Adrenomedullin: Its Role in the Cardiovascular System

Adrenomedullin is a 52-amino acid peptide that was first isolated from human pheochromocytoma. Subsequently, it was found to be distributed widely in the body, including throughout the cardiovascular system. It belongs to a family of peptides that include calcitonin gene-related peptide and amylin. Adrenomedullin causes vasorelaxation and influences vascular proliferation and interacts closely with nitric oxide, and it may have a role in the pathophysiology of hypertension, ischemic heart disease, and cardiac and renal failure. Nonpeptide agonists or antagonists of adrenomedullin may have potential therapeutic application. The role of adrenomedullin in septicemic shock also merits further investigation.

KEYWORDS

Adrenomedullin - peptide - cardiovascular system - vasodilation - nitric oxide

REFERENCES

• 1 Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human phenochromocytoma.  Biochem Biophys Res Commun. 1993;  192 533-560
• 2 Ishimitsu T, Kojima M, Kangawa K et al.. Genomic structure of human adrenomedullin gene.  Biochem Biophys Res Commun. 1994;  203 631-639
• 3 Eto T. A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides.  Peptides. 2001;  22 1693-1711
• 4 Sakata J, Shimokubo T, Kitamura K et al.. Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma.  FEBS Lett. 1994;  352 105-108
• 5 Meeran K, Oshea D, Upton P D et al.. Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study.  J Clin Endocrinol Metab. 1997;  82 95-100
• 6 Sugo S, Minamino N, Shoji H et al.. Interleukin-1 tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells.  Biochem Biophys Res Commun. 1995;  207 25-32
• 7 Ishimitsu T, Miyata A, Matsuoka H, Kangawa K. Transcriptional regulation of human adrenomedullin gene in vascular endothelial cells.  Biochem Biophys Res Commun. 1998;  243 463-470
• 8 Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model.  J Cardiovasc Pharmacol. 1998;  31 S541-S544
• 9 Sugo S, Minamino N, Shoji H, Kangawa K, Matsuo H. Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells.  FEBS Lett. 1995;  369 311-314
• 10 Owji A A, Smith D M, Coppock H A et al.. An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat.  Endocrinology. 1995;  136 2127-2134
• 11 Nuki C, Kawasaki H, Kitamura K et al.. Vasodilator effect of adrenomedullin and calcitonin gene-related peptide receptors in rat mesenteric vascular beds.  Biochem Biophys Res Commun. 1993;  196 245-251
• 12 McLatchie L M, Fraser N J, Main M J et al.. RAMPs regulate the transport, and ligand specificity of the calcitonin-receptor-like receptor.  Nature. 1998;  393 333-339
• 13 Wangensteen R, Quesada A, Sainz J, Duarte J, Vargas F, Osuna A. Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney.  Eur J Pharmacol. 2002;  444 97-102
• 14 Samson W K. Adrenomedullin and the control of fluid and electrolyte homeostasis.  Annu Rev Physiol. 1999;  61 363-389
• 15 Cockcroft J R, Noon J P, Gardner-Medwin J, Bennett T. Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels.  Br J Clin Pharmacol. 1997;  44 57-60
• 16 De Matteo R, May C N. Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide.  Br J Pharmacol. 2003;  140(8) 1414-1420
• 17 Kano H, Kohno M, Yasunari K et al.. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells.  J Hypertens. 1996;  14 209-213
• 18 Lainchbury J G, Troughton R W, Lewis L K, Yandle T G, Richards A M, Nicholls M G. Hemodynamic, hormonal, and renal effects of short-term adrenomedullin infusion in healthy volunteers.  J Clin Endocrinol Metab. 2000;  85 1016-1020
• 19 Szokodi I, Kinnunen P, Ruskoaho H. Inotropic effect of adrenomedullin in the isolated perfused rat heart.  Acta Physiol Scand. 1996;  156 151-152
• 20 Ikenouchi H, Kangawa K, Matsuo H, Hirata Y. Negative inotropic effect of adrenomedullin in isolated adult rabbit cardiac ventricular myocytes.  Circulation. 1997;  95 2318-2324
• 21 Mukherjee R, Multani M M, Sample J A et al.. Effects of adrenomedullin on human myocyte contractile function and beta-adrenergic response.  J Cardiovasc Pharmacol Ther. 2002;  7 235-240
• 22 Ebara T, Miura K, Okumura M et al.. Effect of adrenomedullin on renal hemodynamics and functions in dogs.  Eur J Pharmacol. 1994;  263 69-73
• 23 Jougasaki M, Aarhus L L, Heublein D M, Sandberg S M, Burnett Jr J C. Role of prostaglandins and renal nerves in the renal actions of adrenomedullin.  Am J Physiol. 1997;  272 F260-F266
• 24 Miura K, Ebara T, Okumura M et al.. Attenuation of adrenomedullin-induced renal vasodilation by NG-nitro L-arginine but not glibenclamide.  Br J Pharmacol. 1995;  115 917-924
• 25 Parkes D G, May C N. ACTH-suppressive and vasodilator action of AM in conscious sheep.  J Neuroendocrinol. 1995;  7 923-929
• 26 Jensen B L, Kramer B K, Kurtz A. Adrenomedullin stimulates renin release and renin mRNA in mouse juxtaglomerular granular cells.  Hypertension. 1997;  29 1148-1155
• 27 Yamaguchi T, Babe K, Doi Y, Yano K, Kitamura K, Eto T. Inhibition of aldosterone production by adrenomedullin, a hypotensive peptide, in the rats.  Hypertension. 1996;  28 308-314
• 28 Serrano J, Uttenthal L O, Matrinez A et al.. Distribution of adrenomedullin-like immunoreactivity in the rat central nervous system by light and electron microscopy.  Brain Res. 2000;  853 245-268
• 29 Ueta Y, Kitamura K, Isse T et al.. Adrenomedullin-immunoreactive neurons in the paraventricular, and supraoptic nuclei of the rat.  Neurosci Lett. 1995;  202 37-40
• 30 Samson W K, Murphy T C. Adrenomedullin inhibits salt appetite.  Endocrinology. 1997;  138 613-616
• 31 Takahashi H, Watanabe T X, Nishimura M et al.. Centrally induced vasopressor and sympathetic responses to a novel endogenous peptide, adrenomedullin, in anesthetized rats.  Am J Hypertens. 1994;  7 478-482
• 32 Wang X, Yue T L, Barone F C et al.. Discovery adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage.  Proc Natl Acad Sci USA. 1995;  92 11480-11484
• 33 Jougasaki M, Wei C M, McKinley L J, Burnett Jr J C. Elevation of circulating and ventricular adrenomedullin in human congestive heart failure.  Circulation. 1995;  92 286-289
• 34 Kobayashi K, Kitamura K, Hirayama N et al.. Increased plasma adrenomedullin in acute myocardial infarction.  Am Heart J. 1996;  131(4) 676-680
• 35 Ishimitsu T, Nishikimi T, Saito Y et al.. Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure.  J Clin Invest. 1994;  94 2158-2161
• 36 Cheung B, Leung R. Elevated plasma levels of human adrenomedullin in cardiovascular, respiratory, hepatic and renal disorders.  Clin Sci. 1997;  92 59-62
• 37 Hayashi M, Shimosawa T, Isska M, Yamada S, Fujita R, Fujita T. Plasma adrenomedullin in diabetes.  Lancet. 1997;  350 1449-1450
• 38 Kikumoto K, Kubo A, Hayashi Y et al.. Increased plasma concentration of adrenomedullin in patients with subarachnoid hemorrhage.  Anesth Analg. 1998;  87 859-863
• 39 Hirata Y, Mitaka C, Sato K et al.. Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis.  J Clin Endocrinol Metab. 1996;  81 1449-1453
• 40 Yu C M, Cheung B M, Leung R, Wang Q, Lai W H, Lau C P. Increase in plasma adrenomedullin in patients with heart failure characterised by diastolic dysfunction.  Heart. 2001;  86(2) 155-160
• 41 Washimine H, Yamamoyo Y, Kitamura K et al.. Plasma concentration of human adrenomedullin in patients on hemodialysis.  Clin Nephrol. 1995;  44 389-393
• 42 Wang P, Yoo P, Zhou M, Cioffi W G, Ba Z F, Chaudry I H. Reduction in vascular responsiveness to adrenomedullin during sepsis.  J Surg Res. 1999;  85 59-65
• 43 Yang S, Zhou M, Chaudry I H, Wang P. Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis: role of adrenomedullin and adrenomedullin binding protein-1.  Ann Surg. 2002;  236(5) 625-633
• 44 Shindo T, Kurihara H, Maemura K et al.. Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature.  Circulation. 2000;  101 2309-2316
• 45 Troughton R W, Lewis L K, Yandle T G, Richards A M, Nicholls M G. Hemodynamic, hormone, and urinary effects of adrenomedullin infusion in essential hypertension.  Hypertension. 2000;  36(4) 588-593
• 46 Nishikimi T, Yoshihara F, Horinaka S et al.. Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats.  Hypertension. 2003;  42(5) 1034-1041
• 47 Niu P, Shindo T, Iwata H et al.. Accelerated cardiac hypertrophy and renal damage induced by angiotensin II in adrenomedullin knockout mice.  Hypertens Res. 2003;  26(9) 731-736
• 48 Chao J, Chao L. The Role of adrenomedullin in cardiovascular and renal function.  Drug News Perspect. 2002;  15(8) 511-518
• 49 Hojo Y, Ikeda U, Mizuno O, Katsuki T A, Shimada K. Adrenomedullin expression in coronary circulation after stent implantation as a prognostic factor for restenosis.  Int J Cardiovasc Intervent. 2003;  5(4) 190-194
• 50 Agata J, Zhang J J, Chao J, Chao L. Adrenomedullin gene delivery inhibits neointima formation in rat artery after balloon angioplasty.  Regul Pept. 2003;  15 112 115-20