adrenomedullin and Chronic-Disease

Topics: Adrenomedullin; Chronic Disease; Endothelins; Heart Failure; Hemodynamics; Humans; Natriuretic Peptides; Renin-Angiotensin System; Sympathetic Nervous System; Vasopressins

Circulating biomarkers have become increasingly important in diagnosing and risk-stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus in the past decade, there is increasing interest in the role of other circulating biomarkers such as mid-regional proadrenomedullin (MR-proADM), a stable peptide of the precursor of adrenomedullin (ADM), responsible for volume regulation and electrolyte homeostasis. Increased levels of MR-proADM are associated with an increased risk of mortality and morbidity in patients with HF, independent of natriuretic peptides. MR-proADM outperforms all other established markers in the identification of patients at highest risk of death, particularly death within 30 days. The prognostic superiority has consistently been shown for various cardiovascular disease states, including acute heart failure. In this article, we discuss the potential role of MR-proADM in the syndrome of acute heart failure and its implication on prognosis and risk stratification.

Topics: Acute Coronary Syndrome; Acute Disease; Adrenomedullin; Biomarkers; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Protein Precursors; Vasodilation

The hyperdynamic circulatory syndrome observed in chronic liver diseases is a great example of research that originated from clinical observations and progressed in the last 50 years from the patient to the experimental laboratory. Our knowledge has evolved from the patient to the molecule, using experimental models that serve as a source for understanding the complex pathophysiological mechanisms that govern this complex syndrome. We now know that progressive vasodilatation is central to the detrimental effects observed in multiple organs. Although nitric oxide has been shown to be the primary vasodilator molecule in these effects, other molecules also participate in the complex mechanisms of vasodilatation. This review summarizes three major areas: first, clinical observation in patients; second, experimental models used to study the hyperdynamic circulatory syndrome; and third, the vasodilator molecules that play roles in vascular abnormalities observed in portal hypertension.

Topics: Adrenomedullin; Animals; Biological Factors; Blood Pressure; Cannabinoid Receptor Modulators; Carbon Monoxide; Chronic Disease; Disease Models, Animal; Endothelium, Vascular; Humans; Hydrogen Sulfide; Hypertension, Portal; Liver; Liver Diseases; Nitric Oxide; Peptides; Splanchnic Circulation; Tumor Necrosis Factor-alpha; Vasodilation

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo.. Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported.. Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months.. Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value.. In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Biomarkers; Carbazoles; Carvedilol; Chronic Disease; Heart Failure; Humans; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptide Fragments; Peptides; Prognosis; Propanolamines; Risk Factors; Ventricular Dysfunction, Left

Adrenomedullin is a potent vasodilator peptide and occurs in circulating blood of human beings and experimental animals. Because it is produced in intact aorta of rats and in cultured vascular endothelial cells, adrenomedullin seems to participate in regulation of local vascular tone. To determine the pathophysiological roles of adrenomedullin, we investigated its plasma concentrations in 49 patients with heart failure. Plasma adrenomedullin levels increased significantly with advancing severity of the disease (New York Heart Association functional class I, 4.1 +/- 1.0; II, 5.6 +/- 1.6; III, 6.4 +/- 0.8; IV, 13.2 +/- 6.8 (fmol/l). Plasma adrenomedullin was correlated with pulmonary artery pressure (r = 0.44, p = 0.0114) and pulmonary capillary wedge pressure (r = 0.53, p = 0.0002). These findings indicate that adrenomedullin may play some important role in the pathophysiologic makeup of heart failure by its vasodilating effects against the concomitant exaggeration of humor pressor agents such as catecholamine and the renin-angiotensin system. Hemodynamic changes in pulmonary circulation may have some influence on the increased synthesis and secretion of plasma adrenomedullin in chronic congestive heart failure.

Topics: Adrenomedullin; Adult; Aged; Cardiac Catheterization; Cardiac Output; Chronic Disease; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Peptides; Severity of Illness Index

BACKGROUND Chinese hawthorn (Crataegus pinnatifida) fruit is a traditional Chinese medicine for treatment of digestive system and cardiovascular diseases. The fruit contains polyphenol compounds, such as epicatechin, that have anti-inflammatory activity. This study aimed to investigate the effects of an alcohol extract of hawthorn fruit (HAE) on inflammation and oxidative stress in rats with doxorubicin-induced chronic heart failure (CHF). MATERIAL AND METHODS Rats were intraperitoneally injected with doxorubicin to induce CHF and subsequently treated with HAE intragastrically once daily for 6 weeks. At the end of the experiment, echocardiographic and hemodynamic parameters were assessed, and enzyme-linked immunoassays were used to detect the levels of cardiac injury markers (brain natriuretic peptide, creatine kinase-MB, aspartate aminotransferase, lactate dehydrogenase, copeptin, and adrenomedullin), oxidative stress markers (glutathione peroxidase and malondialdehyde), and inflammatory cytokines (interleukin [IL]-6, IL-8, IL-1ß, and tumor necrosis factor-a). The IL-1ß, IL-6, glutathione peroxidase-1, and catalase mRNA levels were also measured by quantitative real-time polymerase chain reaction. RESULTS Our findings indicated that HAE exerts a cardioprotective effect, as shown by improved echocardiographic and hemodynamic parameters, decreased activity of serum myocardial enzymes, reduced serum levels of CHF markers, and inhibited inflammatory response in cardiac tissue. In addition, HAE treatment downregulated the mRNA expression of IL-1ß and tumor necrosis factor-alpha and upregulated the mRNA expression of glutathione peroxidase-1 and catalase compared with untreated doxorubicin-induced CHF rats. CONCLUSIONS HAE shows promise for the prevention and treatment of CHF. The cardioprotective effect of HAE appears to be related to inhibition of both the inflammatory response and oxidative stress in vivo.

Topics: Adrenomedullin; Animals; Antioxidants; Aspartate Aminotransferases; Chromatography, High Pressure Liquid; Chronic Disease; Crataegus; Creatine Kinase; Cytokines; Doxorubicin; Electrocardiography; Ethanol; Fruit; Glutathione Peroxidase; Glycopeptides; Heart Failure; Heart Function Tests; Inflammation; L-Lactate Dehydrogenase; Male; Malondialdehyde; Natriuretic Peptide, Brain; Oxidative Stress; Plant Extracts; Polyphenols; Rats, Wistar; RNA, Messenger

Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR.. A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow-up.. Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR-proADM (adj.OR 2.25, 95% CI 1.29-3.93; P = .004), MR-proANP (adj.OR 1.84, 95% CI 1.14-3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04-2.67; P = .035) and CT-pro-ET1 (adj.OR 1.68, 95% CI 1.06-2.68; P = .027) but not with NT-proBNP (P = .54).. Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT-proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR-proANP, primarily produced in the atria, copeptin partly triggered by intra-cardiac and intra-arterial pressures and MR-proADM, a marker of forward failure and peripheral released vasoactive CT-proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Disease Progression; Echocardiography; Endothelin-1; Female; Glycopeptides; Heart Failure, Systolic; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Natriuretic Peptide, Brain; Peptide Fragments; Phenotype; Prognosis; Protein Precursors; Risk Assessment; Stroke Volume

Besides the established biomarker NT-proBNP, the new cardiovascular biomarkers MR-proANP, MR-proADM, Copeptin, and CT-proET-1 are promising to evaluate hemodynamics, exercise parameters, and prognosis in patients with pulmonary hypertension (PH).. 125 consecutive patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) were prospectively enrolled at five German PH centers. Blood samples were taken during right heart catheterization. The primary study endpoint was the correlation between biomarkers and hemodynamic and exercise parameters. As secondary endpoint, prediction of 1-year mortality was evaluated.. MR-proADM showed the strongest correlations with 6MWD and VO2peak, whereas NT-proBNP showed the strongest correlations with PVR, PAPm, and CI. In multivariate analysis, only MR-proADM was independently associated with exercise variables, whereas only NT-proBNP independently predicted hemodynamic parameters. All biomarkers were associated with 1-year survival, with MR-proADM showing the highest C index of 0.78. In multivariate analysis, MR-proADM predicted survival independent of age, 6-MWD, CI, RAP, and NT-proBNP. The cut-off of 1.08 nmol/l provided a sensitivity of 83 % and specificity of 66 %.. Different biomarkers reflect distinctive disease aspects in PH. NT-proBNP best predicts hemodynamic impairment while MR-proADM strongly correlates with exercise capacity. Additionally, MR-proADM represents a promising new marker to evaluate prognosis in patients with PAH and CTEPH. Multi-marker strategies should further be evaluated.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Chronic Disease; Endothelin-1; Exercise Tolerance; Female; Germany; Glycopeptides; Heart Atria; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Pulmonary Embolism; Pulmonary Wedge Pressure; Vascular Resistance

Adrenomedullin is a neuropeptide known for its cardiovascular activities and anti-inflammatory effects. Here, we investigated the effect of adrenomedullin in a model of experimental autoimmune encephalomyelitis (EAE) that mirrors chronic progressive multiple sclerosis. A short-term systemic treatment with adrenomedullin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord and the subsequent demyelination and axonal damage. This effect was exerted at multiple levels affecting both early and late events of the disease. Adrenomedullin decreased the presence/activation of encephalitogenic Th1 and Th17 cells and down-regulated several inflammatory mediators in peripheral lymphoid organs and central nervous system. Noteworthy, adrenomedullin inhibited the production by encephalitogenic cells of osteopontin and of Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), two critical cytokines in the development of EAE. At the same time, adrenomedullin increased the number of IL-10-producing regulatory T cells with suppressive effects on the progression of EAE. Furthermore, adrenomedullin generated dendritic cells with a semi-mature phenotype that impaired encephalitogenic responses in vitro and in vivo. Finally, adrenomedullin regulated glial activity and favored an active program of neuroprotection/regeneration. Therefore, the use of adrenomedullin emerges as a novel multimodal therapeutic approach to treat chronic progressive multiple sclerosis.

Topics: Adrenomedullin; Animals; Brain; Chronic Disease; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Female; Lymph Nodes; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Spinal Cord; Spleen

Adrenomedullin (ADM) is a vasodilatory peptide expressed in many tissues. Its levels are elevated in various diseases including chronic heart failure (CHF) and it has been suggested that the up-regulation of ADM in cardiac disease represents a protective mechanism. Similarly, intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide family, is considered a potential endogenous protector of the heart. Previous studies demonstrated that in CHF patients, elevated plasma concentrations of ADM and IMD reflect the patient's disease severity and prognosis, while the behavior of mRNA expression is not known. The aim of this study was to evaluate ADM/IDM transcriptomic profiling in human leukocytes of CHF patients as a function of clinical severity, assessing possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and from CHF patients (NYHA I-II n=10; NYHA III-IV n=14) with PAXgene Blood RNA Kit. Significantly higher levels of ADM and IMD mRNA were found in CHF as a function of clinical severity (ADM: C=0.03 ± 0.013, NYHA I-II=0.11 ± 0.084, NYHA III-IV=11.46 ± 4.72, p=0.037 C vs NYHA III-IV, p=0.028 NYHA I-II vs NYHA III-IV; IMD: C=0.158 ± 0.041, NYHA I-II=0.93 ± 0.40, NYHA III-IV=2.6 ± 0.67, p=0.014 C vs NYHA III-IV, p=0.014 NYHA I-II vs NYHA III-IV). This study highlights, for the first time, the possibility of evaluating ADM and IMD mRNA expression in human whole blood samples by Real-Time PCR study providing further relevant information and providing a more complete interpretation of the pathophysiology of the disease.

Topics: Adrenomedullin; Chronic Disease; Female; Heart Failure; Humans; Leukocytes; Male; Middle Aged; Peptide Hormones; RNA, Messenger; Transcription, Genetic

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heart failure (CHF) rats. The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats.. Rats were subjected to left descending coronary artery ligation to induce CHF or sham-operation (Sham). Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Acute experiments were carried out 8 weeks after coronary ligation or sham surgery under anesthesia. IMD and angiotensin II (Ang II) levels in the PVN were up-regulated in CHF rats. Bilateral PVN microinjection of IMD caused greater decreases in CSAR and the baseline RSNA and MAP in CHF rats than those in Sham rats. The decrease of CSAR caused by IMD was prevented by pretreatment with AM receptor antagonist AM22-52, but not CGRP receptor antagonist CGRP8-37. Ang II in the PVN significantly enhanced CSAR and superoxide anions level, which was inhibited by PVN pretreatment with IMD or tempol (a superoxide anions scavenger) in Sham and CHF rats.. IMD in the PVN inhibits CSAR via AM receptor, and attenuates the effects of Ang II on CSAR and superoxide anions level in CHF rats. PVN superoxide anions involve in the effect of IMD on attenuating Ang II-induced CSAR response.

Topics: Adrenomedullin; Afferent Pathways; Angiotensin II; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Chronic Disease; Heart Failure; Heart Rate; Hemodynamics; Kidney; Male; Neuropeptides; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Rats; Rats, Sprague-Dawley; Superoxides; Sympathetic Nervous System

Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM(+/-) group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM(+/-) group (P < 0.05). Oxidative stress was detected in oligodendrocytes, with a larger increase in the AM(+/-) group (P < 0.05). Aged mice showed the same tendency, but white matter damage was worse, especially in the aged AM(+/-) group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM(+/-) group. Adrenomedullin may be an important target in the control of ischemic white matter injury.

Topics: Adrenomedullin; Aging; Animals; Chronic Disease; Hypoxia-Ischemia, Brain; Male; Mice; Mice, Mutant Strains; Neural Stem Cells; Oligodendroglia; White Matter

To the authors' knowledge, no prospectively validated, biomarker-based risk stratification tools exist for elderly patients presenting to the emergency department (ED) with nonspecific complaints (NSCs), such as generalized weakness, despite the fact that an acute serious disease often underlies nonspecific disease presentation. The primary purpose for this study was to validate the retrospectively derived model for outcome prediction using copeptin and peroxiredoxin 4 (Prx4), in a different group of patients, in a prospective fashion, in a multicenter setting. The secondary goals were to evaluate the potential contribution of the midregional portion of the precursor of adrenomedullin (MR-proADM) for outcome prediction and to investigate whether disposition decisions show promise for potential improvement by using biomarker levels in addition to a clinical assessment.. The Basel Nonspecific Complaints (BANC) study is a delayed-type cross-sectional diagnostic study, carried out in three EDs in Switzerland, with a prospective 30-day follow-up. Patients presenting to the ED with NSCs, as defined previously, were included if their vital signs were within predefined limits. Measurement of biomarkers was performed in serum samples with sandwich immunoluminometric assays. To examine the disposition process, the final disposition was compared with a combination of the first clinical disposition decision and the risk assessment, which included the biomarker MR-proADM in a retrospective simulation. Patients were divided into three groups according to MR-proADM concentration, defining three risk classes with three disposition possibilities (admission to tertiary care, transfer to geriatric hospital, discharge).. Thirty-three 30-day nonsurvivors were observed from among 504 study patients with NSCs. Biomarker levels were significantly greater in nonsurvivors than survivors (p < 0.0001 for all three biomarkers). Univariate Cox models reveal a C-index of 0.732 for MR-proADM, 0.719 for Prx4, and 0.723 for copeptin. The incremental added value for chi-square obtained via multivariate modeling showed that models inclusive of MR-proADM, copeptin, or Prx4 are superior to and independent of models limited to sex and age. The incrementally added chi-square for MR-proADM, beyond the chi-square of a base model consisting of age and sex, was 29.79 (p < 0.00001). In a multimarker approach, only Prx4 provided additional information to MR-proADM alone (C-index = 0.77). Applying an algorithm combining physicians' first clinical assessment plus biomarker information to derive a modified risk assessment, reassignment would lead to a potential decrease of 48 admissions to acute care, seven additional transfers to geriatric care, and 41 additional discharges (negative likelihood ratio [-LR] = 0.13). Analysis of 30-day mortality reveals that our algorithm is not inferior in terms of safety.. In this study the authors confirm that these new stress biomarkers permit reliable prognostication of adverse outcomes in a heterogeneous group of patients with NSCs. A simulation showed that this prognostic information could be useful to enhance the appropriateness of disposition decisions of ED patients with NSC. The use of biomarkers for risk stratification in this patient group should be evaluated with prospective intervention studies.

Topics: Acute Disease; Adrenomedullin; Aged; Aged, 80 and over; Algorithms; Analysis of Variance; Biomarkers; Cause of Death; Chi-Square Distribution; Chronic Disease; Cross-Sectional Studies; Emergency Service, Hospital; Fatigue; Female; Geriatric Assessment; Glycopeptides; Hospital Mortality; Hospitals, University; Humans; Length of Stay; Male; Multivariate Analysis; Peroxiredoxins; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment; Sensitivity and Specificity; Stress, Psychological; Survival Analysis; Switzerland

Colorectal cancer (CRC) is the most severe complication in inflammatory bowel disease (IBD). In the present study we investigated different mechanistic links between chronic colonic inflammation and its progression to adenocarcinoma. Along these lines, given that adrenomedullin (AM) has been implicated in carcinogenesis, we also analyzed changes in its colonic expression.. Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. After each period, macroscopic and histological studies, as well as characterization of inflammatory and tumor biomarkers, were carried out.. The disease activity index (DAI) showed that the disease was present from the third cycle and it gradually increased during the course of DSS treatment. Macroscopic tumors were only seen after 15 cycles, and microscopic study showed that inflammation, dysplasia, and adenocarcinomas correlated with DSS cycles. β-Catenin and proliferating cell nuclear antigen expressions progressively increased in animals treated with the different cycles of DSS. TNF-α and IFN-γ showed the highest production at the tenth cycle. COX-2, mPGES-1, and iNOS levels were also appreciably higher at the fifth and tenth cycles. Moreover, we observed a progressive enhancement in AM expression and changes in its intracellular location during the progression of the disease.. Our results show an early induction of proinflammatory factors, which may contribute to the development of colon cancer, as well as demonstrate, for the first time, the expression of AM in IBD-derived CRC.

Topics: Adenocarcinoma; Adrenomedullin; Animals; beta Catenin; Biomarkers, Tumor; Blotting, Western; Cell Transformation, Neoplastic; Chronic Disease; Colitis, Ulcerative; Colorectal Neoplasms; Cytokines; Dextran Sulfate; Female; Immunoenzyme Techniques; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha

Serial measurements of neurohormones have been shown to improve prognostication in the setting of acute heart failure (HF) or chronic HF without therapeutic intervention. We investigated the prognostic role of serial measurements of emerging neurohormones and BNP in a cohort of chronic HF patients undergoing increases in HF-specific therapy.. In this prospective study we included 181 patients with chronic systolic HF after an episode of hospitalization for worsening HF. Subsequently, HF therapy was gradually increased in the outpatient setting until optimized. We measured copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide before and after optimization of HF therapy. The primary endpoint was all-cause mortality at 24 months.. Angiotensin-converting enzyme/angiotensin receptor blocker and beta-blockers were increased significantly during the 3-month titration period (P < 0.0001 for both). In a stepwise Cox regression analysis adjusted for age, sex, glomerular filtration rate, diabetes mellitus, and ischemic HF, baseline and follow-up neurohormone concentrations were predictors of the primary endpoint as follows (baseline hazard ratios): copeptin 1.92, 95% CI 1.233-3.007, P = 0.004; midregional proadrenomedullin 2.79, 95% CI 1.297-5.995, P = 0.009; midregional proatrial natriuretic peptide 2.05, 95% CI 1.136-3.686, P = 0.017; C-terminal endothelin-1 precursor fragment 2.24, 95% CI 1.133-4.425, P = 0.025; B-type natriuretic peptide 1.46, 95% CI 1.039-2.050, P = 0.029.. In pharmacologically unstable chronic HF patients, baseline values and follow-up measures of copeptin, midregional proadrenomedullin, C-terminal endothelin-1 precursor fragment, midregional proatrial natriuretic peptide, and B-type natriuretic peptide were equally predictive of all-cause mortality. Relative change of neurohormone values was noncontributory.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Chronic Disease; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Prognosis; Protein Precursors

Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers.. A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminometric assay.. Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p

Topics: Adrenomedullin; Aged; Biomarkers; Chronic Disease; Cross-Sectional Studies; Endothelin-1; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Ventricular Dysfunction, Left

Adrenomedullin (AM) is a 52 amino acid peptide and member of the calcitonin gene-related peptide (CGRP) super family. Given that AM has emerged as a potential immuno-regulatory and anti-inflammatory agent in various experimental models, this study has deepened into its possible therapeutic effect in intestinal inflammation analyzing the responses in both acute and chronic (14 and 21 days) phases of TNBS-induced colitis in rats. In the acute model, AM treatment reduced the incidence of diarrhea and the severity of colonic damage, and improved the survival rate at the three doses assayed (50, 100, and 200ng/kg animal). AM administration was able to reduce the early production of TNF-alpha and collaborated to maintaining basal levels of IFN-gamma and IL-10. In the chronic studies the peptide attenuated the extent of the damage with lesser incidence of weight loss and diarrhea (50 and 100ng/kg animal). Cellular neutrophil infiltration, with the subsequent increase in myeloperoxidase (MPO) levels caused by TNBS, was reduced after chronic AM administration. The peptide played a role in the evolution of Th1/Th2 cytokines balance and chronic disease recuperation: levels of proinflammatory TNF-alpha and IFN-gamma decreased and anti-inflammatory IL-10 increased significantly. Cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were not modified by AM administration, although a reduction of nitric oxide (NO) production could be detected in the chronic model. These results support a role of AM as an anti-inflammatory factor with beneficial effects in intestinal inflammatory colitis.

Topics: Acute Disease; Adrenomedullin; Animals; Anti-Inflammatory Agents; Chronic Disease; Colitis; Colon; Female; Interferon-gamma; Interleukin-10; Male; Peroxidase; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Periodontal disease is an inflammatory disorder characterized by the involvement of chemokines that are important for the recruitment of leucocytes. Several cytokines, including tumour necrosis factor alpha (TNF-alpha), are involved in regulating levels of chemokines in periodontal disease. CXC chemokine ligand 10 (CXCL10) is a chemokine related to the migration of T helper 1 cells. In this study, we examined CXCL10 expression in human gingival fibroblasts (HGFs). Moreover, we investigated the effects of adrenomedullin (AM), which is a multi-functional regulatory peptide, on the production of CXCL10 by HGFs. We revealed that TNF-alpha stimulation induced CXCL10 production by HGFs. HGFs expressed AM and AM receptors, calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) 2, mRNAs constitutively. AM treatment supressed CXCL10 production by TNF-alpha-stimulated HGFs. Moreover, we elucidated that AM produced by HGFs inhibited CXCL10 production by HGFs, because AM antagonist enhanced CXCL10 production by HGFs. TNF-alpha treatment enhanced CRLR and RAMP2 mRNA expression in HGFs. Furthermore, AM is expressed in human periodontal tissues, including both inflamed and clinically healthy tissues. These results suggest that the CXCL10 produced by HGFs may be involved in the migration of leucocytes into inflamed tissues and related to exacerbation of periodontal disease. AM might be a therapeutic target of periodontal disease, because AM can inhibit CXCL10 production by HGFs.

Topics: Adrenomedullin; Adult; Aged; Calcitonin Receptor-Like Protein; Cells, Cultured; Chemokine CXCL10; Chronic Disease; Female; Fibroblasts; Gingiva; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Periodontitis; Periodontium; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin; Receptors, Peptide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

To investigate the levels of serum cortisol, dehydroepiandrosterone sulfate (DHEA-S), nitric oxide (NO) and adrenomedullin (AM) in schizophrenic patients.. Sixty-six male patients with chronic schizophrenia and 28 normal male subjects participated in this study. The duration of disease was 145 +/- 120 (mean +/- SD) months. Serum levels of cortisol and DHEA-S were measured by electrochemiluminescence; plasma nitrite levels as an index of NO were measured with the Griess reaction, while plasma AM concentration was measured by using high-performance liquid chromatography.. Patients (12.48 +/- 3.2 microg/dl), as compared to controls (10.31 +/- 3.1 microg/dl), had higher levels of baseline cortisol (p < 0.05). DHEA-S levels were lower in patients though this did not reach statistical significance (302 +/- 156 microg/dl compared to control, 322 +/- 96 microg/dl, p > 0.05). The mean levels of plasma AM and NO in the schizophrenic group (44.33 +/- 5.07 pmol/l and 36.27 +/- 17.6 micromol/l) were significantly higher than the levels in the control group (14.56 +/- 4.03 pmol/l and 32.54 +/- 7.14 micromol/l; p < 0.001, p < 0.03, respectively). There was a positive association between duration of disease and cortisol/DHEA-S ratio and cortisol level.. The data show that schizophrenia is associated with abnormal levels of cortisol, DHEA-S, NO and AM.

Topics: Adrenomedullin; Adult; Case-Control Studies; Chromatography, High Pressure Liquid; Chronic Disease; Dehydroepiandrosterone; Humans; Hydrocortisone; Male; Nitric Oxide; Schizophrenia; Statistics, Nonparametric

Adrenomedullin (AM) has been shown to be present in the stomach but the role of gastric AM is obscure. To investigate the effects of starvation on AM in the stomach, we studied the changes in gene expression of preproadrenomedullin (preproAM) and AM receptors by reverse transcription-polymerase chain reaction (RT-PCR), and tissue AM concentrations by radioimmunoassay (RIA) in the fundus and pylorus of the stomach of rats subjected to either acute (1-day) or chronic (4-day) starvation. An up-regulation of preproAM gene expression was observed in the fundus after acute starvation, and in the pylorus after chronic starvation. Immunoreactive AM (ir-AM) levels were increased in both fundus and pylorus after chronic starvation. In addition, marked reductions in the gene expression of fundic calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein (RAMP) 3 as well as the pyloric CRLR and RAMP2 were observed in the chronically starved rats. The present study suggests that the gene expression of preproadrenomedullin mRNA is differentially regulated by starvation in the different parts of the stomach.

Topics: Acute Disease; Adrenomedullin; Animals; Body Weight; Chromatography, Gel; Chronic Disease; Gastric Fundus; Gastric Mucosa; Gene Expression Regulation; Immunohistochemistry; Kinetics; Male; Organ Size; Pylorus; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Starvation; Stomach

1. The present study was designed to examine the cardiovascular effects of intravenously administered pcDNA3.1AM, a recombinant non-virus vector carrying a rat adrenomedullin (AM) gene translation fragment, in rats with chronic cardiac dysfunction induced by ligation of the left descending coronary artery. 2. Haemodynamic parameters were recorded by intraventricular catheterization. In situ hybridization and polymerase chain reaction (PCR) were performed to identify the distribution of the introduced vector. The concentration of AM was determined by radioimmunoassay. 3. Progressive cardiac dysfunction was observed following coronary artery ligation, as indicated by a significant reduction in mean arterial pressure (MAP) and increases in both central venous pressure (CVP) and end-diastolic pressure of the left ventricle (LVEDP; P < 0.01). Administration of pcDNA3.1AM significantly attenuated the progressive cardiac dysfunction and lowered the elevated CVP and LVEDP. The introduced vector was widely distributed in different organs, including the lungs, kidney, heart, liver, spleen and brain. However, intense staining of pcDNA3.1 AM was observed in the lungs and kidneys. The introduced vector was localized mainly in the endothelial cells of blood vessels. Radioimmunoassay showed elevated levels of AM in the plasma and lung and heart after surgery, but there was no significant further increase in the concentration of AM after pcDNA3.1AM delivery. 4. The present study has provided some novel findings on the potential beneficial effects of AM gene delivery on chronic cardiac function in rats. Expression of AM by a non-virus vector may also have therapeutic value against cardiac dysfunction in vivo.

Topics: Adrenomedullin; Animals; Blood Pressure; Central Venous Pressure; Chronic Disease; Coronary Vessels; Disease Models, Animal; Endothelial Cells; Genetic Therapy; Genetic Vectors; Heart Failure; Kidney; Ligation; Lung; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Time Factors; Ventricular Function, Left; Ventricular Pressure

To investigate whether adrenomedullin (ADM), a multifunctional peptide with key roles in host antimicrobial defence and inflammation, was present and quantifiable in human gingival crevicular fluid (GCF) and to study its relationship with periodontal health and disease.. GCF samples (30s) were collected using perio-paper strips from one diseased site in 21 subjects with periodontal disease and one healthy site from 19 control subjects with no evidence of periodontal disease. Samples were analysed by radioimmunoassay using a specific anti-human ADM antibody.. Measurable adrenomedullin-like immunoreactivity (ADM-LI) was present in all the GCF samples collected. ADM-LI was significantly higher in periodontitis sites (mean 493.6 pg) than in control healthy sites (mean 248.5 pg), p = 0.0016.. It is concluded that ADM is present in GCF at levels at which it could have an antibacterial role in the gingival crevice and modulate the pathophysiology of periodontal inflammation.

Topics: Adrenomedullin; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Female; Gingival Crevicular Fluid; Humans; Male; Middle Aged; Periodontitis; Periodontium; Radioimmunoassay; Statistics, Nonparametric

To explore the effect of adrenomedullin(1-50) (ADM(1-50)) on hypoxic pulmonary hypertension and pulmonary vascular structural remodeling and the plasma concentration of nitric oxide (NO) and hydrogen sulfide (H(2)S) in rats.. Twenty male Wistar rats were randomly divided into control group (n=7), hypoxic group (n=6) and hypoxic with ADM(1-50) group (n=7). ADM(1-50) was subcutaneously administered into rats of hypoxic with ADM(1-50) group by mini-osmotic pump (300 ng/h). After two weeks' hypoxic challenge, mean pulmonary arterial pressure (mPAP) was evaluated by using a right cardiac catheterization procedure. The ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV+S)] was detected. Pulmonary vascular microstructure was measured and the ultrastructural changes in intra-acinar pulmonary arteries were observed. Meanwhile, plasma concentrations of NO and H(2)S were measured.. mPAP was significantly increased in hypoxic rats than that in controls [(24.9+/-6.8) mmHg vs (14.3+/-2.4) mmHg, P<0.01,1 mmHg=0.133 kPa]; RV/(LV+S) was also significantly increased in hypoxic rats than that in controls [(0.318+/-0.054) vs (0.182+/-0.007), P<0.01]. Microstructure and ultrastructure of pulmonary arteries changed obviously in hypoxic rats with the development of hypoxic pulmonary vascular structural remodeling. Meanwhile, plasma NO and H(2)S concentrations in hypoxic rats were markedly decreased compared with controls. However, mPAP was significantly decreased in hypoxic rats treated with ADM(1-50) than that in hypoxic rats [(14.9+/-3.0) mmHg vs (24.9+/-6.8) mmHg, P<0.01]; RV/(LV+S) was also significantly decreased than that in hypoxic rats [(0.185+/-0.011) vs (0.318+/-0.054), P<0.01]. ADM(1-50) ameliorated pulmonary vascular structural remodeling of hypoxic rats in association with an increase in plasma NO and H(2)S concentrations.. ADM(1-50) plays an important role in regulation of the development of hypoxic pulmonary hypertension and hypoxic pulmonary vascular structural remodeling, through promoting NO and H(2)S production in hypoxic rats.

Topics: Adrenomedullin; Airway Remodeling; Animals; Chronic Disease; Hydrogen Sulfide; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide; Peptide Fragments; Pulmonary Artery; Rats; Rats, Wistar

Our previous study showed that static handgrip caused increases in the plasma adrenomedullin (ADM) both in patients with heart failure (HF) and healthy subjects. The present study was designed to determine the role of the sympathetic nervous system in mediating plasma ADM changes during handgrip in patients with HF. Twelve male HF patients (II class NYHA) treated with carvedilol, a non-selective adrenergic blocker (TC) and 12 patients untreated with carvedilol (UC) performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand. At the end of both exercise bouts and in 5 min of the recovery period, plasma ADM and catecholamines were determined. In addition, heart rate, blood pressure and stroke volume (SV) were measured. The baseline plasma ADM, noradrenaline (NA) and adrenaline (A) levels were similar in the two groups of patients, while SV was higher (P<0.05) in TC than in UC. During exercise plasma ADM concentrations were lower (P<0.05) in TC than in UC, but the handgrip-induced increases in plasma ADM did not differ between the groups. Plasma ADM correlated with NA concentrations (r = 0.764) and with SV (r = -0.435) and increases in plasma ADM expressed as percentage of baseline values correlated with those of plasma NA (r = 0.499), diastolic BP (r = 0.550) and total peripheral resistance (r = 0.435). The study suggests that the sympathetic nervous system may be involved in the stimulation of ADM secretion during static exercise either directly or by changes in the haemodynamic response.

Topics: Adrenergic beta-Antagonists; Adrenomedullin; Aged; Analysis of Variance; Biomarkers; Blood Pressure; Carbazoles; Cardiac Output; Carvedilol; Chronic Disease; Coronary Artery Disease; Epinephrine; Exercise Test; Heart Failure; Heart Rate; Humans; Linear Models; Male; Middle Aged; Norepinephrine; Propanolamines; Sympathetic Nervous System; Treatment Outcome; Vascular Resistance

To study the clinical significance of plasma adrenomedullin (ADM) and brain natriuretic polypeptide (BNP) in the patients with chronic cor pulmonale on highland (HACCP).. The levels of ADM and BNP in plasma of 44 patients with HACCP in the acute and in the remission stages were determined with radioimmunoassay. Their correlations with partial pressure of oxygen in arterial blood (PaO(2)), endothelin-1 (ET-1), and the ratio of right ventricular pre-ejection time to the pulmonary flow acceleration time (RVPEP/AT), which reflected the degree of pulmonary hypertension, were investigated. Twenty healthy subjects served as a normal control group.. The levels of ADM [(38.8+/-7.2)ng/L and (26.2+/-5.3)ng/L] and BNP [(81.4+/-13.8)ng/L and (58.9+/-9.3)ng/L] in the acute and remission stages of cor pulmonale groups were both significantly higher than those in the normal control group [(15.0+/-3.2)ng/L, (38.6+/-3.4)ng/L, respectively, all P<0.01]. The levels of ADM and BNP in acute stage were both significantly higher than those in remission stage (both P<0.01). In the acute and in the remission stages, the levels of ADM in plasma were negatively correlated with PaO(2) (r(a)=-0.826, P<0.01; r(r)=-0.783, P<0.01), positively correlated with ET-1 (r(a)=0.755, P<0.01; r(r)=0.668, P<0.01) and RVPEP/AT ratio (r(a)=0.788, P<0.01; r(r)=0.734, P<0.01). In the acute and in the remission stages, the levels of BNP in plasma were negatively correlated with PaO(2) (r(a)=-0.787, P<0.01; r(r)=-0.554, P<0.01), positively correlated with ET-1 (r(a)=0.725, P<0.01; r(r)=0.679, P<0.01) and RVPEP/AT ratio (r(a)=0.771, P<0.01; r(r)=0.722, P<0.01).. The study suggests that ADM and BNP are involved in the pathophysiological process of HACCP in the patients and may play a compensatory role in the disease.

Topics: Adrenomedullin; Aged; Altitude; Chronic Disease; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Heart Disease

Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia.. Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ionically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60+/-0.02, 0.72+/-0.03, 0.42+/-0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group.. AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.

Topics: Adrenomedullin; Animals; Chronic Disease; Gelatin; Gene Expression; Genetic Vectors; Ischemia; Lower Extremity; Male; Neovascularization, Physiologic; Peptides; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rabbits; Radiography

Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM+/-) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia.. Ten-week-old male wild-type (AM+/+) or AM+/- mice were housed under 10% oxygen conditions for 3 to 21 days. In AM+/+ mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM+/- mice housed under hypoxia than in AM+/+ mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM+/- mice than in AM+/+ mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM+/+ but also AM+/- mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung.. The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.

Topics: Adrenomedullin; Animals; Antioxidants; Chronic Disease; Cyclic N-Oxides; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Lung; Male; Mice; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Peptides; Pulmonary Artery; Reactive Oxygen Species; RNA, Messenger; Spin Labels; Tunica Media

Adrenomedullin is known to exert anti-atherosclerotic actions by inhibiting proliferation and migration of smooth muscle cells in vitro. Here we examine the relationship between the plasma concentration of adrenomedullin and ultrasonographic characteristics of carotid arteries both in ischemic stroke and in the absence of cerebrovascular disease.. We studied 61 patients with atherothrombotic ischemic stroke in the chronic phase and 50 patients without any cerebrovascular disease. Intima-media thickness and vascular lumen diameters were evaluated by carotid ultrasonography. Plasma mature-adrenomedullin was determined by radioimmunoassay.. Plasma mature-adrenomedullin in the patients with atherothrombotic ischemic stroke in the chronic phase (2.01 +/- 0.58 fmol/ml) was significantly higher than that in the patients without any cerebrovascular disease (1.24 +/- 0.18 fmol/ml, P < 0.001). With multiple regression analysis, plasma mature-adrenomedullin was found to be predicted by: stroke status (atherothrombotic ischemic stroke versus no cerebrovascular disease), diabetes status (yes/no), left ventricular ejection fraction, internal carotid artery intima-media thickness, and common carotid artery pressure strain elastic modulus (R = 0.79; F5,105 = 85.39, P < 0.0001).. Plasma mature-adrenomedullin showed significantly positive associations with carotid atherosclerosis and atherothrombotic ischemic stroke, independent of systolic blood pressure.

Topics: Adrenomedullin; Aged; Blood Pressure; Brain Ischemia; Carotid Arteries; Carotid Artery Diseases; Carotid Artery Thrombosis; Carotid Artery, Common; Carotid Artery, Internal; Case-Control Studies; Chronic Disease; Diabetic Angiopathies; Elasticity; Female; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Peptides; Stress, Mechanical; Stroke; Stroke Volume; Tunica Intima; Tunica Media; Ultrasonography

A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis.. Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA.. Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated.. These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.

Topics: Acute Disease; Adrenomedullin; Animals; Bacteremia; Bacteroides fragilis; Bacteroides Infections; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Escherichia coli Infections; Male; Multiple Organ Failure; Peptides; Portal System; Rats; Rats, Sprague-Dawley; Shock, Septic; Time Factors; Vasodilator Agents

To investigate the changes in plasma levels of adrenomedullin (ADM) and cyclic adenosine monophosphate (cAMP) in patients with chronic heart failure (CHF) in an attempt to understand the role of ADM in the occurrence and development of CHF.. The plasma levels of cAMP and ADM were measured by radioimmunoassay in 45 patients with CHF (including 10 of NYHA classII, 15 of class III, and 20 of class IV) and 20 healthy controls respectively.. Plasma ADM and cAMP levels significantly increased in patients of NYHA class II, III, and IV as compared with the healthy controls (P<0.05), with those of class III patients being the highest. Positive correlation between ADM and cAMP was noted in CHF patients(r=0.735, P<0.01).. Plasma levels of ADM and cAMP were in close correlation with the degree of heart failure, varying dynamically with the development of heart failure. There was mutual accommodation between ADM and cAMP, and increased cAMP level partly results from elevated ADM level in CHF patients.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Chronic Disease; Cyclic AMP; Female; Heart Failure; Humans; Male; Middle Aged; Radioimmunoassay

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent vasodilators in humans and improved myocardial ischemia is observed after CGRP administration. Receptors for CGRP and ADM were already identified in heart. Receptor activity-modifying proteins (RAMPs) determine the ligand specificity of the calcitonin receptor-like receptor (CRLR); co-expression of RAMP1 and CRLR results in a CGRP receptor, whereas the association of RAMP2 or RAMP3 with CRLR gives an ADM receptor. As CGRP and ADM may play a beneficial role in heart failure, we investigated whether the CGRP and ADM receptors are upregulated in chronic heart failure. We have used semi-quantitative RT-PCR and Western-blot analysis to detect and quantify the mRNA and the protein of RAMP1 and RAMP3 in both atria and ventricles of failing hearts 6 months after aortic banding in rats. Our results showed for the first time an up-regulation of RAMP1 and RAMP3 mRNAs and proteins in this model of cardiac failure. No change was observed in mRNAs coding for CRLR, RAMP2, RDC1 (canine orphan receptor), and ADM. The present results suggested after congestive heart failure in adult rats, an up-regulation of the CGRP receptor (by an increase in RAMP1 that is associated with CRLR) in atria and ventricles and of ADM receptor (by increased RAMP3 expression that is associated with CRLR) in atria. These findings support a functional role for CGRP and ADM receptors to compensate the chronic heart failure in rats.

Topics: Adrenomedullin; Animals; Aortic Valve Stenosis; Calcitonin Gene-Related Peptide; Calcitonin Receptor-Like Protein; Chronic Disease; Disease Models, Animal; Heart Atria; Heart Failure; Heart Ventricles; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Myocardium; Peptides; Rats; Rats, Wistar; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Receptors, Cell Surface; Receptors, Chemokine; Receptors, CXCR; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.

Topics: Adrenomedullin; Antihypertensive Agents; Arteries; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Failure; Humans; In Vitro Techniques; Male; Peptides; Protease Inhibitors; Thiorphan; Vascular Resistance; Vasoconstriction

Adrenomedullin is a potent vasodilator peptide exerting anti-atherosclerotic actions in vitro. We investigated the impact of the severity of atherosclerosis on plasma mature-adrenomedullin (m-AM) levels in 38 patients with chronic ischemic stroke. The variables of carotid artery atherosclerosis assessed using ultrasound measurement, blood pressure, and risk factors were related to m-AM levels. Severe atherosclerosis was associated with a further elevation of the increased m-AM level in patients with high systolic blood pressure. Even in patients with fewer risk factors, the presence of severe atherosclerosis was associated with an increased m-AM level. Thus, atherosclerosis elevates m-AM independent of the blood pressure level or presence of risk factors.

Topics: Adrenomedullin; Aged; Antihypertensive Agents; Blood Pressure; Brain Ischemia; Carotid Artery Diseases; Chronic Disease; Heart Rate; Humans; Peptides; Risk Factors; Stroke

Adrenomedullin, a potent endogenous vasodilating and natriuretic peptide, may play an important role in the pathophysiology of chronic heart failure. Plasma levels of immunoreactive adrenomedullin were examined for prediction of prognosis in chronic heart failure.. Plasma levels of immunoreactive-ADM (ir-ADM) were measured by radioimmunoassay in 117 chronic heart failure patients with idiopathic or ischaemic cardiomyopathy (mean ejection fraction: 28 +/- 10%, in the NYHA functional class I/II/III/IV:8/73/29/7, and treated with ACE inhibitors and diuretics. Plasma levels of immunoreactive adrenomedullin were significantly increased in chronic heart failure patients by comparison to controls (618 +/- 293 pg x ml(-1) vs 480 +/- 135 pg x ml(-1), P=0.01). During the follow-up period (237 +/- 137 days) 14 cardiovascular deaths and four urgent cardiac transplantations occurred. In the univariate Cox model, immunoreactive adrenomedullin plasma levels were related to prognosis (P=0.004). A multivariate analysis including heart rate, systolic blood pressure, NYHA class, left ventricular ejection fraction, left ventricular echocardiographic end-diastolic diameter, plasma levels of immunoreactive adrenomedullin, endothelin-1, norepinephrine and atrial natriuretic peptide was performed: plasma levels of immunoreactive adrenomedullin (P=0.03), of endothelin-1 (P=0.0001), and systolic blood pressure (P=0.003) were significantly associated with outcome.. Our results suggest that elevated plasma levels of immunoreactive adrenomedullin are an independent predictor of prognosis in predominantly mild to moderate chronic heart failure treated by conventional therapy and provide additional prognostic information.

Topics: Adrenomedullin; Adult; Aged; Cardiac Output, Low; Chronic Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peptides; Prognosis; Radioimmunoassay

Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 +/- 0.17 v 3.87 +/- 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 +/- 0.95 v control, 8.93 +/- 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 +/- 0.08 v 1.23 +/- 0.20 fmol/mL; P < 0.05 and 25.0 +/- 3.0 v 35.0 +/- 3.6 fmol/mg of creatinine, respectively; P < 0. 05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = -0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r = 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.

Topics: Adrenomedullin; Adult; Calcitonin Gene-Related Peptide; Case-Control Studies; Chronic Disease; Female; Glomerulonephritis; Humans; Male; Natriuresis; Peptide Fragments; Peptides; Proteins; Vasodilator Agents

Cultured vascular endothelial and smooth muscle cells actively produce adrenomedullin, a novel vasodilator peptide discovered in human pheochromocytoma tissue. This present study was designed to determine whether the plasma level of adrenomedullin is a useful indicator for estimating the degree of endothelial injury in patients with atherosclerotic disease.. We used a radioimmunoassay to measure plasma adrenomedullin concentrations in 51 patients with chronic cerebrovascular disease (34 infarctions and 17 haemorrhages) and in 10 subjects without symptomatic cerebrovascular disease. We also measured the plasma concentrations of thrombomodulin and endothelin as markers of endothelial injury. The patients were divided into three groups (A, B, and C) on the basis of the number of risk factors for atherosclerosis: hypertension, hyperlipidemia, smoking, low HDL-cholesterol, diabetes mellitus, and hyperuricaemia. Group A (68.7+/-2.7 years) consisted of patients with 0 or 1 risk factors; B (68.3+/-4.2 years) those with 2 risk factors; and C (69.2+/-3.6 years) those with 3 or more risk factors.. The plasma concentration of adrenomedullin in these patients showed a significant positive correlation with age (r=0.33, p<0.05), as well as with the plasma concentrations of thrombomodulin (r=0.54, p<0.001) and endothelin (r=0.53, p<0.001). Moreover, the plasma concentrations of adrenomedullin and thrombomodulin (p<0.005 and p<0.02, respectively) tended to be higher in Group B and to be significantly higher in Group C as compared to Group A. Plasma adrenomedullin concentrations did not, however, significantly differ between the infarction and haemorrhage patients.. These findings suggest that the plasma adrenomedullin concentrations reflect the degree of endothelial injury in patients with atherosclerotic disease.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Blood Urea Nitrogen; Brain Ischemia; Cerebral Angiography; Cerebral Hemorrhage; Cholesterol; Chronic Disease; Endothelins; Female; Humans; Intracranial Arteriosclerosis; Magnetic Resonance Imaging; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptides; Risk Factors; Thrombomodulin; Tomography, X-Ray Computed; Vasodilator Agents

Adrenomedullin (AM) is a novel vasodilator with structural similarities to calcitonin gene-related peptide (CGRP). This study investigated AM activity in the rat lung during hypoxia-induced pulmonary hypertension. Both rat AM (0.2-10 nmol) and alpha-CGRP (0.2-2 nmol) produced dose-related reductions in pulmonary artery pressure in the isolated perfused lung ventilated with 2% O2. Pretreatment with alpha-CGRP, which demonstrated tachyphylaxis, or its antagonist, CGRP-(8-37), reduced the hypotensive response to AM, suggesting that part of the response to AM is mediated by CGRP receptors. 125I-labeled AM and 125I-labeled CGRP binding was significantly increased in lung membranes from 7-day hypoxic animals (AM from 1.94 +/- 0.3 to 3.36 +/- 0.4 and CGRP from 0.06 +/- 0.01 to 0.12 +/- 0.02 pmol/mg protein), with no change in dissociation constant. Moreover, the hypotensive response to both peptides was increased in the lungs of 7-day hypoxic rats. There was no significant change in lung immunoreactive AM concentrations (hypoxic 5.04 +/- 0.48 vs. control 6.28 +/- 0.76 pmol/g wet wt of tissue) or steady-state AM mRNA levels in 7-day hypoxic rats. Nonetheless, AM may be useful for the acute pharmacological manipulation of pulmonary artery pressure in hypoxia-induced pulmonary hypertension.

Topics: Adrenomedullin; Animals; Base Sequence; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Lung; Molecular Sequence Data; Peptides; Polymerase Chain Reaction; Radioligand Assay; Rats; Rats, Wistar; Reference Values; RNA, Messenger; Vasodilator Agents