Elsevier

Peptides

Volume 22, Issue 11, November 2001, Pages 1693-1711
Peptides

A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides

https://doi.org/10.1016/S0196-9781(01)00513-7Get rights and content

Abstract

Adrenomedullin (AM), identified from pheochromocytoma and having 52 amino acids, elicits a long-lasting vasodilatation and diuresis. AM is mainly mediated by the intracellular adenylate cyclase coupled with cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) pathway through its specific receptor. The calcitonin receptor-like receptor (CLCR) and receptor-activity modifying protein (RAMP) 2 or RAMP3 models have been proposed as the candidate receptor. AM is produced mainly in cardiovascular tissues in response to stimuli such as shear stress and stretch, hormonal factors and cytokines. Recently established AM knockout mice lines revealed that AM is essential for development of vitelline vessels of embryo. Plasma AM levels elevate in cardiovascular diseases such as heart failure, hypertension and septic shock, where AM may play protective roles through its characteristic biological activities. Human AM gene delivery improves hypertension, renal function, cardiac hypertrophy and nephrosclerosis in the hypertensive rats. AM decreases cardiac preload and afterload and improves cardiac contractility and diuresis in patients with heart failure and hypertension. Advances in gene engineering and receptor studies may contribute to further understandings of biological implication and therapeutic availability of AM.

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 6ā€“8, 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

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