oa Editorial [Hot Topic: Adrenomedullin in Hypertension and Beyond (Guest Editor: Johji Kato)]

Numerous humoral factors have been shown to be involved in regulating blood pressure and electrolyte-fluid balance in mammals, such as catecholamines, angiotensin peptides, aldosterone, natriuretic peptides, and endothelins. In 1993, a biologically active peptide discovered in human pheochromocytoma tissue by Kitamura and coworkers was added to the list. This peptide was termed adrenomedullin (AM) because it was abundantly present in adrenal medulla as well as in pheochromocytoma tissue. The action first characterized for AM was a potent blood pressure-lowering effect secondary to vasodilatation; however, 18 years have passed since the discovery, and AM is now known as a bioactive peptide with pleiotropic actions, including suppression of oxidative stress, angiogenesis, and neuroprotection, in various tissues and organs. It is widely recognized that humoral factors increasing blood pressure or fluid volume, such as angiotensin II and endothelins, exert undesirable effects exacerbating hypertensive organ damage, while those lowering them, such as natriuretic peptides, play protective roles in the cardiovascular system. Since the discovery of AM, many researchers have made substantial efforts to reveal the actions or roles of this bioactive peptide in the cardiovascular system. As a result, a large amount of scientific data has been accumulated, indicating a role of AM in the mechanism acting against elevation of blood pressure and progression of hypertensive organ damage. For example, experiments in vitro and in vivo have shown that AM has a protective role, probably as a local modulator in the cardiac ventricles by inhibiting hypertrophy or interstitial fibrosis of the myocardium. The active form of human AM consists of 52 amino acids with a ringed structure formed by a disulfide bond and an amidated carboxyl terminal, both of which are essential for biological activity. Based on homology in the amino acid sequence, AM is assumed to belong to the calcitonin gene-related peptide (CGRP) superfamily. The discovery of AM led to the identification of two bioactive peptides: proadrenomedullin N-terminal 20 peptide (PAMP), a blood pressure-lowering peptide, which was found to be processed from the AM precursor peptide preproAM; and adrenomedullin-2/intermedin, a member of the CGRP superfamily identified by two independent groups by searching genomes of humans and other vertebrates. This new peptide member has been shown to have biological actions, which are similar to those of AM. A number of basic and clinical studies have been carried out to verify the beneficial effects on hypertension or cardiovascular diseases associated with hypertension. Meanwhile, because AM levels in the blood of patients with hypertension or cardiovascular diseases are elevated in association with the severity of the illness, efforts have been made to explore the diagnostic values of measuring plasma AM levels in patients with those diseases. As discussed in this issue, it is now assumed that AM is beneficial as a therapeutic tool or as a diagnostic or prognostic marker for heart failure, acute myocardial infarction, or pulmonary hypertension. The receptors of AM or CGRP had been controversial, but the discovery of three subtypes of trans-membrane proteins of receptor activity-modifying proteins (RAMPs) revealed a unique receptor system: calcitonin receptor-like receptor (CLR) functions as a CGRP receptor or the AM type 1 or type 2 receptor depending on the subtype of RAMPs co-expressed. Experiments manipulating the genes of AM and these receptor components revealed not only the cardiovascular or neural protective actions of AM but also the indispensable role of AM and its signaling system in the process of embryogenesis. The detailed findings of these interesting studies are also described in this special issue. The aim of publishing this special issue is to provide current comprehensive knowledge on AM and related peptides. Each article was written by an expert in research on these bioactive peptides. The editor hopes that this special issue will help medical professionals in fields from basic research to clinical medicine understand the actions or role of AM in the cardiovascular and central nervous systems. It will also provide clear information about what is currently known and what remains to be clarified about AM for researchers working in a wide range of scientific fields. Finally, the editor would like to express sincere gratitude to all of the authors and reviewers for their thoughtful contributions to this special issue.