Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Co-localization of adrenomedullin (AM) and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in peripheral tissues, including the heart, kidney, and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, we previously reported that AM gene expression and / or immunoreactivity are increased in the ventricles of cardiac hypertrophy and heart failure. Recently, we also found that not only levels of AM peptide and AM gene expression, but also mRNA levels of CRLR, RAMP2 and RAMP3 are increased in cardiac hypertrophy and failing heart. Cardiac myocytes and fibroblast produce and secrete two molecular forms of AM and express CRLR, RAMP2 and RAMP3, and AM is known to have inhibitory effect of collagen synthesis and antiproliferative effect in cardiac fibroblasts. Stimulation by IL-1beta significantly increased gene expression of AM and its receptor components in cardiac fibroblasts. Preincubated IL-1beta elevated the intracellular cAMP response to exogenous administered AM. AM antisense oligodeoxynucleotide treatment significantly lowered AM levels in cultured medium. IL-1beta significantly increased (3)H-proline incorporation and AM antisense oligodeoxynucleotide treatment further increased (3)H-proline incorporation. Collectively, these results support a protective role for increased AM in the cardiac hypertrophy and heart failure. Then, we tested the effects of acute administration of AM in experimental and human heart failure, because AM has hemodynamic effects including vasodilation, increases in cardiac contractility, cardiac output, diuresis, and natriuresis. We observed profound and sustained cardiovascular, hormonal and renal effects. These effects may incorporate many of the therapeutic goals of heart failure management.
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PMID:Cardiac adrenomedullin: its role in cardiac hypertrophy and heart failure. 1597 87

Plasma levels of B-type natriuretic peptide (BNP) and its N-terminal propeptide (NT-BNP) are elevated in renal impairment and provide a robust prognostic index. The effect of peritoneal dialysis on plasma NT-BNP, however, is unknown. Furthermore, no information exists regarding levels of the N-terminal propeptide for C-type natriuretic peptide (NT-CNP) in renal failure and the effects of peritoneal dialysis. Accordingly, we documented venous levels of these peptides, and adrenomedullin, across peritoneal dialysis. We measured venous BNP, NT-BNP, NT-CNP, adrenomedullin, blood urea nitrogen (BUN) and creatinine before, during and after completion of overnight peritoneal dialysis in 11 patients, and identical sampling was carried out in eight patients (controls) but between peritoneal dialysis treatments. Peptide levels were measured using well-validated, published methods. Baseline levels of NT-CNP (212, 150-303 pmol/l, median and 25th and 75th percentiles) were much higher than recorded previously in healthy volunteers or in heart failure, and correlated with plasma creatinine (rs=0.53, P<0.05). Peritoneal dialysis had no effect on plasma NT-CNP, nor on NT-BNP, BNP or adrenomedullin (all elevated above normal), whereas both BUN and creatinine levels, as expected, declined (P<0.001). We conclude that plasma levels of NT-CNP are grossly elevated in chronic renal failure and correlated with plasma creatinine, but are not altered by peritoneal dialysis. Likewise, BNP, NT-BNP and adrenomedullin are elevated but are not altered by peritoneal dialysis. This information is needed if levels of these hormones are to be used as prognostic indicators or as a guide to the management of patients with chronic renal failure.
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PMID:Natriuretic peptide and adrenomedullin levels in chronic renal failure and effects of peritoneal dialysis. 1637 36

Plasma and myocardial levels of proinflammatory cytokines such as tumor necrosis factor(TNF)-alpha, interleukin 1beta, and interleukin 6 are elevated in patients with heart failure. Not only viral infection but also cardiac overload, ischemia, and neuro-humoral factors stimulate systemic and myocardial production of these cytokines. Administration of proinflammatory cytokines directly depresses myocardial contractility in vitro and in vivo. In addition, TNF and interleukin induce myocardial apoptosis and promote cardiac hypertrophy and fibrosis, suggesting that these cytokines are involved in the progression of cardiac remodeling. Vasoactive peptides such as endothelin and adrenomedullin also have cytokine-like functions in the heart, acting as autocrine and paracrine factors. Thus, proinflammatory cytokines and these peptides play important roles in the pathogenesis and pathophysiology of heart failure.
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PMID:[Pathophysiological role of cytokines in heart failure]. 1668 63

Intermedin is a novel member of the calcitonin/calcitonin gene-related peptide (CGRP) family peptide, which has vasodilatory and hypotensive actions identical to those of adrenomedullin and CGRP. Cleavage sites located between 2 basic amino acids at Arg93-Arg94 result in the production of prepro-intermedin95-147, namely intermedin1-53. The bioactive action of intermedin1-53 and its physiological significance are unclear. In this work, we aimed to explore the effects of intermedin1-53 on acute myocardial injury induced by isoproterenol. Myocardial ischemia injury in rats was induced by subcutaneous injection of a high dose of isoproterenol, and the therapeutic effect of intermedin1-53 was observed. Plasma lactate dehydrogenase activity, myocardial and plasma malondialdehyde content were higher in the isoproterenol group than that in controls. Isoproterenol-treated rats showed lower maximal rate of increase and decrease of left-ventricle pressure development (+/-left-ventricle dp/dtmax) and higher left-ventricle end-diastolic pressure (all P<0.01), which suggested severe heart failure and myocardial injury. Semi-quantitative RT-PCR analysis showed that the gene expression of calcitonin receptor-like receptor and receptor-activity-modifying protein (RAMP)1, RAMP2 and RAMP3 in ventricular myocardia were up-regulated by 79% (P<0.01), 48% (P<0.01), 31% (P<0.05) and 130% (P<0.01), respectively, compared with controls. In myocardial sarcolemmal membranes, the maximum binding capacity for [125I]-intermedin1-53 was increased by 118% (P<0.01) in the isoproterenol group compared with controls. Rats treated with low dosage intermedin1-53 (5 nmol/kg/day, 2 days) showed 21% (P<0.05) higher myocardial cAMP content, 18% and 31% higher+left-ventricle dp/dtmax and -left-ventricle dp/dtmax respectively, 288% lower left-ventricle end-diastolic pressure (all P<0.01), and attenuated myocardial lactate dehydrogenase leakage and malondialdehyde formation (all P<0.01). Treatment with high dosage intermedin1-53 (20 nmol/kg/day, 2 days) gave better results than that with low dosage intermedin1-53. These results suggest that the intermedin receptor system was up-regulated in isoproterenol-induced myocardial ischemic injury and intermedin1-53 might play a pivotal cardioprotective role in such injury.
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PMID:Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats. 1698 13

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.
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PMID:Effect of adrenergic blockade on plasma adrenomedullin concentration during static handgrip in patients with heart failure. 1704 97

Recent clinical studies demonstrated beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with heart failure and other cardiovascular diseases. However, the underlying molecular mechanisms are poorly understood, and the genes that mediate direct effects of aldosterone in the cardiovascular system are yet to be identified. The goal of this study was to identify genes that are directly regulated by aldosterone in cardiomyocytes and thus potentially play a role in initiating MR-mediated effects in the heart. We generated clonal cell lines of cardiomyocytes (H9C2 cells) stably expressing the MR. Using these cell lines and Affymetrix microarrays, we determined the effects of physiological concentrations of aldosterone on the gene expression profile. In two independent microarrays we identified 48 genes that were induced more than 1.5-fold (27 known genes and 21 expressed sequence tags) and five (three known genes and two expressed sequence tags) that were suppressed by a 2-h aldosterone treatment. We focused on eight genes that have a potential function in cardiovascular regulation and verified their aldosterone regulation using quantitative RT-PCR. These include genes related to extracellular matrix regulation (tenascin-X, ADAMTS1, PAI-1, UPAR, and hyaluronic acid synthase-2), signaling, and regulation of vascular tone (RGS2, adrenomedullin) and inflammation (orosomucoid). Protein synthesis inhibitors did not prevent aldosterone induction of these genes. We conclude that in cardiomyocytes aldosterone rapidly and directly regulates the expression of several genes that are involved in cardiac remodeling and regulation of blood pressure and thus might be mediators of the physiological and pathophysiological effects of aldosterone on the cardiovascular system.
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PMID:Early aldosterone-regulated genes in cardiomyocytes: clues to cardiac remodeling? 1736

In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water-soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner.
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PMID:[Effects of colforsin daropate hydrochloride on myocardium, smooth muscle and renal function]. 1771 81

Both inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the cardiac protective peptide adrenomedullin (AM) are increased in cardiac tissues and plasma in patients with myocardial infarction (MI) and chronic heart failure. Recently they have been increasingly recognized as important factors in the pathophysiology of MI and resultant congestive heart failure. Compared with sham-operated spontaneously hypertensive rats (SHR), we investigated myocardial immunoreactivity of TNF-alpha and AM and also their mutual relations in vivo in SHR+MI. Residual myocardial depression after MI was studied also in isolated perfused hearts. In chronic experiments, 24 and 48 h after permanent ligation of the descending anterior branch of the left coronary artery, we examined hemodynamics, plasma and myocardial peptide levels. Left ventricular function was assessed in isolated perfused hearts subjected to "global ischemia and reperfusion" and after induction of "calcium paradox". Circulating and myocardial TNF-alpha concentrations increased early after MI in SHR. Studies with global ischemia and calcium paradox in isolated heart showed early myocardial depression and calcium-dependent gradual increase of left-ventricular end-diastolic pressure. In the SHR+MI myocardial AM concentrations were increased 9- and 49-fold after respective 24 h and culminated 48 h following MI. Circulating and myocardial AM was increased in SHR+MI in association with TNFalpha-induced myocardial depression. The both studied cardiac parameters displayed the beneficial effect of the enhanced myocardial AM concentration.
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PMID:Enhanced early after-myocardial infarction concentration of TNF-alpha subsequently increased circulating and myocardial adrenomedullin in spontaneously hypertensive rats. 1843 78

Angiotensin II (Ang II) plays a major role in the progression of myocardial hypertrophy to heart failure. Inhibiting the angiotensin converting enzyme (ACE) or blockade of the corresponding Ang II receptors is used extensively in clinical practice, but there is scope for refinement of this mode of therapy. This review summarizes the current understanding of the direct effects of Ang II on cardiomyocytes and then focus particularly on interaction of components of the renin-angiotensin system with other hormones and cytokines. New findings described in approximately 400 papers identified in the PubMed database and published during the 2.5 years are discussed in the context of previous relevant literature. The cardiac action of Ang II is influenced by the activity of different isoforms of ACE leading to different amounts of Ang II by comparison with other angiotensinogen-derived peptides. The effect of Ang II is mediated by at least two different AT receptors that are differentially expressed in cardiomyocytes from neonatal, adult and failing hearts. The intracellular effects of Ang II are influenced by nitric oxide (NO)/cGMP-dependent cross talk and are mediated by the release of autocrine factors, such as transforming growth factor (TGF)-beta1 and interleukin (IL)-6. Besides interactions with cytokines, Ang II is involved in systemic networks including aldosterone, parathyroid hormone and adrenomedullin, which have their own effects on cardiomyocytes that modify, amplify or antagonize the primary effect of Ang II. Finally, hyperinsulemia and hyperglycaemia influence Ang II-dependent processes in diabetes and its cardiac sequelae.
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PMID:Angiotensin II: a hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks. 1861 89

Adrenomedullin 2/intermedin (AM2/IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. To investigate the pathophysiological role of AM2/IMD in heart failure, we examined the expression of AM2/IMD, adrenomedullin (AM) and receptor complex components (calcitonin receptor-like receptor, three types of receptor activity-modifying proteins) by quantitative RT-PCR and immunohistochemistry in the hearts and kidneys of rats with congestive heart failure (CHF). Significantly increased levels of AM2/IMD mRNA were found in the atrium, right ventricle, non-infarcted part of the left ventricle and the infarcted part of the left ventricle of CHF rats, compared with sham operated rats (about 2.8-fold, 1.7-fold, 1.7-fold and 2.5-fold, respectively). Expression levels of mRNA encoding AM and the receptor complex components were also increased in the hearts of CHF rats. In a separate experiment, AM2/IMD mRNA levels in the heart did not differ between Wistar-Kyoto and spontaneously hypertensive rats. In both sham operated and CHF rats, the myocardium was diffusely immunostained with AM2/IMD. The fibrotic infarcted layer was not immunostained with AM2/IMD but was surrounded by positively immunostained myocardial layers. These findings suggest that the expression of AM2/IMD is enhanced in the failing heart, and AM2/IMD has a certain pathophysiological role in heart failure.
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PMID:Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure. 1869 36


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