Structure–activity relationships of adrenomedullin in the circulation and adrenal gland

Abstract

Adrenomedullin (ADM) is a recently discovered vasoactive peptide that has potent vasodilator activity in the pulmonary and peripheral vascular beds and has significant effects on endocrine function. ADM is a member of the CGRP/amylin superfamily of peptides based largely on the presence of the six-membered ring structure and C-terminal amidation that is highly conserved in this family. Proadrenomedullin is a 185 amino acid precursor with enzymatic cleavage sites for both ADM and a unique 20 amino acid peptide named proadrenomedullin N-terminal 20 peptide (PAMP). ADM and PAMP are found in a variety of organ systems, and plasma levels of the peptides are increased in pathophysiologic conditions. Both peptides have hypotensive and vasodilator activity in the pulmonary and regional vascular beds and have significant effects on the endocrine system, including the adrenal gland. ADM (15–52), which retains the six-membered ring structure, maintains the vasodilator activity of ADM, suggesting that the 14 amino acid N-terminal extension is not necessary for the full agonist activity. However, analogs, such as ADM-(22–52) and ADM-(40–52), which do not contain the six-member ring structure, lack agonist activity. Unlike the full-sequence peptide, hADM-(15–22) and ADM-(16–21), which contain the ring structure, increase systemic arterial pressure in the rat but not in the cat. The present review discusses the structure–activity relationship for the actions of ADM and related peptides and discusses the mechanisms which mediate responses to these widely distributed peptides.

Introduction

Adrenomedullin (ADM) is a novel hypotensive peptide first isolated from human pheochromocytoma cells [1], [2], [3]. Human adrenomedullin (hADM) consists of 52 amino acids and a disulfide bond that forms a six-membered ring structure similar to the ring structure found in calcitonin gene-related peptide (CGRP) and pancreatic amylin [1], [2], [3], [4], [5]. Although ADM shares slight (21%) sequence homology with CGRP, it is considered to be a member of the CGRP/amylin superfamily of peptides based largely on the presence of the six-membered ring structure and C-terminal amidation that is highly conserved in this peptide family (Fig. 1) [1], [2], [3], [4], [5]. The most notable difference between ADM, CGRP, and amylin is an additional 14-residue extension at the amino terminus of the ADM sequence that is not present in CGRP or amylin (Fig. 1) [1], [2], [3], [4], [5]. The amino acid sequence for human (h), rat (r), and porcine (p) ADM has been elucidated [1], [2], [3]. pADM and hADM differ by one amino acid substitution of glycine for asparagine at position 40 of the sequence [1], [2], [3]. The sequence of rADM differs from the human sequence in the deletion of two residues at positions 7 and 8 and 6 amino acid substitutions at positions 11, 14, 23, 40, 41, and 45 of the human sequence [1], [2], [3]. It is of interest to note that, although the six-membered ring structure sequence is conserved in hADM, rADM, and pADM, these sequences are different from the sequences of the ring structures present in CGRF and amylin [1], [2], [3], [4], [5].

Although ADM was first isolated from pheochromocytoma tissue, the peptide is localized in a variety of organs [6], [7], [8], [9], [10], [11], [12]. ADM has been found to be expressed in the adrenal medulla, lung, kidney, ventricle, spinal cord, stomach, anterior pituitary, thalamus, and hypothalamus [6], [7], [8], [9], [10], [11], [12]. It has also been reported that ADM is actively synthesized and secreted by vascular endothelial cells and that this secretion rate is similar to that of the endothelial-derived contractile peptide endothelin-1 [12]. This observation may be interpreted to suggest that ADM may act as an endothelium-derived relaxing factor (EDRF) and may oppose the actions of endothelin-1 [12]. Moreover, it has also been reported that vascular smooth muscle cells produce and secrete ADM [13]. In addition to the presence of ADM in tissue and plasma under physiologic conditions, plasma levels of ADM are increased in disease states, such as congestive heart failure, hypertension, renal failure, septic shock, primary aldosteronism, diabetes, myocardial infarction, and pulmonary hypertension [14], [15], [16], [17], [18], [19], [20], [21]. ADM has been shown to have actions in the CNS, gut, kidney, in addition to having vasodilator activity in many species and vascular beds, including the hindlimb, mesenteric, and pulmonary vascular beds [1], [2], [3], [7], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50]. Although ADM has pronounced effects on renal vascular resistance and electrolyte excretion in the dog, it has been shown that constant infusion of ADM at a dose that results in a minimal hypotensive response increases renal plasma flow and urinary sodium excretion in the rat [50].

The DNA sequence encoding the ADM precursor, proadrenomedullin, has been determined in rat, porcine, and human tissue [2], [51], [52], [53]. Proadrenomedullin contains 185 amino acids, and cleavage of the signal peptide between amino acids Thr²¹ and Ala²² yields a shortened propeptide composed of 164 amino acids, which contains ADM [51], [52], [53]. Proadrenomedullin contains three paired basic amino acids that can be sites for enzymatic cleavage of the 20 amino acid peptide named proadrenomedullin N₂-terminal 20 peptide (PAMP), Fig. 1, [51], [52], [53]. Like hADM, hPAMP is found in a number of organ systems, such as the adrenal medulla, heart, kidney, and brain, and is detectable in plasma [54].