Introduction Toshio Nishikimi

Introduction Toshio Nishikimi

The present publication is an up-to-date review of the most relevant aspects of adrenomedullin. It encompasses a broad range of fields, including biochemistry, molecular biology, physiology, pharmacology, pathophysiology of cardiovascular disease, and clinical applications of adrenomedullin to cardiovascular disease. The authors are distinguished colleagues, each one an expert in one or more fields.

The cardiovascular system is regulated by many neurohumoral factors, such as the sympathetic nervous system, renin-angiotensin-aldosterone system, natriuretic peptides, endothelin, and vasopressin. The study of these neurohumoral factors has not only enhanced our understanding of the pathophysiology of cardiovascular disease, but has also contributed to improved diagnosis and therapy. In fact, research on neurohumoral factors led to the development of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone receptor blockers, endothelin antagonists, and recombinant atrial and brain natriuretic peptides, contributing substantially to cardiovascular medicine. Indeed, these drugs are now widely used in daily clinical practice and have become essential for the treatment of patients with cardiovascular disease. Diagnostically, the measurement of atrial and brain natriuretic peptides is a useful tool for evaluating the status of heart failure as well as cardiac remodeling and hypertrophy. Thus, the discovery and evaluation of new hormones has opened new doois leading to further progress in cardiovascular research and medicine.

Adrenomedullin was discovered in 1993 in an extract of human pheochromocytoma while monitoring cAMP levels in rat platelets.

Adrenomedullin consists of 52 amino acids and shows slight homology

with calcitonin gene-related peptide. More than 1500 peer-reviewed articles

have been published regarding its biochemistry, molecular biology,

physiology, pharmacology, and pathophysiology over the past 12 years.

Because of its actions on the cardiovascular system, adrenomedullin has attracted considerable interest among cardiologists.

Adrenomedullin significantly decreases blood pressure in vivo, directly acts on vascular smooth muscle cells, and increases cAMP levels.

Adrenomedullin also acts on vascular endothelial cells and activates endothelial NOS by increasing intracellular Ca

levels. Thus, adrenomedullin reduces blood pressure indirectly. Strong expression of adrenomedullin mRNA is found in vascular smooth muscle cells and endothelial cells. Its expression in these cells is 20 times higher than that in the adrenal gland. Thus, adrenomedullin is produced and secreted from vascular walls and acts as an autocrine and paracrine factor involved in the regulation of vascular tonus. Furthermore, recent studies suggest a role of adrenomedullin in the pathogenesis of arteriosclerosis.

Not only the vasculature, but also the heart and kidney are considered important target organs of adrenomedullin. Adrenomedullin is expressed in cardiac myocytes, which have abundant adrenomedullin receptors. Indeed, adrenomedullin has positive inotropic action in vivo and in vitro.

Adrenomedullin is also expressed in renal tubular cells and glomerular endothelial cells. These cells also have an abundant supply of adrenomedullin receptors. Intrarenal administration of adrenomedullin induces natriuresis, diuresis, and an increase in glomerular filtration rate.

Thus, adrenomedullin has a wide variety of unique actions. Recent studies have shown that long-term administration of adrenomedullin or gene delivery of adrenomedullin significantly improves cardiac function, cardiac hypertrophy, and renal disease in hypertension or heart failure. These results suggest that adrenomedullin can be used for the treatment of cardiovascular disease.

The present volume is an effort to summarize our knowledge about

adrenomedullin as of the end of 2004. It will hopefully benefit young

investigators who specialize in cardiovascular disease and endocrinology.