Elsevier

Pharmacology & Therapeutics

Volume 103, Issue 3, September 2004, Pages 179-201
Pharmacology & Therapeutics

Associate Editor: G.L. Wainright
The clinical relevance of adrenomedullin: a promising profile?

https://doi.org/10.1016/j.pharmthera.2004.07.002Get rights and content

Abstract

Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.

Introduction

Since the initial discovery of the peptide adrenomedullin (AM) by Kitamura et al. (1993a), the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Almost as prevalent has been the number of disease areas in which prospective clinical manipulation of the AM system has been suggested, areas ranging widely from heart failure through to oncology. As one would expect, there has been a steady growth in our knowledge base so that today, a full decade on from discovery, we are very much better informed on the molecular biology, pharmacology, and systems biology unique to this molecule. However, surprisingly, it may be argued that we are perhaps no further forward in our expectation as to which clinical area is likely to benefit most significantly.

Structurally, AM was easily characterized to consist of 52 amino acids with an intramolecular disulfide bond forming a ring structure of 6 residues with C-terminal amidation (Fig. 1) with both the disulfide bond and amidation being essential for its activity. A key feature of AM is, however, the homology it shares with calcitonin gene-related peptide (CGRP) and amylin (Kitamura et al., 1993a). Although this homology is only slight, it is still sufficient to allow significant cross-reactivity with the receptors of these other peptides as well as with calcitonin itself. Very recently, mRNA of a second member of the AM family has been identified in mice, rats, and humans, although the anticipated ‘new’ protein has yet to be detected (Takei et al., 2004).

Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. However, its early promise as a potential mediator/modulator of disease was not entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma (Ichiki et al., 1994, Kitamura et al., 1994a, Lewis et al., 1998) in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid (glycine-extended) peptide (Kitamura et al., 1998, Asakawa et al., 2001). Plasma levels of AM have now been shown to be increased in a number of pathological states including congestive heart failure (Kobayashi et al., 1996a), sepsis (Hirata et al., 1996), essential hypertension (Ishimitsu et al., 1994b, Kohno et al., 1996a), acute myocardial infarction (Nagaya et al., 1999a, Asakawa et al., 2001), and renal impairment (Ishimitsu et al., 1994b, Ishihara et al., 1999). These earliest associations have now been further supplemented with evidence of a role for AM in other pathologies including most intriguingly cancer.

Here, in this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.

Section snippets

Genetic regulation

The genomic DNA sequence encoding human, rat, porcine, and canine AM has been cloned showing significant conservation across species (Kitamura et al., 1993c, Ishimitsu et al., 1994a, Ono et al., 1998). In humans, the gene, which is made up of 4 exons and 3 introns, is found on chromosome 11 (Fig. 2). The cDNA clone was shown to encode a 185-amino acid AM precursor prepro-AM. The 21-residue N-terminal signaling peptide is cleaved to produce a 164-amino acid peptide pro-AM (Fig. 3), which is then

Vascular control, hypertension, and atherosclerosis

In a variety of species including humans, AM and biologically active fragments have been shown to have potent systemic and pulmonary vasodilator effects (Ishiyama et al., 1993, Nakamura et al., 1997, Nagaya et al., 2003). AM, CGRP, and amylin all have potent hypotensive and vasorelaxant effects in vivo and in vitro (Ishiyama et al., 1993, Kitamura et al., 1993c, Nuki et al., 1993, Santiago et al., 1995, Nakamura et al., 1997). AM causes both vasodilatation and hypotension in experimental

Summary

In summary, the molecular, pharmacological, and physiological profile of AM has been greatly clarified over the last decade to such an extent that it appears to be an important component in a wide range of physiological mechanisms. The breadth of actions that appear to be demonstrated by AM ranks it alongside other ubiquitous and now therapeutically critical targets such as endothelin and angiotensin, with particular potential in disorders of the cardiovascular system. It seems clear that early

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