adrenomedullin and Myocardial-Ischemia

Outcomes of victims of cardiac arrest or acute myocardial ischemic events have improved with advances in medical therapy. Heart failure, however, remains a leading cause of morbidity and mortality after these conditions have occurred. Clinical features may be useful for predicting patients who are at risk of developing such complications, but they lack of sensitivity and specificity. Biomarkers have been therefore suggested as means to provide relevant prognostic information. The more commonly used biomarkers after cardiovascular ischemic events, including cardiac arrest, are creatin kinases and troponins. In addition, natriuretic peptides and C-reactive protein have gained great interest and now sufficient data has been collected such to justify their clinical applicability. Finally, several other novel biomarkers, to be used after resuscitation from cardiac arrest or more generally after a myocardial ischemic event, have been anticipated. Nevertheless, the "perfect" biomarker, able to provide diagnosis and prognosis with high sensitivity and specificity does not exit. A multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation is therefore suggested.

Topics: Adrenomedullin; Arginine Vasopressin; Biomarkers; C-Reactive Protein; Cardiopulmonary Resuscitation; Creatine Kinase; Endothelin-1; Heart Arrest; Heart Failure; Humans; Immunity, Innate; Myocardial Ischemia; Natriuretic Peptides; Serum Amyloid P-Component; Troponin

The myocardium represents a major source of several families of peptide hormones under normal physiological conditions and the plasma concentrations of many of these "cardiac peptides" (or related pro-peptide fragments) are substantially augmented in many cardiac disease states. In addition to well-characterised endocrine functions of several of the cardiac peptides, pleiotropic functions within the myocardium and the coronary vasculature represent a significant aspect of their actions in health and disease. Here, we focus specifically on the cardioprotective roles of four major peptide families in myocardial ischemia and reperfusion: adrenomedullin, kinins, natriuretic peptides and the urocortins. The patterns of early release of all these peptides are consistent with roles as autacoid cardioprotective mediators. Clinical and experimental research indicates the early release and upregulation of many of these peptides by acute ischemia and there is a convincing body of evidence showing that exogenously administered adrenomedullin, bradykinin, ANP, BNP, CNP and urocortins are all markedly protective against experimental myocardial ischemia-reperfusion injury through a conserved series of cytoprotective signal transduction pathways. Intriguingly, all the peptides examined so far have the potential to salvage against infarction when administered specifically during early reperfusion. Thus, the myocardial secretion of peptide hormones likely represents an early protective response to ischemia. Further work is required to explore the potential therapeutic manipulation of these peptides in acute coronary syndromes and their promise as biomarkers of acute myocardial ischemia.

Topics: Adrenomedullin; Bradykinin; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Natriuretic Peptides; Peptide Hormones; Signal Transduction

The authors determined the changes in adrenomedullin (AM) expression in the coronary circulation of patients with ischemic heart disease who underwent coronary stent implantation. Blood samples were drawn from the coronary sinus before, immediately after and four hours after coronary stent implantation, and plasma levels of AM were measured. AM levels in the coronary sinus blood were significantly increased four hours after stent implantation. On the other hand, in the femoral arterial blood, no significant changes in AM levels were observed. A significant positive correlation was found between AM level in the coronary sinus blood four hours after stent implantation and late loss index six months after the procedure. These results suggest that inflammation after coronary stent implantation induces AM expression, which might play an important role in restenosis after stenting.

Topics: Adrenomedullin; Angioplasty, Balloon, Coronary; Case-Control Studies; Coronary Angiography; Coronary Circulation; Coronary Restenosis; Coronary Stenosis; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Peptides; Prognosis; Stents; Time Factors; Vasodilator Agents

Topics: Adrenomedullin; Angioplasty, Balloon, Coronary; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardium; Peptides

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67 +/- 10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42 +/- 14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Adrenomedullin; Adult; Aged; Antihypertensive Agents; Blood Pressure; Epinephrine; Female; Gene Expression; Heart Rate; Heart Ventricles; Humans; Hypertension; Kidney; Lung; Male; Metabolic Clearance Rate; Middle Aged; Myocardial Ischemia; Myocardium; Norepinephrine; Peptide Biosynthesis; Peptides; Pheochromocytoma; Pulmonary Artery; Pulmonary Circulation; RNA, Messenger

Intermedin (IMD)(1-53) is a novel member of the calcitonin gene-related peptide superfamily and has potent cardioprotective effects against myocardial injury induced by ischemia-reperfusion (I/R). To explore the mechanism of the IMD(1-53) cardioprotective effect, we studied the anti-oxidant effects of IMD(1-53) on myocardial injury induced by I/R in vivo in rat and H(2)O(2) treatment in vitro in rat cardiomyocytes. Compared with sham treatment, I/R treatment induced severe lipid peroxidation injury in rat myocardium: plasma malondialdehyde (MDA) content and myocardial LDH activity was increased by 34% and 85% (all P<0.01); Mn-superoxide dismutase (Mn-SOD) and catalase (CAT) activity was reduced 80% and 86% (all P<0.01), respectively, and the protein levels of the NADPH oxidase complex subunits gp91(phox) and p47(phox) were markedly increased, by 86% (P<0.05) and 95% (P<0.01), respectively; IMD(1-53) treatment ameliorated lipid peroxidation injury: plasma MDA content and myocardial LDH activity was decreased by 30% (P<0.05) and 36% (P<0.01); Mn-SOD and CAT activity was elevated 1.0- and 4.3-fold (all P<0.01), respectively; and the protein levels of gp91(phox) and p47(phox) were reduced, by 28% and 36% (both P<0.05), respectively. Concurrently, IMD(1-53) treatment markedly promoted cell viability and inhibited apoptosis in cardiomyocytes as compared with H(2)O(2) treatment alone. Furthermore, IMD(1-53) increased the ratio of p-ERK to ERK by 66% (P<0.05) as compared with I/R alone, and the protective effect of IMD(1-53) on H(2)O(2)-induced apoptosis was abolished by preincubation with PD98059, a MEK inhibitor. IMD(1-53) may improve the oxidative stress injury induced by I/R via inhibiting the production of reactive oxygen species and enhancing ERK phosphorylation.

Topics: Adrenomedullin; Animals; Antioxidants; Caspase 3; Catalase; Cell Survival; Cells, Cultured; Cytoprotection; Enzyme Activation; Hydrogen Peroxide; L-Lactate Dehydrogenase; Male; Malondialdehyde; MAP Kinase Signaling System; Membrane Glycoproteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NADPH Oxidase 2; NADPH Oxidases; Neuropeptides; Oxidants; Oxidative Stress; Peptide Fragments; Protein Isoforms; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Female; Glycopeptides; Heart Failure; Humans; Hypertension; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptide Fragments; Protein Precursors; Stroke Volume

To investigate the effect and potential mechanism of intermedin (IMD) in acute cardiac ischemic injury and to provide a new approach for exploring mechanism of sudden cardiac death.. Seventy-two healthy male rats were randomly divided into 3 groups: control, ischemic and the IMD-treated group. The activity of lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) in heart blood were tested by enzyme chemistry method. The mRNA changes of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) in cardiac were measured by real-time PCR analysis. Myocardial cyclic adenosine monophosphate (cAMP) content was determined by enzyme linked immunosorbent assay (ELISA). Apoptosis related factors Bcl-2 and Bax were detected by immunohistochemistry.. Comparing with the control group, LDH and MDA activity of ischemic group in heart blood increased and SOD activity decreased. The concentration of cAMP increased in ventricular muscle, Bcl-2 and Bax proteins expression ratio level decreased. The intravenation of IMD decreased the level of increased activity of LDH and MDA, and lessened the level of decreased activity of SOD. The mRNA expression of CRLR and RAMPs obviously increased in ventricular muscle.. The protective effect of IMD against myocardial ischemic injury could be caused by decreasing the oxidative stress of ischemia and inhibiting the myocardial apoptosis.

Topics: Adrenomedullin; Animals; Apoptosis; Calcitonin Receptor-Like Protein; Cardiotonic Agents; Cyclic AMP; Disease Models, Animal; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocardial Ischemia; Myocardium; Neuropeptides; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor Activity-Modifying Proteins; RNA, Messenger; Superoxide Dismutase

Topics: Adrenomedullin; Aged; Exercise Test; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Protein Precursors; Proteins

In this work we aimed to observe (1) the changes in adrenomedullin (AM) and its receptor system - calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) - in myocardial ischemic injury and (2) the response of injuried myocardia to AM and the phosphorylation of Akt to illustrate the protective mechanism of AM in ischemic myocardia. Male SD rats were subcutaneously injected with isoproterenol (ISO) to induce myocardial ischemia. The mRNA levels of AM, CRLR, RAMP1, RAMP2 and RAMP3 were determined by RT-PCR. Protein levels of Akt, phosphor-Akt, CRLR, RAMP1, RAMP2 and RAMP3 were assayed by Western blot. Results showed that, compared with that of the controls, ISO-treated rats showed lower cardiac function and myocardial injury. The mRNA relative amount of AM, CRLR, RAMP1, RAMP2 and RAMP3 in the myocardia of ISO-treated rats was increased. The elevated mRNA levels of CRLR, RAMP1, RAMP2 and RAMP3 were positively correlated with AM content in injured myocardia. The protein levels of CRLR, RAMP1, RAMP2 and RAMP3 in injured myocardia were increased compared with that of control myocardia. AM-stimulated cAMP generation in myocardia was elevated in the ISO group, and was antagonized by AM(22-52) and CGRP(8-37). Western blot analyses revealed that AM significantly enhanced Akt phosphorylation in injured myocardia, which was blocked by pretreatment with AM(22-52) or CGRP(8-37). Ischemia-injured myocardia hyper-expressed AM and its receptors - CRLR, RAMP1, RAMP2 and RAMP3 - and the response of ischemic myocardia to AM was potentiated, and the level of Akt phosphorylation was also increased, which suggests that changes in cardiac AM/AM receptor might play an important role in the pathogenesis of myocardial ischemic injury.

Topics: Adrenomedullin; Animals; Blotting, Western; Calcitonin Receptor-Like Protein; Cardiotonic Agents; Cyclic AMP; Disease Models, Animal; Gene Expression Regulation; Heart; Intracellular Signaling Peptides and Proteins; Isoproterenol; Lipid Peroxides; Male; Membrane Proteins; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

1. The overall aim of this study was to determine if adrenomedullin (AM) protects against myocardial ischaemia (MI)-induced arrhythmias via nitric oxide (NO) and peroxynitrite. 2. In sham-operated rats, the effects of in vivo administration of a bolus dose of AM (1 nmol kg-1) was assessed on arterial blood pressure (BP), ex vivo leukocyte reactive oxygen species generation and nitrotyrosine deposition (a marker for peroxynitrite formation) in the coronary endothelium. 3. In pentobarbitone-anaesthetized rats subjected to ligation of the left main coronary artery for 30 min, the effects of a bolus dose of AM (1 nmol kg-1, i.v.; n=19) or saline (n=18) given 5 min pre-occlusion were assessed on the number and incidence of cardiac arrhythmias. In a further series of experiments, some animals received infusions of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA) (0.5 mg kg-1 min-1) or the peroxynitrite scavenger N-mercaptopropionyl-glycine (MPG) (20 mg kg-1 h-1) before AM. 4. AM treatment significantly reduced mean arterial blood pressure (MABP) and increased ex vivo chemiluminescence (CL) generation from leukocytes in sham-operated animals. AM also enhanced the staining for nitrotyrosine in the endothelium of coronary arteries. 5. AM significantly reduced the number of total ventricular ectopic beats that occurred during ischaemia (from 1185+/-101 to 520+/-74; P<0.05) and the incidences of ventricular fibrillation (from 61 to 26%; P<0.05). AM also induced a significant fall in MABP prior to occlusion. AM-induced cardioprotection was abrogated in animals treated with the NO synthase inhibitor LNNA and the peroxynitrite scavenger MPG. 6. This study has shown that AM exhibits an antiarrhythmic effect through a mechanism that may involve generation of NO and peroxynitrite.

Topics: Adrenomedullin; Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Glycine; Male; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Peroxynitrous Acid; Placebos; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds

Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide (CT/CGRP) family identified from human and other vertebrate tissues. Preprointermedin can generate a 47-amino acid mature peptide (IMD(1-47)) and a shorter 40-amino acid one (IMD(8-47)) by proteolytic cleavage. The present study was designed to determine the protective effect of IMD on cardiac ischemia/reperfusion (I/R) injury and its possible mechanism. Isolated rat hearts were perfused on a Langendorff apparatus and subjected to 45-min global ischemia and 30-min reperfusion. Cardiac function was measured. The release of myocardial protein and lactate dehydrogenase (LDH) and the formation of malondialdehyde (MDA) were assayed. Myocardial cAMP content was determined by radioimmunoassay (RIA). Cardiac I/R induced a marked inhibition of cardiac function and myocardial injury. Reperfusion with IMD significantly attenuated the I/R injury. Compared with I/R alone, perfusion with 10(-8)mol/L IMD(1-47) and IMD(8-47) induced a 36% and 33% increase in Delta left ventricular pressure (DeltaLVP), 30% and 28% in maximal rate of increase of LV pressure (+LVdP/dt max), and 34% and 31% in maximal rate of decrease of LV pressure (-LVdP/dt max), respectively (all P<0.01) but an approximately 58% and 51% decrease in LV diastolic pressure, respectively (P<0.01). In addition, perfusion with IMD markedly attenuated the leakage of LDH, total protein and myoglobin from myocardia compared with I/R alone. The contents of ventricular myocardia cAMP after reperfusion with 10(-8)mol/L IMD(1-47) and IMD(8-47) were 130% and 91% higher, respectively, than that with I/R alone (all P<0.01). However, formations of myocardial MDA were 52% and 50% lower than that with I/R alone (all P<0.01), respectively. Interestingly, the above IMD effects were similar to those of adrenomedullin (10(-8)mol/L). These results suggest that IMD, like adrenomedullin, exerts cardio-protective effects against myocardial I/R injury.

Topics: Adrenomedullin; Animals; Blotting, Western; Cyclic AMP; Dose-Response Relationship, Drug; Heart; Humans; Kinetics; L-Lactate Dehydrogenase; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neuropeptides; Peptides; Perfusion; Pressure; Protein Binding; Radioimmunoassay; Rats; Reperfusion Injury; Time Factors

We investigated by immunocytochemistry (ICC) the acute effects of ischemia on the distribution in the rat heart of adrenomedullin (AM), a potent hypotensive peptide which is expressed in the cardiovascular system, where it is known to play a major regulatory and protective role. Hearts, collected from adult male Sprague-Dawley rats, were perfused with the Langendorff technique, and "global" ischemia was obtained by stopping perfusion for 20 min. Hearts were frozen, and ICC was performed using a specific anti-rat AM1-50 antibody and secondary peroxidase-conjugated antibodies. ICC demonstrated AM-immunoreactivity (IR) in cardiomyocytes and especially in the wall of coronary vessels. Quantitative densitometry showed that acute ischemia significantly decreased AM-IR in coronary arterioles, thereby suggesting that it markedly stimulates AM release. The conclusion is drawn that acute ischemia and ensuing hypoxia activate in the rat heart the release of AM, which by its coronarodilatory action may enhance heart blood flow.

Topics: Adrenomedullin; Animals; Immunochemistry; In Vitro Techniques; Male; Myocardial Ischemia; Myocardium; Peptides; Rats; Rats, Sprague-Dawley

Adrenomedullin is a potent vasodilator peptide originally isolated from a pheochromocytoma. Recently, a novel adrenomedullin receptor has been identified as a complex of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 2 (RAMP2). To explore the pathophysiological roles of adrenomedullin and its receptor component RAMP2 in ischemic cardiovascular diseases, we studied the changes of adrenomedullin and RAMP2 mRNA in myocardium and aorta in rats with isoproterenol (ISO)-induced myocardial impairment. In ISO-treated rats, heart became enlarged markedly, the ratio of heart to body weight was increased by 54% (P<0.01), and myocardial malondialdehyde content and plasma lactate dehydrogenase activity was elevated by 43% (P<0.01) and 138% (P<0.01), respectively. Immunoreactive adrenomedullin (ADM) in plasma, myocardium and aorta was augmented by 116.7% (P<0.01), 50.8% (P<0.01) and 12.5% (P>0.05), respectively. ADM mRNA in myocardium and aorta was increased by 96.8% (P<0.01) and 38.5% (P<0.01), respectively. RAMP2 mRNA in myocardium and aorta was increased by 19.6% (P<0.05) and 15.8% (P<0.01), respectively. These results suggest that the increase of ADM level and the up-regulation of ADM and RAMP2 gene in myocardium and aorta may be significant in the pathogenesis of ischemic myocardiopathy.

Topics: Adrenomedullin; Animals; Aorta; Disease Models, Animal; Heart; Intracellular Signaling Peptides and Proteins; Isoproterenol; Male; Membrane Proteins; Myocardial Ischemia; Myocardium; Peptides; Rats; Rats, Wistar; Receptor Activity-Modifying Proteins; RNA, Messenger

Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8-37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.

Topics: Adrenomedullin; Animals; Apoptosis; Arrhythmias, Cardiac; Blotting, Western; Cyclic AMP; Cyclic GMP; Gene Transfer Techniques; Hemodynamics; Humans; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NADPH Oxidases; Peptides; Proteins; Rats; Rats, Wistar; Superoxides

Experimental studies have demonstrated that adrenomedullin (AM) has a positive inotropic action and exerts inhibitory effects against ventricular remodelling as an autocrine and paracrine factor. However, there is no clinical evidence for AM acting as a local regulator in the human heart. We measured the levels of various molecular forms of AM, i.e. an active form of mature AM (AM-m), an intermediate inactive form of glycine-extended AM (AM-Gly) and total AM (AM-T=AM-m+AM-Gly), in plasma and pericardial fluid using our newly developed immunoradiometric assay in consecutive 67 patients undergoing coronary artery bypass graft surgery. Pericardial fluid and plasma cAMP, atrial natriuretic peptide and brain natriuretic peptide levels were also measured. The relationships between pericardial fluid AM levels and ventricular functions and other hormone levels were analysed. The level of each molecular form of AM in pericardial fluid was closely correlated with that of the other molecular forms of AM in the fluid. However, levels were not correlated with those in plasma. AM-T levels were slightly higher in pericardial fluid than in plasma (+72%; P<0.05), whereas AM-m levels and AM-m/AM-T ratios were markedly higher in pericardial fluid than in plasma (AM-m, +994%; AM-m/AM-T ratio, +443%; both P<0.01). AM-m, AM-Gly and AM-T levels in pericardial fluid were correlated with indices of left ventricular function, and with atrial natriuretic peptide and brain natriuretic peptide levels. Interestingly, AM and cAMP levels were positively correlated in plasma, but negatively correlated in pericardial fluid. In addition, AM-m, AM-Gly and AM-T levels in pericardial fluid were higher in patients with acute coronary syndrome than in those with stable ischaemic heart disease (AM-m, +80%; AM-Gly, +96%; AM-T, +83%; all P<0.01). These results suggest that AM in pericardial fluid reflects cardiac synthesis, and that enhanced cardiac secretion of AM is associated with left ventricular dysfunction, ventricular overload and myocardial ischaemia. Considering that AM has positive inotropic, coronary vasodilatory and anti-remodelling actions, increased cardiac AM may play a compensatory role in the ischaemic and failing myocardium.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Coronary Artery Bypass; Coronary Disease; Cyclic AMP; Female; Humans; Immunoradiometric Assay; Male; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Peptides; Pericardial Effusion; Ventricular Function, Left

Increased plasma adrenomedullin (ADM) levels have been reported in congestive heart failure (HF). The present study was designed to investigate myocardial regulation of the different components of the ADM signaling system (ADM, ADM receptor, and receptor-activity-modifying protein-2, RAMP-2) during ischemic HF in rats and to identify the cells in the myocardium displaying ADM-like immunoreactivity (ADM-ir). Furthermore, the effects of endothelin (ET) receptor antagonism on expression of the myocardial ADM system during HF were investigated.. Northern blot analysis revealed increased ADM mRNA expression in the nonischemic left ventricle, with maximal levels 28 days after induction of myocardial infarction (1.5-fold, P<0.05) compared with the sham group. Parallel elevations of myocardial ADM receptor and RAMP-2 mRNA levels were also observed (2.3- and 1.5-fold increase, respectively; P<0.05). In addition, high levels of ADM mRNA were seen in the ischemic region. Immunohistochemical analysis revealed a substantial increase of ADM-ir in microvascular endothelium and perivascular interstitial cells of myocardial tissue contiguous to the ischemic region. In addition, radioligand binding studies demonstrated a 1.6-fold increase of specific ADM binding sites in the failing left ventricle (P<0.05). Intervention with the mixed ET(A)/ET(B) receptor antagonist bosentan (100 mg. kg(-1). day(-1) PO) for 15 days prevented the increase of RAMP-2 mRNA.. The study demonstrates a concerted induction of several components of the myocardial ADM signaling system during postinfarction failure and that the vessels are the main source of myocardial ADM. Our observations indicate a role for ADM as an autocrine/paracrine factor during ventricular remodeling after myocardial infarction.

Topics: Adrenomedullin; Animals; Cardiotonic Agents; Gene Expression Regulation; Heart Failure; Hemodynamics; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardium; Peptides; Radioligand Assay; Rats; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Systole; Time Factors; Transcription, Genetic; Ventricular Function, Left

Human adrenomedullin (AM) precursor is converted to glycine-extended AM (AM-Gly), an inactive intermediate form of AM. Subsequently, AM-Gly is converted to active mature AM (AM-m) by enzymatic amidation. A recent study showed that two molecular forms of adrenomedullin (AM) are present in human plasma. In this study we investigated the production and clearance sites of two molecular forms of adrenomedullin in humans. We measured plasma levels of AM-m and AM-Total (T) (AM-m+AM-Gly) by immunoradiometric assay and calculated plasma levels of AM-Gly in blood samples taken from various sites during cardiac catheterization in patients with ischemic heart disease. Plasma AM-m levels were significantly lower in left-sided sites after passing through pulmonary circulation than in right-sided sites, whereas there were no significant differences in AM-Gly levels between left-sided sites and right-sided sites. These results suggest that AM-m produced in many organs is released into veins and that the main clearance sites of AM-m are the lungs. Considering that AM preferentially dilates pulmonary vessels rather than systemic vessels, a possible role of this peptide is suggested in the regulation of pulmonary vascular tonus.

Topics: Adrenomedullin; Aged; Cardiac Catheterization; Female; Humans; Immunoradiometric Assay; Male; Middle Aged; Myocardial Ischemia; Peptides

To investigate if adrenomedullin (Adm) is concerned with cardiac ischemia-reperfusion (I/R) process and to study its effects on I/R injury.. Plasma Adm dynamic levels were tested in 17 patients with acute myocardial infarction (AMI), who had got successful blood reperfusion through intravenous thrombolytic therapy. The indices of I/R injury were measured in I/R models of isolated perfused rat heart when Adm (10(-7) mol/L) was given in reperfusion period.. Plasma Adm concentrations before thrombolytic therapy in AMI patients were significantly higher than those of control group (3.8 pmol/L +/- 0.8 pmol/L vs 1.9 pmol/L +/- 0.8 pmol/L P < 0.01), and rose further after successful thrombolytic therapy, which resulted in efficient myocardial reperfusion. The peak level of plasma Adm, which appeared 4 hours after thrombolytic therapy, was 42.9% higher than that before therapy. The levels began to decrease and dropped to the levels before therapy at 12 and 24 hours after thrombolysis, respectively. In isolated perfused rat heart models, when Adm (10(-7) mol/L) was added in perfusion fluid for 15 minutes reperfusion after 45 minutes ischemic period, +/-LVdp/dt max of the heart increased 76.9% and 67.9%, and the average volume of coronary efflux increased 48.8%, respectively, compared with that of control group of ischemia-reperfusion. The amount of total protein, myoglobin and activities of LDH in effluent samples of Adm group were 34.3%, 63.6% and 29.2% lower than those of control group, respectively.. Plasma Adm concentrations in AMI patients increase significantly during myocardiac reperfusion period after thrombolytic therapy. To some extent, Adm may have myocardial protective effects during ischemia-reperfusion period.

Topics: Adrenomedullin; Adult; Aged; Animals; Cardiotonic Agents; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Peptides; Rats; Rats, Wistar

Human adrenomedullin (ADM), a peptide comprising 52 amino acids, is a circulating hormone with vasodilator properties. We have evaluated its release by the heart following ischaemic myocardial damage, as indicated by elevated levels of the cardiospecific protein troponin-T (Tn-T) during cardiopulmonary bypass. ADM (pg/ml) and Tn-T (ng/ml) were measured in coronary sinus blood before and after aortic cross-clamp and in venous blood 6 h after surgery in 22 coronary-bypass patients. Based on the pre- and post-clamp Tn-T levels in the coronary sinus, the patients were divided into group I (no change; n=10) and group II (two times increase; n=12). Baseline ADM (362.7+/-106.2 and 303+/-58.7 pg/ml in groups I and II respectively; means+/-S.D.) and Tn-T (0.66+/-0.14 and 0.57+/-0.13 ng/ml respectively) levels were similar in both groups. In group I, the post-clamp ADM (317.6+/-80.8 pg/ml) and Tn-T (0.68+/-0.15 ng/ml) levels did not change significantly. In group II, the post-clamp ADM levels rose significantly above the baseline, mimicking the change in Tn-T (ADM, 541.4+/-89.4 pg/ml; Tn-T, 1.37+/-0.31 ng/ml; P=0.009). After 6 h, the systemic Tn-T levels were similar in both groups (2. 09+/-0.44 and 1.95+/-0.52 ng/ml in groups I and II respectively). We suggest that: (1) minor degrees of myocardial ischaemic damage result in release of ADM by the heart, and (2) ADM may play a protective role in the myocardium during an ischaemic insult. This suggests a possible therapeutic role for ADM in the management of intra-operative myocardial ischaemia.

Topics: Adrenomedullin; Cardiopulmonary Bypass; Coronary Disease; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardium; Peptides; Postoperative Period; Troponin T

In the biosynthesis of adrenomedullin (AM), glycine-extended AM, an intermediate form (iAM) processed from proAM is converted to AM[1-52]-NH2, the bioactive mature form of AM (mAM), by enzymatic amidation. We earlier showed that both molecular forms of AM circulate in human plasma. In the present study, to investigate the secretion and clearance sites of mAM and iAM in humans, we examined the plasma mAM and iAM concentrations in the femoral artery and vein (FA and FV), the aortic root and coronary sinus (AO and CS), and the pulmonary artery and capillary (PA and PC) of patients with ischemic heart disease. Plasma mAM in FV was significantly (p<0.001) higher than in FA. There also was a significant (p<0.001) step-up in the plasma mAM of the CS as compared to the AO. In contrast, plasma mAM was significantly (p<0.001) reduced in the PC as compared to the PA. However, such differences were not observed in plasma iAM levels. These findings suggest that in humans the vasculature of the lower extremities and the heart produce and secrete mAM and that the lung is a clearance site of circulating mAM.

Topics: Adrenomedullin; Adult; Aged; Aorta; Capillaries; Female; Femoral Artery; Femoral Vein; Humans; Lung; Male; Middle Aged; Myocardial Ischemia; Myocardium; Peptides; Protein Precursors; Protein Processing, Post-Translational; Pulmonary Artery

Topics: Adrenomedullin; Aorta; Heart Failure; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Peptides; Pulmonary Artery; Reference Values; Renal Insufficiency; Renal Veins; Time Factors

Newly discovered circulating peptides, N-terminal pro-brain natriuretic peptide (N-BNP) and adrenomedullin (ADM), were examined for prediction of cardiac function and prognosis and compared with previously reported markers in 121 patients with myocardial infarction.. The association between radionuclide left ventricular ejection fraction (LVEF) and N-BNP at 2 to 4 days (r=-.63, P<.0001) and 3 to 5 months (r=-.58, P<.0001) after infarction was comparable to that for C-terminal BNP and far stronger than for ADM (r=-.26, P<.01), N-terminal atrial natriuretic peptide (N-ANP), C-terminal ANP, cGMP, or plasma catecholamine concentrations. For prediction of death over 24 months of follow-up, an early postinfarction N-BNP level > or = 160 pmol/L had sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 72%, 39%, and 97%, respectively, and was superior to any other neurohormone measured and to LVEF. Only 1 of 21 deaths occurred in a patient with an N-BNP level below the group median (Kaplan-Meier survival analysis, P<.00001). For prediction of heart failure (left ventricular failure), plasma N-BNP > or = 145 pmol/L had sensitivity (85%) and negative predictive value (91%) comparable to the other cardiac peptides and was superior to ADM, plasma catecholamines, and LVEF. By multivariate analysis, N-BNP but not ADM provided predictive information for death and left ventricular failure independent of patient age, sex, LVEF, levels of other hormones, and previous history of heart failure, myocardial infarction, hypertension, or diabetes.. Plasma N-BNP measured 2 to 4 days after myocardial infarction independently predicted left ventricular function and 2-year survival. Stratification of patients into low- and high-risk groups can be facilitated by plasma N-BNP or BNP measurements, and one of these could reasonably be included in the routine clinical workup of patients after myocardial infarction.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Cyclic GMP; Epinephrine; Female; Heart; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Norepinephrine; Peptides; Predictive Value of Tests; Prognosis; Radionuclide Imaging; Regression Analysis; Sensitivity and Specificity; Survival Rate; Ventricular Function, Left