eight patients improved and one died. 4. With improvement plasma ANP and BNP fell. Initial renin activity was within the normal range but increased on treatment. Plasma neuropeptide Y and adrenaline remained normal before and after treatment in the eight patients who improved. Initial plasma noradrenaline was in the normal range in four of these patients and just above normal in a further four. In the patient who died, initial plasma neuropeptide Y and catecholamines were very high. 5. Plasma BNP emerged as complementary to ANP as a dynamic index in severe heart failure; however, renal function is also an important determinant of plasma BNP and ANP. There is little evidence for activation of the circulating renin-angiotensin-aldosterone system or neuropeptide Y before treatment of acute heart failure.

Topics: Acute Disease; Aged; Aged, 80 and over; Aldosterone; Atrial Natriuretic Factor; Biomarkers; Diuretics; Epinephrine; Female; Furosemide; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neuropeptide Y; Norepinephrine; Renin; Severity of Illness Index

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y-like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [3H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119 +/- 5% of arterial, n = 7) and after a meal (132 +/- 12%, n = 7), with neuropeptide Y overflows of 6 +/- 2 and 11 +/- 2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norep

Topics: Adult; Aged; Coffee; Eating; Exercise; Heart Failure; Heart Transplantation; Humans; Mental Processes; Middle Aged; Neuropeptide Y; Rest; Stress, Physiological; Sympathetic Nervous System

Two-legged knee extensor training activates only about half the muscle mass used in traditional cycle ergometer training. With such an exercise model it is possible to achieve a substantial local training effect in spite of a restricted circulatory capacity. The present study sought to investigate the systemic effects of such local training on ventilation and neurohumoral activity in patients with moderate heart failure.. Thirteen male patients with chronic heart failure (age 56 +/- 3 years, EF 28 +/- 3%) performed two-legged knee extensor exercises (about 4 kg of working muscle) for 15 minutes 3 times a week during 8 weeks at 65-75% of peak VO2 of a two-legged kick and were compared to a non-training control group (n = 7, age 62 +/- 3, EF 27 +/- 3%). Before and after the training period VO2, VCO2 and the minute ventilation (1/min) were determined at rest and at submaximal and maximal workloads. Also measured before and after training were two-legged knee extensor peak exercise capacity (W), strength (Nm), a 6-minute walking test (m), quadriceps femoris citrate synthase activity, plasma catecholamines, vasoactive amines and blood lactate during submaximal knee extension exercise, and perceived health-related quality of life. After training, VO2 and VCO2 were reduced at submaximal exercise by 20-30% (P < .01) but were unchanged at peak exercise. With training, the two-legged knee extensor peak exercise capacity increased by 38% (P < .01). The 6-minute walking gait velocity increased by 12% (P < .01) and skeletal muscle citrate synthase activity by 28% (P < .01). Training improved the quality of life (P < .01). After training, VO2 (P < .001), VCO2 (P < .001) and minute ventilation (P < .001) were reduced at the workload corresponding to the maximal workload before training. The ratio minute ventilation/VO2 was reduced (P < .05) after training at the before-training maximal workload. No change was observed in the control group with regard to two-legged peak exercise capacity or peak VO2. Plasma NPY was reduced both at rest and at submaximal exercise by 35% (P < .01), whereas noradrenaline was reduced only during exercise (P < .05).. Local muscle training is effective in stable chronic heart failure and can improve, in addition to exercise capacity and quality of life, the ventilatory response, and decrease the sympathetic stress.

Topics: Adult; Aged; Atrial Natriuretic Factor; Epinephrine; Exercise Therapy; Exercise Tolerance; Heart Failure; Heart Rate; Humans; Lactic Acid; Leg; Male; Middle Aged; Muscle Contraction; Muscle, Skeletal; Neuropeptide Y; Norepinephrine; Quality of Life; Sympathetic Nervous System

The present investigation was designed to determine the best endogenous plasma marker of early congestive heart failure (CHF).. Forty volunteers with mild CHF (New York Heart Association Class I, n = 12), moderate (Class II, n = 8), or severe (Class III and Class IV, each = n of 5) and 10 age-matched healthy individuals had the simultaneous evaluation of their respective plasma samples by the following radioimmunoassays: atrial natriuretic peptide, ANP; three N-terminal ANP prohormone assays, i.e., proANPs 1-30, 31-67, and 79-98 with the numbers referring to their amino acid (a.a.) sequences in their 126 a.a. prohormone; brain (BNP) and C-natriuretic peptides; N-terminal BNP prohormone; adrenomedullin; neuropeptide Y and endothelin.. ProANPs 31-67, 1-30 and 79-98 had 100% (P = 0.01), 83% (P = 0.09) and 50% (P = 0.74) sensitivity in differentiating Class I CHF subjects from healthy subjects. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y, and endothelin assays could not differentiate mild CHF subjects from healthy individuals. Logistic regression analysis revealed that only proANP 31-67 significantly (P = 0.0001) discriminated between early CHF (5226 +/- 377 pg/ml) and healthy individuals (1595 +/- 157 pg/ml). The positive and negative predicative values of proANP 31-67 were excellent (100% for each). The peptides measured in these assays were found to be independent markers of CHF with respect to left ventricular ejection fraction.. ProANPs 31-67 is the most sensitive marker in discriminating NYHA Class I CHF subjects from healthy individuals. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y and endothelin radioimmunoassays cannot discern mild CHF. These peptides are independent of left ventricular ejection fraction.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Endothelins; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Neuropeptide Y; Peptide Fragments; Peptides; Predictive Value of Tests; Protein Precursors; Regression Analysis

Neuropeptide Y (NPY) has been shown to potentiate the effects of various vasoactive agents in both in vitro and in vivo experiments. The present study was designed to investigate the potentiation effects of NPY on various vasoconstrictive agents and the influence of NPY on the dilatation effects of endothelin-1 in rats with congestive heart failure (CHF). CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Experiments in conscious rats were performed 4-6 weeks after coronary artery ligation or sham operation. The pressor responses of intravenous phenylephrine (12.5 nmol/kg), endothelin-1 (400 pmol/kg) and angiotensin II (10 ng) but not tyramine (40 micrograms) were significantly decreased in CHF rats compared with sham-operated rats (p < 0.01). In sham-operated rats, subthreshold dose of NPY (0.1 microgram/kg/min) potentiated the pressor responses of all the agonists (p < 0.05). In CHF rats, significant enhancement of mean arterial pressure (MAP) by subthreshold dose of NPY was observed with angiotensin II (p < 0.05). The MAP was enhanced by 45.4% in CHF and 40.6% in sham-operated rats respectively. NPY did not enhance the pressor responses induced by phenylephrine, endothelin-1 or tyramine in CHF rats. The initial decrease of MAP after bolus injection of endothelin-1 was observed in both CHF and sham-operated control rats, and magnitude of this response was similar in both groups. Subthreshold dose of NPY significantly reduced the vasodilatation effect of endothelin-1 in CHF (p < 0.05) but not in normal control rats. We conclude that NPY potentiates pressor effects of angiotensin II and reduces vasodilatation effects of endothelin-1 in rats with CHF. These effects of NPY may contribute to the increased vascular tone in CHF.

Topics: Animals; Blood Pressure; Cardiovascular System; Drug Synergism; Endothelin-1; Heart Failure; Heart Rate; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasodilator Agents

Previous studies have demonstrated that alpha-trinositol (D-myo-inositol-1.2.6-trisphosphate; PP56) may act as a functional neuropeptide Y (NPY) inhibitor. Because NPY is known to be a potent vasoconstrictor, the effects of alpha-trinositol on renal function, vascular responses and the potentiating effects of NPY were investigated in rats with congestive heart failure (CHF) induced by ligation of the left coronary artery. Incremental doses of alpha-trinositol were given to conscious rats (bolus 2, 4 or 10 mg/kg i.v. followed by a 15-minute infusion 20, 40 and 100 mg/kg/h, respectively). Urinary volume, sodium and potassium excretions were significantly increased in both CHF and sham-operated control animals after alpha-trinositol administration compared with saline. Diuresis and natriuresis were observed also during co-administration of alpha-trinositol with NPY but not with norepinephrine (NE). In the pithed CHF rats, threshold doses of NPY potentiated the pressor effects of endothelin-1 (ET-1) and angiotensin II (AII), but not preganglionic nerve stimulation or phenylephrine administration. Alpha-trinositol antagonized both the pressor response to NPY and the potentiation by NPY of pressor responses to effects of ET-1 and AII. Our data show that alpha-trinositol exhibis diuretic and natriuretic effects as well as vascular antagonistic effects on NPY in normal and CHF rats. These effects of alpha-trinositol may be due to an interaction with NPY mediated antidiuresis and antinatriuresis.

Topics: Animals; Cardiovascular System; Diuresis; Heart Failure; Hemodynamics; Inositol Phosphates; Kidney; Male; Myocardial Ischemia; Natriuresis; Neuropeptide Y; Rats; Rats, Sprague-Dawley

Plasma neuropeptide Y (NPY) was measured by radioimmunoassay in 43 patients with congestive heart failure (CHF) and 20 healthy control subjects. The results showed that plasma NPY levels were elevated in patients with CHF compared with control subjects (366 +/- 28 ng/L VS. 89 +/- 22 ng/L, P < 0.001). There was a close relationship between the severity of CHF and plasma NPY levels. The severer the CHF, the higher the NPY level. In addition, 20 of the 43 patients with symptoms improved after treatment for heart failure were followed. The results indicated a significant decrease of plasma NPY levels (333 +/- 42 ng/L VS. 157 +/- 25 ng/L, P < 0.01) in these patients. Furthermore, multiple logistic regression analysis demonstrated that the presence and severity of CHF were related to plasma NPY levels significantly and independently. Because of its potent vasoconstrictive and negative cardiac inotropic effects, NPY might be involved in the pathophysiology of CHF. Plasma NPY levels might be taken as a prognostic indicator in patients with CHF, but further investigation is needed.

Topics: Adult; Female; Heart Failure; Humans; Logistic Models; Male; Middle Aged; Neuropeptide Y

We wished to determine if chronic neuropeptide Y (NPY) infusion (1 ng/min for 1 week by Alzet minipump) could decrease plasma renin activity (PRA) and norepinephrine (NE) in a rat myocardial infarction (MI) model of moderate compensated congestive heart failure (CHF). CHF was produced by prior (6-8 weeks) ligation of the left coronary artery; control rats were sham-operated. Carotid arterial blood was drawn for PRA and NE in conscious unrestrained rats that had been instrumented 24 h earlier. MI rats had increased PRA as compared with sham-operated rats [8.73 +/- 1.27 vs. 5.10 +/- 0.91 ng angiotensin (AI) I/ml.h, mean +/- SE]. During chronic NPY infusion, PRA was reduced to normal in the MI group (4.78 +/- 0.91) but was not affected in the sham group (5.65 +/- 0.51). Plasma NE was altered similarly, but the changes did not reach statistical significance. These data suggest that NPY has the capacity to restrain renin release in moderate compensated CHF.

Topics: Animals; Heart; Heart Failure; Infusions, Intravenous; Male; Models, Cardiovascular; Myocardial Infarction; Neuropeptide Y; Norepinephrine; Rats; Rats, Sprague-Dawley; Renin

Plasma neuropeptide Y-like immunoreactivity (NPY-LI) is elevated in patients with acute myocardial ischaemia and congestive heart failure (CHF) owing to increased activity of the sympathetic nervous system. The prognostic value of plasma NPY-LI with regard to mortality was studied in 324 random patients admitted to a coronary care unit. The one-year mortality was 37% in 113 patients with acute myocardial infarction (AMI) and 18% in those without AMI. Several factors were tested by multiple logistical regression analysis to predict the one-year mortality. Plasma NPY-LI > 60 pmol.l-1, advanced age and previous CHF were independent prognostic factors for an increased risk of mortality in patients without AMI. The mortality rate after one year in non-AMI patients with plasma NPY-LI < or = 60 pmol.l-1 was 14% compared to 69% in those with plasma NPY-LI > 60 pmol.l-1. Increased heart rate was the only independent prognostic factor for increased mortality in AMI patients. Plasma NPY-LI on admission was an independent predictor of mortality in CCU patients without AMI and thus resembles plasma noradrenaline.

Topics: Aged; Arrhythmias, Cardiac; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Neuropeptide Y; Prognosis; Risk Factors; Sensitivity and Specificity; Survival Rate

The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone.. Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear.. Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow.. Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons.. Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.

Topics: Brain; Dihydroxyphenylalanine; Heart; Heart Failure; Humans; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Norepinephrine; Pulmonary Wedge Pressure; Sympathetic Nervous System; Thermodilution

We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.

Topics: Animals; Arginine Vasopressin; Atrial Natriuretic Factor; Bicarbonates; Biomarkers; Body Weight; Cardiac Pacing, Artificial; Cardiomegaly; Dogs; Electric Stimulation; Electrolytes; Heart; Heart Failure; Muscle Denervation; Neuropeptide Y; Neuropeptides; Norepinephrine; Oxygen; Partial Pressure; Propranolol; Reference Values; Respiration; Vagus Nerve; Ventricular Function, Left

To measure plasma concentrations of noradrenaline and neuropeptide Y-like immunoreactivity in relation to cardiac function in patients with congestive heart failure.. Retrospective analysis of plasma noradrenaline concentrations and neuropeptide Y-like immunoreactivity in the arterial and coronary circulations, in patients with a high or low ejection fraction (31.3% (1.3%) or 17.7% (1.1%) respectively) and in healthy volunteers.. Cardiology department of a university hospital.. 41 patients with congestive heart failure with various aetiologies. Ten healthy volunteers served as a reference group.. Concentrations of noradrenaline measured by high performance liquid chromatography and of neuropeptide Y-like immunoreactivity measured by radioimmunoassay. Cardiac index, pulmonary capillary wedge pressure, pulmonary vascular resistance, and systemic vascular resistance were derived by catheterisation of the right heart. Ejection fraction was measured by radionuclide angiography, cineangiography, or M mode echocardiography.. There were pronounced and significant increases in circulating arterial concentrations of neuropeptide Y-like immunoreactivity and noradrenaline in both the high and low ejection fraction groups compared with the healthy subjects. In the patients myocardial release of neuropeptide Y-like immunoreactivity tended to be greater compared with normal subjects, but not significantly so. While normal subjects showed myocardial noradrenaline uptake, patients with congestive heart failure showed significant and progressive myocardial noradrenaline release. Arterial as well as coronary sinus concentrations of neuropeptide Y-like immunoreactivity correlated significantly with plasma noradrenaline concentrations from the respective sites. Plasma noradrenaline concentrations in the artery and coronary sinus were negatively correlated with ejection fraction and cardiac index; no such relations were found for concentrations of neuropeptide Y-like immunoreactivity.. Both circulating concentrations of neuropeptide Y-like immunoreactivity and noradrenaline are significantly increased in moderate to severe forms of congestive heart failure. Plasma concentrations of neuropeptide Y-like immunoreactivity correlated with plasma noradrenaline concentrations, but plasma noradrenaline concentrations alone correlated with ejection fraction and cardiac index. Thus plasma noradrenaline concentration seems to be a more sensitive index of cardiac dysfunction than the concentration of neuropeptide Y-like immunoreactivity in congestive heart failure.

Topics: Adolescent; Adult; Aged; Biomarkers; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Retrospective Studies; Stroke Volume

The purpose of the study described here was to study plasma immunoreactive Neuropeptide Y (NPY) at rest and during exercise in patients with congestive heart failure (CHF) and in healthy subjects. Thirty-five patients, mean age 64 years, with CHF in optimal treatment and with a mean ejection fraction of 32%, were studied at rest and during exercise. Twelve age and sex matched healthy subjects were compared for resting values. Another nine healthy subjects were studied at rest and during exercise at a constant low load of 75W and at a high load defined as 80% of their individual maximal capacity. In patients with congestive heart failure mean plasma immunoreactive NPY at rest was 10.3 pmol l-1 and was not significantly different from the control group. No differences between patients with slight and severe CHF were found and there was no correlation between plasma immunoreactive NPY and left ventricular ejection fraction. Mean maximal exercise time was on average 6.3 min. Only three patients exercised more than 10 min. At maximal exercise mean plasma immunoreactive NPY was 10.6 pmol l-1 the same as at rest. Plasma noradrenaline was increased in CHF patients compared to healthy subjects, and rose further during exercise. In healthy subjects plasma immunoreactive NPY rose significantly on both workloads, but more on the high load (p < 0.05), when the rise was first significant after 10 min. Plasma immunoreactive NPY at rest and during exercise was not increased in CHF patients in optimal medical treatment. Consequently plasma immunoreactive NPY is not a useful marker of the severity of CHF in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Epinephrine; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Rest

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

Neuropeptide Y (NPY) is thought to be co-released with catecholamines in response to major cardiovascular stresses, but its relation to the release of catecholamines in response to minor stresses has been less well described. We therefore studied the response of plasma NPY-like immunoreactivity (NPY-Li) levels to standing (10 min) in eight normal subjects and 11 patients with congestive heart failure, and to short-term (6h) vasodilator therapy in 13 patients with congestive heart failure. In both normal and heart failure patients, NPY-Li-decreased (296 +/- 73 to 233 +/- 63 pg.ml-1 and 652 +/- 36 to 516 +/- 25 pg.ml-1 (P < 0.01) respectively) in response to standing, whereas catecholamines increased in both groups (norepinephrine 203 +/- 73 to 507 +/- 165 pg.ml-1 and 493 +/- 197 to 813 +/- 336 pg.ml-1 (P < 0.001) respectively and epinephrine 23 +/- 12 to 38 +/- 12 pg.ml-1 and 46 +/- 19 to 62 +/- 28 pg.ml-1 (P < 0.001) respectively). Both basal circulating NPY-Li and catecholamine levels were markedly increased in congestive heart failure patients, but catecholamines and NPY-Li did not correlate with each other. After 6 h of nitroglycerin infusion, mean arterial pressure was decreased, but circulating neurohumoral levels remained unchanged and NPY-Li levels decreased (653 +/- 37 to 517 +/- 26 pg.ml-1, P < 0.01). It is concluded that basal circulating NPY-Li and catecholamine levels are increased in congestive heart failure and that this neurohormone could play a concomitant role in the increase in peripheral resistance in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arousal; Catecholamines; Female; Heart Failure; Hemodynamics; Humans; Hypotension, Orthostatic; Infusions, Intravenous; Male; Middle Aged; Neuropeptide Y; Nitroglycerin; Radioimmunoassay; Reference Values

The purpose of this study was to investigate the relationship between dopamine (DA) exposure and myocardial catecholamine and neuropeptide Y (NPY) concentrations in patients with severe congestive heart failure due to idiopathic dilated cardiomyopathy (IDC). Both nonfailing (NF) and failing (F) hearts were obtained in collaboration with the Utah Cardiac Transplantation Program and the Intermountain Organ Recovery System. The patients were stratified into five groups according to their preoperative exposure to dobutamine (DBT) and/or DA. Compared to 12 untreated, NF control hearts, norepinephrine (NE) concentrations were significantly decreased in 30 untreated F hearts obtained from patients with IDC. Norepinephrine concentrations were also significantly decreased in DA-treated NF hearts and in DA-treated F hearts compared to untreated NF and untreated or DBT-treated failing hearts, respectively. NPY concentrations were significantly decreased in untreated F hearts and were further decreased in dopamine-treated NF and DA-treated F hearts compared to untreated NF and untreated or DBT-treated F hearts. Thus, NE and NPY depletion related to DA administration was evident in both NF and F myocardium and was specific for DA in that it was not evident in patients who received the direct-acting beta-agonist inotrope DBT. These data suggest that the major inotropic mechanism of action of DA is through cardiac adrenergic neurotransmitter release. The data also provide further support for the concept that indirect acting inotropes such as DA may have limited inotropic potential in F hearts where neuronal NE has been depleted.

Topics: Adult; Cardiomyopathy, Dilated; Catecholamines; Dobutamine; Dopamine; Electrocardiography; Female; Heart; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Neuropeptide Y; Receptors, Adrenergic, beta

In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.

Topics: Adenylyl Cyclases; Adult; Cardiomyopathy, Dilated; Catecholamines; Female; Heart; Heart Failure; Humans; Hypertension, Pulmonary; Iodocyanopindolol; Isoproterenol; Male; Myocardial Contraction; Neuropeptide Y; Pindolol; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta

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

STUDY OBJECTIVE - The aim of the study was to measure plasma neuropeptide Y, which is related to sympathetic nerve stimulation, in patients admitted to a coronary care unit and to relate the findings to clinical information. DESIGN - Plasma neuropeptide Y was measured on admission and the results were related to the cause of admission and to clinical information collected prospectively and retrospectively. SUBJECTS - Plasma subjects were obtained from 377 consecutive daytime admissions to the coronary care unit at Södersjukhuset. Results of only the first sample in each patient are included in this study, so 45 cases observed more than once (readmitted patients) were omitted. Six samples were abandoned because of technical failures. The study therefore comprises 326 patients. Clinical diagnoses were defined as acute myocardial infarction, arrhythmia, angina pectoris, and miscellaneous (all other diagnoses). Heart failure was defined according to a modified Killip scheme. MEASUREMENTS and RESULTS - Neuropeptide Y like immunoreactivity was measured by radio-immunoassay. Plasma concentrations above normal (greater than 30 pmol.litre-1) were found in association with: increased age, female sex, diuretic treatment, tachycardia, arterial hypotension, increased respiratory rate, and mortality in the unit. There was a strong relationship between high neuropeptide Y concentrations and: moderate left heart failure (63%), pulmonary oedema (90%), and cardiogenic shock (100%). Of patients without heart failure only 25% had raised neuropeptide Y. In multivariate analysis, the severity of heart failure (Killip class), heart rate and respiratory rate were the only variables that were significantly and independently related to plasma neuropeptide Y. CONCLUSIONS - The presence and degree of circulatory disturbance, in particular tachycardia and left heart failure, were strongly related to increased plasma concentrations of neuropeptide Y in coronary care patients.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Arrhythmias, Cardiac; Coronary Care Units; Diuretics; Epinephrine; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Neuropeptide Y; Norepinephrine; Pilot Projects; Pulmonary Edema; Risk Factors; Shock, Cardiogenic

Our objectives were to assess whether plasma neuropeptide Y (NPY) levels are elevated in patients with congestive heart failure (CHF) and whether or not NPY levels can serve as a reliable indicator of sympathetic activity in CHF.. Plasma levels of the sympathetic neurotransmitters norepinephrine and epinephrine and of the sympathetic co-transmitter NPY were measured in 17 patients with CHF and 14 healthy control subjects at rest and after maximal exercise.. Under resting conditions, plasma NPY and norepinephrine levels were elevated in patients with CHF compared with control subjects (551 +/- 48 pg/ml versus 311 +/- 22 pg/ml, p less than or equal to 0.001 for NPY, and 306 +/- 73 pg/ml versus 124 +/- 22 pg/ml, p less than or equal to 0.02 for norepinephrine). Plasma NPY correlated better with plasma norepinephrine than with epinephrine, indicating its origin from sympathetic nerve terminals. Acute stimulation of sympathetic activity by dynamic exercise increased plasma norepinephrine levels in control subjects and patients with CHF, but did not significantly alter the mean plasma NPY value in the latter group.. NPY may play a role in the pathophysiology of CHF.

Topics: Adult; Aged; Blood Pressure; Epinephrine; Exercise Test; Heart Failure; Humans; Middle Aged; Neuropeptide Y; Norepinephrine; Oxygen Consumption; Sympathetic Nervous System