Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adrenomedullin (AM) is a novel vasorelaxing peptide which was originally isolated from the extracts of human pheochromocytoma. It is produced by a number of organs among which the adrenal gland exhibits by far the highest concentrations. The peptide circulates in blood and its plasma levels have been reported to be increased in several diseases such as renal failure and sepsis. In the present study plasma concentrations of AM were measured in various forms of severe illness and compared to clinical and biochemical parameters in order to gain an insight into the factors controlling the plasma levels of this peptide. The highest concentrations of AM were found in patients with sepsis (344.4 +/- 60.4 pg/ml, n = 16) who exhibited up to 12-fold higher levels than a group of healthy subjects (74.1 +/- 4.1 pg/ml, n = 20). Markedly elevated levels were also measured in hemorrhagic (250.1 +/- 37.9 pg/ml, n = 9) and cardiogenic (216.2 +/- 29.4 pg/ml, n = 7) shock as well as in patients with cancer of the gastrointestinal tract (155.6 +/- 32.5 pg/ml, n = 11) or the lungs (146.5 +/- 19.1 pg/ml, n = 22). Plasma AM levels were positively correlated with serum creatinine concentrations in shock (r = 0.06, p < 0.001) and with C-reactive protein levels in patients with cancer (r = 0.64, p < 0.001) or sepsis (r = 0.63, p < 0.01). In order to examine the potential role of the adrenal gland as a site of AM release, hypoglycemia was induced in a group of healthy volunteers by graded infusion of insulin. Despite a more than 20-fold increase in plasma adrenalin indicating maximal stimulation of the adrenal medulla, no significant alterations of the plasma AM levels were observed. The study demonstrates that not only sepsis but also various forms of cancer and shock are associated with high levels of circulating AM. The correlation with C-reactive protein levels suggests a role of cytokines in mediating the elevations in plasma AM observed in sepsis and cancer. Reduced clearance of the peptide by the kidneys may be one of the mechanisms involved in the accumulation of AM in shock. The adrenal gland appears not to be a major source for circulating AM.
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PMID:High levels of circulating adrenomedullin in severe illness: correlation with C-reactive protein and evidence against the adrenal medulla as site of origin. 922 12

A large number of studies have been and are being carried out to examine the role of nitric oxide in the hyperdynamic and hypodynamic stages of sepsis. It remains unknown, however, whether adrenomedullin (ADM), a novel potent vasodilatory peptide, is up-regulated during hyperdynamic sepsis and, if so, whether its production is sustained during hypodynamic sepsis. To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP), followed by administration of 3 mL/100 g body weight normal saline to these and sham-operated animals. Blood samples were taken at 1, 1.5, 2, 5, and 10 h (2-10 h post-CLP represents the hyperdynamic stage of sepsis) or at 20 and 30 h after CLP (i.e., the hypodynamic stage). Plasma levels of ADM were measured by radioimmunoassay. Adrenomedullin gene expression in various tissues was examined at 2, 10, or 20 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that plasma levels of ADM did not increase at 1 and 1.5 h after CLP but increased significantly at 2 h after the onset of sepsis. Moreover, circulating ADM increased progressively at 5-20 h and remained elevated at 30 h after CLP. The increased levels of plasma ADM during sepsis were correlated with up-regulation of ADM mRNA in the small intestine, left ventricle, and thoracic aorta. In contrast, ADM gene expression in renal and hepatic tissues was not significantly altered following the onset of sepsis. The association between the up-regulated ADM and the occurrence of hyperdynamic circulation during the early stage of sepsis (both occur at 2 h after CLP) may indicate a possible cause and effect relationship between the two events. Since we have previously shown that ADM-induced vascular relaxation decreased at 20 h after CLP, it appears that the down-regulation of ADM receptors may be responsible for the transition from the hyperdynamic stage to the hypodynamic stage of sepsis.
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PMID:Up-regulation of a novel potent vasodilatory peptide adrenomedullin during polymicrobial sepsis. 984 Jun 56

Adrenomedullin (ADM) is a recently discovered peptide with potent vasorelaxing and natriuretic properties originally isolated from human pheochromocytoma. Adrenomedullin has been reported to be present in normal adrenal medulla, heart, lung and kidney as well as in plasma and urine. ADM shares some structural homology with calcitonin gene related peptide (CGRP). ADM acts on target cells through its unique receptors and CGRP1 receptors. In both cases cyclic AMP seems to be the main second messenger. ADM may function as a circulating hormone and as an autocrine/paracrine mediator involved in the regulation of cardiovascular system and renal function. Plasma concentration of ADM is elevated in patients with congestive heart failure, arterial hypertension, pulmonary hypertension, renal failure and sepsis suggesting its role in pathophysiology of these disorders. Recently another product od adrenomedullin gene, proadrenomedullin N-terminal 20-peptide (PAMP) has been described. This peptide has also vasodilating activity resulting from its inhibitory action on norepinephrine release from sympathetic endings and adrenal medulla.
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PMID:[Adrenomedullin]. 1035 50

Adrenomedullin (ADM) is a potent hypotensive peptide, which is produced during sepsis and ischemia. We demonstrate here that hypoxia induced a time-dependent increase of both ADM mRNA and protein expressions in cultured astrocytes and endothelial cells from rat brain microvessels. Gene reporter analyses showed a 2-fold increase in ADM gene transcription which was suppressed when the ADM promoter was deleted of its hypoxia responsive element. Hypoxia increased 7-fold the stability of pre-formed ADM mRNAs. Rat brain microvessels expressed mRNAs coding for the different putative ADM receptors but they did not respond to exogenous ADM and calcitonin gene-related peptide by the formation of cAMP. In contrast, ADM and calcitonin gene-related peptide increased the formation of cAMP in astrocytes and their actions were potentiated about 2-fold after hypoxia. Messenger RNA species coding for three putative ADM receptors (the L1 orphan receptor, RDC-1, and calcitonin receptor-like receptor) and accessory proteins (receptor-activity modifying proteins) were present in astrocytes. Hypoxia selectively up-regulated expression of RDC-1 receptor mRNAs. The results indicate that ADM and RDC-1 are hypoxia-sensitive genes and that RDC-1 receptors may mediate some actions of ADM in hypoxic astrocytes.
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PMID:Coordinated Up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier. 1098 Feb

Adrenomedullin (AM), a potent vasodilatory peptide, has recently been reported to be involved in the altered cardiovascular responses under various pathophysiological conditions. Although the increase in plasma AM levels is associated with upregulation of AM gene expression in various tissues, it remains unknown whether the gut is an important source of AM release under such conditions. To determine this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation. Systemic and portal blood samples were collected simultaneously at 10 and 20 h after CLP or sham operation. A portion of the jejunum was also harvested. Plasma and tissue levels of AM were then determined by RIA. The localization of AM in the intestinal tissue was examined using immunohistochemistry. In an additional group of normal rats, synthetic rat AM (8.5 microg/kg body wt) was infused for 15 min at a constant rate via the portal vein (which produces a similar level of AM as observed during sepsis). Cardiac output, stroke volume, total peripheral resistance, and microvascular blood flow in various organs were determined before and 30 min after AM administration. The results indicate that AM levels in portal blood were significantly higher than in systemic blood at 10 and 20 h after CLP. Intestinal AM was also markedly elevated. Immunohistochemical visualization shows that AM immunostainings were localized in the mucosa, submucosa, and intestinal nerve fibers, and they were increased at 10-20 h post-CLP. Because AM-immunopositive nerve fibers increase in the gut during sepsis, a nerve pathway may be involved in the regulation of vascular reactivity by this peptide. Moreover, intraportal administration of AM increased cardiac output, stroke volume, and microvascular blood flow in the liver, kidney, small intestine, and spleen. In contrast, total peripheral resistance was significantly reduced. Thus the gut plays an important role in increasing the levels of circulating AM during the progression of sepsis. Gut-derived AM appears to be a major factor in initiating the hyperdynamic response after the onset of sepsis.
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PMID:The small intestine is an important source of adrenomedullin release during polymicrobial sepsis. 1144 71

Sepsis and its complications are leading causes of morbidity and mortality. A better understanding of the mechanisms responsible for the shift from the early, hyperdynamic phase of sepsis to the late hypodynamic phase could lead to novel therapies that might improve the outcome of the septic patient. Adrenomedullin is a vasodilatory peptide which shows sustained elevation starting early in sepsis and is important in initiating the hyperdynamic response. As sepsis progresses, however, the vascular response to adrenomedullin is blunted and this decreased sensitivity is important in producing the shift to the late, hypodynamic phase. The decline in the vascular response to adrenomedullin is related to a sepsis-induced decrease in the binding protein for adrenomedullin (i.e., adrenomedullin binding protein-1) rather than a change in gene expression of the components of adrenomedullin receptors. Treatment of septic animals with the combination of adrenomedullin and its binding protein prevents the transition to the late phase of sepsis, maintains cardiovascular stability, and reduces sepsis-induced mortality. We propose that the mechanisms responsible for the beneficial effect of adrenomedullin and adrenomedullin binding protein-1 in sepsis are associated with downregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), maintainence of endothelial constitutive nitric oxide synthase, and reduction of vascular endothelial cell apoptosis.
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PMID:The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review). 1195 48

Adrenomedullin (AM) is a potent vasodilator that plays a major role in the cardiovascular response during the progression of sepsis. Although pulmonary clearance of AM (i.e., the primary site of AM clearance) is reduced during the late, hypodynamic stage of sepsis, the role of AM receptors under such conditions remains unclear. This study was carried out to test the hypothesis that saturation of AM receptors is responsible for the decreased clearance of AM in the lungs during sepsis. Polymicrobial sepsis was induced in male adult rats by cecal ligation and puncture (CLP). At 20 h after CLP (i.e., the late phase), 125I-labeled rat AM was administered through the jugular vein, both with (+) and without (-) pre-injection of the human AM fragment AM(22-52) (an AM receptor antagonist). Pulmonary tissue samples were harvested after 30 min and the radioactivity was determined. In addition, lung levels of AM were determined at 5 and 20 h after CLP by radioimmunoassay. Alterations in gene expression of the recently identified AM receptor subunits calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 and -3 (RAMP-2 and -3) were assessed in the lungs by reverse transcription-polymerase chain reaction (RT-PCR) at 5 and 20 h after CLP. The results indicate that there was a significant decrease in pulmonary [125I]AM clearance at 20 h in -AM(22-52) CLP animals. Lung clearance in +AM(22-52) sham animals was significantly lower than in -AM(22-52) sham animals and was not statistically different from the -AM(22-52) CLP group. There was no statistical difference between +AM(22-52) and -AM(22-52) CLP groups. However, there was a significant increase in lung AM levels at 20 but not 5 h after CLP. In addition, RAMP-3 expression was significantly upregulated at 5 but not 20 h after CLP. There were no alterations in the expression of CRLR or RAMP-2 at either time point. These results suggest that pulmonary AM receptors become saturated as more AM enters the bloodstream, thereby reducing the ability of the lungs to clear this peptide during late sepsis. Early upregulation of RAMP-3 may be a compensatory mechanism to help clear the upregulated AM from the bloodstream. The lack of upregulation of RAMP-3 during late sepsis could also contribute to the decreased clearance observed during this phase.
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PMID:Saturation of adrenomedullin receptors plays an important role in reducing pulmonary clearance of adrenomedullin during the late stage of sepsis. 1199 81

Adrenomedullin (AM) is a vasodilatory peptide hormone, playing a key role in the regulation of cardiovascular homeostasis. In view of the circulatory failure in sepsis, it is still debated as to whether the occurrence of vascular hyporeactivity against AM plays a causative or protective role. This study was designed as a prospective, controlled trial to elucidate the hemodynamic response following a titrating infusion of human AM in healthy and endotoxemic sheep. ANOVA demonstrated that AM infusion produced hypotension and tachycardia, and increased cardiac index in a dose-dependent manner, both in healthy and endotoxemic sheep. In addition, AM application reduced pulmonary vascular resistance index in ovine endotoxemia (P=0.02). These findings confirm that AM produces a hyperdynamic circulation, in the presence and absence of systemic inflammation. Further, exogenous AM could possibly be a useful adjunct in the common setting of sepsis-associated pulmonary hypertension.
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PMID:Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. 1214 39

Adrenomedullin (AM), a potent vasodilatory peptide, plays an important role in initiating the hyperdynamic response during the early stage of sepsis. Moreover, the reduced vascular responsiveness to AM appears to be responsible for the transition from the early, hyperdynamic to the late, hypodynamic phase of sepsis. Although the novel specific AM binding protein-1 (AMBP-1) enhances AM-mediated action in a cultured cell line, it remains to be determined whether AMBP-1 plays any role in modulating vascular responsiveness to AM during sepsis. To study this, adult male rats were subjected to sepsis by cecal ligation and puncture (CLP). The thoracic aorta was harvested for determination of AM-induced vascular relaxation. Aortic levels of AMBP-1 were determined by Western blot analysis, and AM receptor gene expression in the aortic tissue was assessed by RT-PCR. The results indicate that AMBP-1 significantly enhanced AM-induced vascular relaxation in aortic rings from sham-operated animals. Although vascular responsiveness to AM decreased at 20 h after CLP (i.e., the late, hypodynamic stage of sepsis), addition of AMBP-1 in vitro restored the vascular relaxation induced by AM. Moreover, the aortic level of AMBP-1 decreased significantly at 20 h after CLP. In contrast, AM receptor gene expression was not altered under such conditions. These results, taken together, suggest that AMBP-1 plays an important role in modulating vascular responsiveness to AM, and the reduced AMBP-1 appears to be responsible for the vascular AM hyporesponsiveness observed during the hypodynamic phase of sepsis.
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PMID:Adrenomedullin binding protein-1 modulates vascular responsiveness to adrenomedullin in late sepsis. 1218 87

Adrenomedullin (AM) is a recently discovered regulatory peptide involved in many functions including vasodilatation, electrolyte balance, neurotransmission, growth, and hormone secretion regulation, among others. This 52-amino acid peptide is expressed by specific cell types in many organs throughout the body. A complex receptor system has been described for AM; it requires at least the presence of a seven-transmembrane-domain G-protein-coupled receptor, a single-transmembrane-domain receptor activity modifying protein, and a receptor component protein needed to establish the connection with the downstream signal transduction pathway, which usually involves cyclicAMP. In addition, a serum-binding protein regulates the biological actions of AM, frequently by increasing AM functional attributes. Changes in levels of circulating AM correlate with several critical diseases, including cardiovascular and renal disorders, sepsis, cancer, and diabetes. Whether AM is a causal agent, a protective reaction, or just a marker for these diseases is currently under investigation. New technologies seeking to elevate and/or reduce AM levels are being investigated as potential therapeutic avenues.
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PMID:Cell and molecular biology of the multifunctional peptide, adrenomedullin. 1245 46


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