Adrenomedullin in Hypertension

Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. The gene expression of AM is widely distributed in the cardiovascular system and many physiological actions of AM on cardiovascular system have been reported. Previous studies demonstrated that the plasma AM level is increased in patients with hypertension and further increased in patients with organ damage. We and other groups recently showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma and that the major molecular form in plasma is AM-glycine. Recent studies using AM antagonist or AM knockout mice confirmed the role of AM in the regulation of blood pressure. Indeed, administration of AM is beneficial in patients with hypertension, renal disease, and heart failure. In addition, recent studies revealed that AM and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP) 2, and RAMP3 are colocalized in peripheral tissues, including the heart, kidney, and vasculature, suggesting a role of AM as a regulator of local function. In fact, tissue AM levels and the gene expression levels of AM and its receptor are altered in hypertension. We recently showed that cardiac tissue AM levels and the gene expression levels of AM, CRLR, RAMP2, and RAMP3 are increased in left ventricular hypertrophy and further increased in hypertensive heart failure. These findings imply that increased expression of the AM system including the ligand and receptor components may modulate the pathophysiology in hypertension via the effects of AM not only as a circulating factor, but also as a local regulator. This review describes the structure, structure-activity relationships, tissue distribution, receptors, physiological action, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in hypertension.