Adrenomedullin in Hypertension

Abstract

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.

Adrenomedullin in the Kidney-Renal Physiological and Pathophysiological Roles

“…They showed that an N-terminaltruncated derivative, hAM-(13-52)-NH 2 retaining the cyclic structure and the amidated C-terminus, showed Ki and cAMPgenerating activities comparable to those of mature form hAM-(1-52)-NH 2 , whereas the N-terminal fragment hAM-(1-10)-OH had no effect. These data suggest that N-terminal residues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) of the AM molecule are not essential for interaction with the AM receptor. Removal of the C-terminal amidation [hAM-(1-52)-OH] resulted in a remarkable decrease in receptor-binding activity and cAMP response.…”

Changes of adrenomedullin and natriuretic peptides in patients with adrenal medullary hyperplasia prior to and following pharmacological therapy and adrenalectomy

“…As aforementioned, a number of investigations showed increased plasma ADM, ANP and BNP levels in patients with EH, or primary aldosteronism or pheochromocytoma (14,26,27,(29)(30)(31); however, this is the first study to assess plasma ADM, ANP and BNP levels in patients with AMH.…”

“…ANP and BNP are similar to ADM in cardiovascular effects, including natriuresis, diuresis, hypotensive action and anti-hypertrophic action, thereby reducing fluid volume and increasing oxygen transport (24,25). Previous studies have shown that plasma levels of ADM, ANP and BNP were elevated in patients with essential hypertension (26,27).…”

Adrenomedullin in Heart Failure: Molecular Mechanism and Therapeutic Implication

“…AM induces cAMP in vascular smooth muscle cells, which leads to vasodilation and the inhibition of proliferation and migration [22]. In contrast, another study showed that AM induces a rapid increase in extracellular signal-regulated kinase (ERK) activity, followed by the expression of the immediate early proto-oncogene c-fos and promotes proliferation in quiescent vascular smooth muscle cells [23].…”

“…This hypothesis is supported by the results of recent studies using AM gene delivery, long-term AM infusion and knockout mice. The beneficial effects of increased AM might be associated with the inhibition of oxidative stress, the renin-angiotensin-aldosterone system and other factors [22,45,[81][82][83][84].…”