A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides
Introduction
Adrenomedullin (AM) was discovered from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cAMP in rat platelets in 1993 [78]. During the seven years from its discovery and up to November 6ā8, 2000 when the Second International Symposium on Adrenomedullin and PAMP was held at Miyazaki, Japan, more than seven hundred papers concerning AM were published.
AM acts as a circulating hormone as well as elicits multiple biological activities in a paracrine or autocrine manner. Among them the most characteristic biological activity of AM is a very powerful hypotensive activity caused by dilatation of resistance vessels. A sensitive and specific radioimmunoassay demonstrated that AM circulates in blood and occurs in a variety of tissues. Plasma AM levels elevate in various diseases including cardiovascular and renal disorders or septic shock. Thus, AM may be involved in pathophysiological processes in these diseases, especially in disorders controlling circulation and body fluid. In this short review, the history of AM and proadrenomedullin N-terminal 20 peptide (PAMP) will be reviewed with special references to biological properties and function, receptors, gene engineering and clinical viewpoints. This review includes oral presentations from the aforementioned symposium; some of which have not yet been published. These unpublished oral presentations are quoted in this paper from the abstracts of this symposium.
Section snippets
Chemical and gene structure of adrenomedullin
Chemical and gene structure of human AM and PAMP, and their synthetic pathway are summarized in Fig. 1. AM consists of 52 amino acids and has a ring structure formed by one intramolecular disulfide bond and an amidated structure of carboxyl terminal tyrosine [78]. AM shares structural homology such as the ring structure and the C-terminal amide structure with a family of human calcitonin gene-related peptide (CGRP) and amylin. The amino sequence homology between AM and these peptides is not
Pharmacological and 125l-adrenomedullin binding studies
In rat vascular smooth muscle cells, the CGRP [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], CGRP1 receptor antagonist, competitively inhibits the intracellular accumulation of cAMP induced by AM [52]. Vasodilation of the rat mesenteric vascular bed elicited by AM and CGRP is also blocked by CGRP [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19],
Blood vessels
Among the multi-functional properties of AM (Table 1), the most characteristic one is an intensive, long-lasting hypotension that is dose-dependent in humans, rats, rabbits, dogs, cats and sheep. AM dilates resistance vessels in the kidneys, brain, lung, hindlimbs in animals as well as in the mesentery. Moreover, AM elicits relaxation of ring preparations of the aorta [105] and cerebral arteries [8]. An i.v. injection of human AM to conscious sheep causes a dose-dependent fall of blood
Proadrenomedullin N-terminal 20 peptide (PAMP)
The N-terminal region of preproadrenomedullin, the precursor of AM, contains a unique 20-residue sequence followed by Gly-Lys-Arg, a typical amidation signal, which was termed as proadrenomedullin N-terminal 20 peptide (PAMP). PAMP was purified from porcine adrenal medulla and human pheochromocytoma by using radioimmunoassay for the peptide and its complete amino acid sequence was determined [77]. In addition to the original form of PAMP [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11],
Gene engineering
By using a preproendothelin-1 promoter, transgenic mice lines were established, which overexpress AM mainly in vascular endothelial and smooth muscle cells [160]. These mice show significantly lower blood pressure and higher plasma cGMP levels than their wild-type littermates. Administration of a NO synthetase inhibitor in the transgenic mice results in an elevation of blood pressure. Even though the basal blood pressure is very low, the administration of bacterial lipopolysaccharide elicits
Pathophysiology
AM is processed from its precursor, proadrenomedullin, as the intermediate or immature form, AM-glycine (AM [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52]-COOH, immature AM). Subsequently, immature AM is converted to the biologically active
Gene therapy
Gene therapy was performed with adenovirus carrying the human AM cDNA under the control of cytomegalovirus promoter/enhancer (Ad.CMV-hAM), which was generated by homologous recombination of E. coli. The Ad.CMV-hAM was i.v. administered into hypertensive animals such as spontaneously hypertensive rats [14], DOCA-salt rats [26] and Dahl salt sensitive rats [194]. In each experimental model, expression of human AM mRNA was identified in the heart, kidney, lung, liver, aorta and adrenal gland, and
References (194)
- et al.
A cDNA encoding the calcitonin gene-related peptide type 1 receptor
J Biol Chem
(1996) - et al.
Proadrenomedullin N-terminal 20 peptide (PAMP) inhibits proliferation of human neuroblastoma TGW cells
FEBS Lett
(1997) - et al.
Glycosylation of the calcitonin receptor-like receptor at Asn60 or Asn112 is important for cell surface expression
FEBS Lett
(2000) - et al.
Adrenomedullin suppresses mitogenesis in rat mesangial cells via cAMP pathway
Biochem Biophys Res Commun
(1995) - et al.
Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes
J Biol Chem
(1998) - et al.
Effect of adrenomedullin on renal hemodynamics and functions in dogs
Eur J Pharmacol
(1994) - et al.
Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells
FEBS Lett
(1994) - et al.
Tissue-specific mRNA expression of a calcitonin receptor-like receptor during fetal, and postnatal development
Brain Res
(1997) - et al.
Plasma adrenomedullin in diabetes
Lancet
(1997) - et al.
Secretion and clearance of the mature form of adrenomedullin in humans
Life Sci
(1999)
Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma
FEBS Lett
Transcription factor AP-2 mediates induction by two different signal-transduction pathwaysprotein kinase C and cAMP
Cell
Genomic structure of human adrenomedullin gene
Biochem Biophys Res Commun
Transcriptional regulation of human adrenomedullin gene in vascular endothelial cells
Biochem Biophys Res Commun
Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells
Biochem Biophys Res Commun
Diuretic and natriuretic action of adrenomedullin administered intracerebroventricularly in conscious rats
Regul Pept
Plasma adrenomedullin levels in the coronary circulation in vasospastic angina pectoris
Am J Cardiol
Comparison of bronchodilator responses to adrenomedullin and proadrenomedullin N-terminal 20 peptide
Life Sci
Adrenomedullin, a newly discovered hypotensive peptide, is a potent bronchodilator
Biochem Biophys Res Commun
Adrenomedullin has mitogenic effects on human oral keratinocytesinvolvement of cyclic AMP
FEBS Lett
Cloning, and expression of cDNA encoding a rat adrenomedullin receptor
J Biol Chem
Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor
Biochem Biophys Res Commun
Plasma and urine levels of adrenomedullin and proadrenomedullin N-terminal 20 peptide in chronic glomerulonephritis
Am J Kidney Dis
Immunoreactive adrenomedullin in human plasma
FEBS Lett
Identification and hypotensive activity of proadrenomedullin N-terminal 20 peptide (PAMP)
FEBS Lett
Adrenomedullina novel hypotensive peptide isolated from human pheochromocytoma
Biochem Biophys Res Commun
Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor
FEBS Lett
The intermediate form of glycine-extended adrenomedullin is the major circulating molecular form in human plasma
Biochem Biophys Res Commun
Cloning and characterization of cDNA encoding a precursor for human adrenomedullin
Biochem Biophys Res Commun
Adrenomedullin receptors in rat cerebral microvessels
Brain Res Mol Brain Res
Selective inhibition of nicotinic receptors by proadrenomedullin N-terminal 12 peptide in bovine adrenal chromaffin cells
Brain Res Mol Brain Res
Increased plasma adrenomedullin in acute myocardial infarction
Am Heart J
An accelerated increase of plasma adrenomedullin in acute asthma
Metabolism
Stimulation of cyclic adenosine monophosphate formation by the novel vasorelaxant peptide adrenomedullin in cultured rat mesangial cells
Metabolism
Human proadrenomedullin N-terminal 20 peptide in pheochromocytoma and normal adrenal medulla
Biochem Biophys Res Commun
Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling
J Biol Chem
Proadrenomedullin N-terminal 20 peptide (PAMP) immunoreactivity in vertebrate juxtaglomerular granular cells identified by both light, and electron microscopy
Gen Comp Endocrinol
Detection of adrenomedullin, a hypotensive peptide, in amniotic fluid and fetal membranes
Am J Obstet Gynecol
Changes in plasma adrenomedullin levels during the menstrual cycle
Regul Pept
Proadrenomedullin N-terminal 20 peptide inhibits aldosterone secretion of human adrenocortical, and Connās adenoma cellscomparison with adrenomedullin effect
J Clin Endocrinol Metab
Novel distribution of adrenomedullin-immunoreactive cells in human tissues
Histochem Cell Biol
Elevation of two molecular forms of adrenomedullin in plasma and urine in patients with acute myocardial infarction treated with early coronary angioplasty
Clin Sci
Mechanisms involved in adrenomedullin-mediated modulation of angiotensin signaling in the heart
Second International Symposium on Adrenomedullin and PAMP, Miyazaki, Japan
Adrenomedullin and nitrite levels in children with Bartter syndrome
Pediatr Nephrol
Effects of adrenomedullin, calcitonin gene-related peptide, and amylin on cerebral circulation in dogs
J Cereb Blood Flow Metab
Receptor-Activity-Modifying Proteins (RAMP) in interaction with receptors of the adrenomedullin peptide family
Second International Symposium on Adrenomedullin and PAMP, Miyazaki, Japan
A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor is a calcitonin gene-related peptide receptor when co-expressed with human RAMP1
Endocrinology
Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional adrenomedullin gene
Proc Natl Acad Sci USA
CGRP, and adrenomedullin binding correlates with transcript levels for calcitonin receptor-like receptor (CRLR), and receptor activity modifying proteins (RAMPs) in rat tissues
Br J Pharmacol
Adrenomedullin gene delivery reduces blood pressure in spontaneously hypertensive rats
Hypertens Res
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