Disease relevance of Adm

• OBJECTIVE: The adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function [1].
• ADM level increases progressively during sepsis except in the jejunum [2].
• Adrenomedullin is a potent vasodilator peptide originally isolated from a pheochromocytoma [3].
• Relationship between contents of adrenomedullin and distributions of neutral endopeptidase in blood and tissues of rats in septic shock [2].
• In the present study, we have examined gene expression of RAMP2, CRLR and adrenomedullin in hearts and kidneys of rats with congestive heart failure caused by coronary artery ligation [4].

Psychiatry related information on Adm

• Collectively, the present findings indicate that ADM system is up-regulated in newborn rat thymus, thereby making it likely that ADM may be involved in the thymus growth and in the development of immunological defense mechanisms [5].
• Additionally, 88 pmol AdM significantly inhibited the drinking response to overnight water deprivation and hyperosmotic challenge [6].
• No significant effects of AdM in the doses tested were observed on blood pressure, heart rate, or motor activity [6].

High impact information on Adm

• Thus, it suggests that PAMP and adrenomedullin, which are derived from the same gene, exhibit different hypotensive mechanisms: PAMP inhibits neural transmission at peripheral sympathetic nerve ending, although adrenomedullin directly dilates vascular smooth muscle, possibly through CGRP-like receptor [7].
• Proadrenomedullin NH(2)-terminal 20 peptide, a new product of the adrenomedullin gene, inhibits norepinephrine overflow from nerve endings [7].
• In contrast, vasoconstrictive response of mesenteric arteries to exogenous norepinephrine was significantly attenuated by 10 pmol/ml of adrenomedullin but not by the same dose of PAMP [7].
• Calcitonin gene-related peptide (CGRP), a widespread neuropeptide with multiple actions, has substantial homology with amylin, a peptide implicated in insulin-resistant diabetes, and adrenomedullin, a recently discovered potent vasodilator [8].
• Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and -50 mV transmembrane voltage, consistent with an increase in L-type Ca2+ channel current during the plateau [9].

Chemical compound and disease context of Adm

• Changes of adrenomedullin and receptor activity modifying protein 2 (RAMP2) in myocardium and aorta in rats with isoproterenol-induced myocardial ischemia [3].
• Upregulation of ligand, receptor system, and amidating activity of adrenomedullin in left ventricular hypertrophy of severely hypertensive rats: effects of angiotensin-converting enzyme inhibitors and diuretic [10].
• We focused particularly on pulmonary endothelin-1, a major vasoconstrictor in acute respiratory distress syndrome, and on adrenomedullin, a potent vasodilator that is up-regulated by inflammatory stimuli [11].
• This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2) [12].
• Adrenomedullin administered peripherally in the rabbit (at doses of 1.25, 2.5 and 5 microg/kg ) caused a dose-dependent conjunctival hyperemia accompanied by an increase of inflammatory cell number and prostaglandin E(2) concentration in the aqueous humor, and of uveal vascular response and myeloperoxidase activity [13].

Biological context of Adm

• This study was designed to characterise adrenomedullin binding sites in the rat adrenal medulla, using ligand binding studies, immunocytochemistry, and mRNA analysis [14].
• The left ventricular adrenomedullin level correlated with the gene expression of type III collagen (R=0.42) [15].
• Adrenomedullin (ADM), a multifunction peptide with important roles in regulating cardiovascular homeostasis, has the vasodilatory properties and is of particular interest in the pathophysiology of sepsis [2].
• Upregulation of intracardiac adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy [15].
• There is evidence that ADM, in addition to regulating blood pressure and water and electrolyte balance, may be also involved during embryogenesis in the growth and differentiation of organs and tissues, especially of those where strong mesenchymal-epithelial interactions take place [5].

Anatomical context of Adm

• CONCLUSION: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels [1].
• In contrast to known levels in plasma (about 10%), adrenomedullin-mature was a major molecular form in the culture medium of cardiac fibroblasts and myocytes (65-80%) [1].
• Further evidence to support this conclusion was provided by the demonstration of colocalisation of adrenomedullin receptors with dopamine beta-hydroxylase, confirming the presence of the receptors in medullary chromaffin cells [14].
• Characterization and effects on cAMP accumulation of adrenomedullin and calcitonin gene-related peptide (CGRP) receptors in dissociated rat spinal cord cell culture [16].
• Alterations of adrenomedullin and its receptor system components in calcified vascular smooth muscle cells [17].

Associations of Adm with chemical compounds

• These studies revealed that both CRLR and L1 were expressed only in cells that did not express PNMT, suggesting that adrenomedullin receptors are only found in noradrenaline-secreting cells [14].
• Recently, we found that adrenomedullin, but not calcitonin gene-related peptide (CGRP), stimulates histamine release from rat peritoneal mast cells [18].
• 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 [3].
• Estrogen and phytoestrogen regulate the mRNA expression of adrenomedullin and adrenomedullin receptor components in the rat uterus [19].
• We identified the gene for receptor-activity-modifying protein 2 (Ramp2), known to be a component of the adrenomedullin (ADM) receptor, as responsive to both E2 and the phytoestrogen coumestrol (Cou) [19].

Physical interactions of Adm

• The results indicate that ADM interacts with COX to yield prostanoids, which mediate its negative inotropic effect in LPS-treated rat ventricular myocytes [20].
• Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors [21].

Regulatory relationships of Adm

• Thus, in sepsis, the local concentration and action of ADM in tissues may be differentially regulated by NEP [2].
• These results suggest that ADM induces HO-1 gene expression and cGMP formation in rat VSMCs [22].
• We identified the transcript of the adrenomedullin gene (AM) as an mRNA that is specifically down-regulated in v-Myc overexpressing C3H10T1/2 cell lines as well as in a Rat 1a cell line inducible for c-Myc [23].
• In quiescent rat endothelial cells, adrenomedullin stimulated the expression of Max without affecting c-Myc [24].
• Adrenomedullin inhibits spontaneous and bradykinin-induced but not oxytocin- or prostaglandin F(2alpha)-induced periodic contraction of rat uterus [25].

Other interactions of Adm

• Analysis of mRNA revealed that the genes encoding both the putative adrenomedullin receptors, termed calcitonin receptor-like receptor (CRLR) and L1, were expressed in the rat adrenal medulla [14].
• We sought to investigate the effect of ADM on heme oxygenase-1 (HO-1) gene expression and cGMP formation in cultured rat vascular smooth muscle cells (VSMCs) [22].
• Taken together, these data suggest that adrenomedullin acts through a specific adrenomedullin receptor in the rat adrenal medulla [14].
• (3) Preincubated IL-1beta elevated the intracellular cAMP response to exogenous adrenomedullin administered at a concentration of 10(-7) M (+26%, P<0.05) [1].
• Neither adrenomedullin nor CGRP affected c-Myc expression [24].

Analytical, diagnostic and therapeutic context of Adm

• In the present studies, we investigated the expression of mRNA for calcitonin-receptor-like receptor (CRLR) and receptor-activity modifying proteins (RAMPs), the components of proposed adrenomedullin receptors, in rat peritoneal mast cells by reverse transcription-polymerase chain reaction (RT-PCR) [18].
• Reverse transcription (RT)-polymerase chain reaction (PCR) allowed the detection of the specific mRNAs of pADM and peptidyl-glycine alpha-amidating monooxigenase (PAM), the enzyme which converts immature ADM to the mature peptide, in both newborn and adult rat thymuses [5].
• We measured the secretion of adrenomedullin by radioimmunoassay and detected adrenomedullin mRNA expression by Northern blot analysis in primary cultures of rat cerebral endothelial cells (RCECs), pericytes and astrocytes [26].
• Radioimmunoassay for adrenomedullin of media from Rat-2 cells showed a linear release of adrenomedullin-like immunoreactivity of 3.1 fmol/h per 2x10(6) cells [27].
• Recent adrenomedullin (AM) gene-targeting studies have proposed a novel concept that AM plays a protective role against oxidative stress in vivo [28].

References