Adrenomedullin and its Related Peptide

Abstract

MORE than 100 years have passed since Riva-Rocci [1] modified the sphygmograph by Marey [2], Mahomed [3] and Von Basch [4] to make conventional blood pressure measurements possible. Two years after the method was established, existence of hypertensive agents, now known as renin, was reported [5]. Since then laboratory investigations as well as clinical and epidemiological studies in hypertension research have been advancing at an exponential rate [6]. Since the 1950s, several circulation-regulating peptides, both hypertensive and hypotensive, were discovered. Among them, a novel vasodilative peptide, adrenomedullin (AM) was isolated from pheochromocytoma tissue in 1993 [7]. Another processing site in a propeptide of AM was found and a new hypotensive peptide, named proadrenomedullin N-terminal 20 peptide (PAMP), was isolated from human plasma and urine [7,8].Blood circulates throughout the body by the pressure force generated by cardiac output and peripheral resistance. Each of these primary determinants of blood pressure is determined by the interaction of an exceedingly complex series of factors. Thus it is crucial to determine this complex of interactions in order to better understand the physiological role of these newly found factors. AM and PAMPAs mentioned above, AM, originally isolated from pheochromocytoma cell, is also produced and secreted in endothelial cells [7,19], and has been shown to exhibit hypotensive action by direct vasodilation via both the elevation of intracellular cAMP and alteration of calcium sensitivity in vascular smooth muscle cells [20]. Besides these actions, recent studies have shown that AM increases nitric oxide synthesis in endothelial cell by elevating intracellular calcium [21][22][23][24]. Studies on the physiological action of AM have also revealed that AM increases intracellular cAMP [22] [28]. Moreover, AM inhibits smooth muscle cell migration and proliferation [29, 30]. AM also shares a slight homology with CGRP and the above mentioned physiological effects are inhibited by CGRP antagonist CGRP(8-37) [21]. Together with the evidence that AM production is increased in failing heart [31, 32], it is speculated that

Human adrenomedullin and its binding protein ameliorate sepsis-induced organ injury and mortality in jaundiced rats

“…The inflammatory cytokines TNF-α, IL-1β, and bacterial endotoxin strongly stimulate the synthesis and secretion of AM [16,39]. It is speculated that the elevation in AM levels may be a protective mechanism to counteract cardiovascular disorders under such conditions [37]. In the current study, we also show that the upregulation of AM occurs after sepsis, jaundice as well as jaundice plus sepsis in rats.…”

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

“…In this study, we also found that circulating levels of AM increased significantly at 24 hours after MCAO. The elevation in AM levels may be a protective mechanism to counteract cardiovascular disorders under disease conditions (33). However, the regulation of AM activity was largely unknown until the discovery of its novel binding protein, AMBP-1 (12).…”

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…However, hypoxia per se stimulates xanthine oxidase and NADPH oxidase, resulting in the increased production of oxidative stress (57). The pathogenic role of oxidative stress under hypoxic conditions was further emphasized by studies on the pulmonary vasculature using adrenomedullin, a potent antioxidant (58,59) that inhibits angiotensin II-induced oxidative stress (60). Chronic hypoxia was shown to induce pulmonary vascular remodeling, which was associated with an increased production of oxidative stress as measured by electron spin resonance and immunostaining of 3-nitrotyrosine.…”