AM a Vasoactive Hormone

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AM is a multifunctional peptide, which is present ubiquitously in the body. The normal plasma concentration of AM is in the range of 1 to 15pmol/L, and AM is derived mostly from endothelial cells. Its plasma half life is about 20 minutes. It is degraded initially by metalloproteases followed by an aminopeptidase. The lungs are the main clearance site of AM in humans.

AM molecule shows some homology with calcitonin gene-related peptide (CGRP) and amylin, suggesting that AM belongs to the CGRP superfamily. AM consists of 52 amino acid residues in humans and 50 amino acid residues in rats. It has two characteristic structures, a ring structure formed by an intermolecular disulfide bridge and a C-

terminal amide structure, which are essential for the receptor binding and the biological activity of AM.

The biological actions of AM are mediated via two specific adrenomedullin receptors, and at higher concentrations AM also can cross-react with the CGRP type 1 (CGRP1) receptor. Although the pharmacology of these receptors is distinct, the main component of both is the calcitonin-receptor-like receptor (CRLR). Whether CRLR functions as an AM or CGRP receptor is dependent on the presence of one of the three receptor activity modifying proteins (RAMP). When CRLR combines with RAMP1 it defines the CGRP1 receptor, whereas the combination of CRLR with either RAMP2 or 3 forms the AM receptors.

CRLR is a member of the type II G-protein coupled receptor family, and like other members of this receptor family it signals via Gs and adenylate cyclase activation. Increased intracellular cyclic adenosine 3',5'-monophos-phate (cAMP) level is the usual result of AM challenge. Intracellular calcium concentrations appear to be unaffected by AM in many different cell types expressing endogenous AM receptors, except endothelial cells where AM can also increase intracellular calcium concentration. When injected intravenously, AM acts predominantly in organs in which the AM gene is highly expressed. These observations suggest a local autocrine and/or paracrine role for AM.

AM has been shown to have a wide range of physiological effects. It is implicated in the regulation of fluid/ electrolyte homeostasis, insulin secretion, and glucose metabolism. AM has an important role in pregnancy and fetal growth, inhibits apoptosis, and regulates cell proliferation.

The major role of AM is in the paracrine control of vascular function, supported by the high levels of AM secreted by endothelial cells and vascular smooth muscle cells. AM is a powerful hypotensive peptide. Its vasodilator effects are mediated in part by an elevation of cytoplasmic cAMP leading to relaxation of vascular smooth muscle cells. In addition, AM acts on endothelial cells; it stimulates nitric oxide production via calcium-dependent activation of endothelial nitric oxide synthase, which also contributes to vasodilatation. AM regulates vascular smooth muscle cell proliferation, inhibits endothelial apoptosis, promotes angiogenesis, and regulates blood coagulation and fibrinolysis. Transgenic overexpressing and knockout models further emphasize that AM is crucial to vascular morphogenesis and function.

Numerous studies defining the circulating AM plasma concentration in different clinical settings showed an elevated AM plasma concentration in a variety of pathological conditions including essential hypertension, chronic heart failure, acute myocardial infarction, pulmonary hypertension, chronic renal failure, diabetes, hyperthyroidism, hyperparathyroidism, sepsis, schizophrenia, autism, bipolar affective disorders, surgical interventions, or during normal pregnancy. Because such a broad range of conditions are associated with elevated AM levels, it seems likely that increases in AM are not causative of disease but rather are compensatory to these pathological events. The results from transgenic mice overexpressing AM gene support the idea of a protective role for AM.

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