Adrenomedullin in the Treatment of Cardiovascular Dysfunction and Sepsis

  • C. Ertmer
  • H. Van Aken
  • M. Westphal


The existence of vasoactive peptide hormones was first reported more than 100 years ago [1]. Since then, several oligo- and polypeptides influencing blood pressure regulation have been identified. Some of these are direct vasoconstrictors, such as vasopressin, angiotensin II, endothelin-1, and neuropeptide Y and are classified as hypertensive agents. Other peptides, e.g., the natriuretic peptides, vasoactive intestinal peptide (VIP), and calcitonin-gene related peptide (CGRP), have direct vasodilatory properties and, thus, lower systemic blood pressure. Adrenomedullin belongs to the vasodilatory peptide hormones and plays a crucial role in the regulation and preservation of cardiovascular, endocrine and immunologic homeostasis [2].


Septic Shock Pulmonary Hypertension Mean Arterial Pressure Cardiac Index Cardiovascular Dysfunction 
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  1. 1.
    Tigerstedt R, Bergman PG (1898) Niere und Kreislauf. Skand Ark Physiol 7–8:223–271Google Scholar
  2. 2.
    Holmes CL, Patel BM, Russell JA, Walley KR (2001) Physiology of vasopressin relevant to management of septic shock. Chest 120:989–1002PubMedCrossRefGoogle Scholar
  3. 3.
    Kitamura K, Kangawa K, Kawamoto M, et al (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192:553–560PubMedCrossRefGoogle Scholar
  4. 4.
    Kitamura K, Eto T (1997) Adrenomedullin—physiological regulator of the cardiovascular system or biochemical curiosity? Curr Opin Nephrol Hypertens 6:80–87PubMedCrossRefGoogle Scholar
  5. 5.
    Kato J, Tsuruda T, Kita T, Kitamura K, Eto T (2005) Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol 25:2480–2487PubMedCrossRefGoogle Scholar
  6. 6.
    Hinson JP, Kapas S, Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21:138–167PubMedCrossRefGoogle Scholar
  7. 7.
    Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, Eto T (1993) Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun 194:720–725PubMedCrossRefGoogle Scholar
  8. 8.
    Sugo S, Minamino N, Shoji H, et al (1995) Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 207:25–32PubMedCrossRefGoogle Scholar
  9. 9.
    Minamino N, Shoji H, Sugo S, Kangawa K, Matsuo H (1995) Adrenocortical steroids, thyroid hormones and retinoic acid augment the production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 211:686–693PubMedCrossRefGoogle Scholar
  10. 10.
    Sugo S, Minamino N, Shoji H, Kangawa K, Matsuo H (1995) Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. FEBS Lett 369:311–314PubMedCrossRefGoogle Scholar
  11. 11.
    Letizia C, Cerci S, Centanni M, et al (1998) Circulating levels of adrenomedullin in patients with Addison’s disease before and after corticosteroid treatment. Clin Endocrinol (Oxf) 48:145–148CrossRefGoogle Scholar
  12. 12.
    Ornan DA, Chaudry IH, Wang P (1999) Pulmonary clearance of adrenomedullin is reduced during the late stage of sepsis. Biochim Biophys Acta 1427:315–321PubMedGoogle Scholar
  13. 13.
    McLatchie LM, Fraser NJ, Main MJ, et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339PubMedCrossRefGoogle Scholar
  14. 14.
    Hayakawa H, Hirata Y, Kakoki M, et al (1999) Role of nitric oxide-cGMP pathway in adrenomeduliin-induced vasodilation in the rat. Hypertension 33:689–693PubMedGoogle Scholar
  15. 15.
    Nishimatsu H, Suzuki E, Nagata D, et al (2001) Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res 89:63–70PubMedCrossRefGoogle Scholar
  16. 16.
    Ando K, Fujita T (2003) Lessons from the adrenomedullin knockout mouse. Regul Pept 112:185–188PubMedCrossRefGoogle Scholar
  17. 17.
    Shimosawa T, Fujita T (2005) Adrenomedullin as a potent antioxidative and antiatherosclerotic substance. Drug News Perspect 18:185–189PubMedCrossRefGoogle Scholar
  18. 18.
    Murakami S, Kimura H, Kangawa K, Nagaya N (2006) Physiological significance and therapeutic potential of adrenomedullin in pulmonary hypertension. Cardiovasc Hematol Disord Drug Targets 6:125–132PubMedGoogle Scholar
  19. 19.
    Westphal M, Stubbe H, Bone HG, et al (2002) Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. Biochem Biophys Res Commun 296:134–138PubMedCrossRefGoogle Scholar
  20. 20.
    Ishizaka Y, Tanaka M, Kitamura K, et al (1994) Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophys Res Commun 200:642–646PubMedCrossRefGoogle Scholar
  21. 21.
    Nagaya N, Miyatake K, Kyotani S, Nishikimi T, Nakanishi N, Kangawa K (2003) Pulmonary vasodilator response to adrenomedullin in patients with pulmonary hypertension. Hypertens Res 26Suppl:S141–146PubMedCrossRefGoogle Scholar
  22. 22.
    Brett SJ, Simon J, Gibbs R, Pepper JR, Evans TW (1996) Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension. Thorax 51:89–91PubMedCrossRefGoogle Scholar
  23. 23.
    He H, Bessho H, Fujisawa Y, et al (1995) Effects of a synthetic rat adrenomedullin on regional hemodynamics in rats. Eur J Pharmacol 273:209–214PubMedCrossRefGoogle Scholar
  24. 24.
    Ebara T, Miura K, Okumura M, et al (1994) Effect of adrenomedullin on renal hemodynamics and functions in dogs. Eur J Pharmacol 263:69–73PubMedCrossRefGoogle Scholar
  25. 25.
    Del Bene R, Lazzeri C, Barletta G, et al (2000) Effects of low-dose adrenomedullin on cardiac function and systemic haemodynamics in man. Clin Physiol 20:457–465PubMedCrossRefGoogle Scholar
  26. 26.
    Saita M, Shimokawa A, Kunitake T, et al (1998) Central actions of adrenomedullin on cardiovascular parameters and sympathetic outflow in conscious rats. Am J Physiol 274:R979–984PubMedGoogle Scholar
  27. 27.
    Szokodi I, Kinnunen P, Tavi P, Weckstrom M, Toth M, Ruskoaho H (1998) Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide. Circulation 97:1062–1070PubMedGoogle Scholar
  28. 28.
    Allaker RP, Grosvenor PW, McAnerney DC, et al (2006) Mechanisms of adrenomedullin antimicrobial action. Peptides 27:661–666PubMedCrossRefGoogle Scholar
  29. 29.
    Pio R, Martinez A, Unsworth EJ, et al (2001) Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 276:12292–12300PubMedCrossRefGoogle Scholar
  30. 30.
    Pio R, Elsasser TH, Martinez A, Cuttitta F (2002) Identification, characterization, and physiological actions of factor H as an adrenomedullin binding protein present in human plasma. Microsc Res Tech 57:23–27PubMedCrossRefGoogle Scholar
  31. 31.
    Parkes DG, May CN (1995) ACTH-suppressive and vasodilator actions of adrenomedullin in conscious sheep. J Neuroendocrinol 7:923–929PubMedCrossRefGoogle Scholar
  32. 32.
    Samson WK, Murphy T, Schell DA (1995) A novel vasoactive peptide, adrenomedullin, inhibits pituitary adrenocorticotropin release. Endocrinology 136:2349–2352PubMedCrossRefGoogle Scholar
  33. 33.
    Yamaguchi T, Baba K, Doi Y, Yano K, Kitamura K, Eto T (1996) Inhibition of aldosterone production by adrenomedullin, a hypotensive peptide, in the rat. Hypertension 28:308–314PubMedGoogle Scholar
  34. 34.
    Taylor MM, Samson WK (2002) Adrenomedullin and the integrative physiology of fluid and electrolyte balance. Microsc Res Tech 57:105–109PubMedCrossRefGoogle Scholar
  35. 35.
    Owji AA, Smith DM, Coppock HA, et al (1995) An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat. Endocrinology 136:2127–2134PubMedCrossRefGoogle Scholar
  36. 36.
    Lippton H, Chang JK, Hao Q, Summer W, Hyman AL (1994) Adrenomedullin dilates the pulmonary vascular bed in vivo. J Appl Physiol 76:2154–2156PubMedGoogle Scholar
  37. 37.
    Nagaya N, Nishikimi T, Horio T, et al (1999) Cardiovascular and renal effects of adrenomedullin in rats with heart failure. Am J Physiol 276:R213–218PubMedGoogle Scholar
  38. 38.
    Yoshihara F, Nishikimi T, Horio T, et al (1998) Chronic infusion of adrenomedullin reduces pulmonary hypertension and lessens right ventricular hypertrophy in rats administered monocrotaline. Eur J Pharmacol 355:33–39PubMedCrossRefGoogle Scholar
  39. 39.
    Westphal M, Booke M, Dinh-Xuan AT (2004) Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension. Eur Respir J 24:518–520PubMedCrossRefGoogle Scholar
  40. 40.
    Nagaya N, Kyotani S, Uematsu M, et al (2004) Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation 109:351–356PubMedCrossRefGoogle Scholar
  41. 41.
    Nagaya N, Nishikimi T, Uematsu M, et al (2000) Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart 84:653–658PubMedCrossRefGoogle Scholar
  42. 42.
    Nanto S, Kitakaze M, Takano Y, Hori M, Nagata S (1997) Intracoronary administration of adenosine triphosphate increases myocardial adenosine levels and coronary blood flow in man. Jpn Circ J 61:836–842PubMedCrossRefGoogle Scholar
  43. 43.
    Kobayashi K, Kitamura K, Etoh T, et al (1996) Increased plasma adrenomedullin levels in chronic congestive heart failure. Am Heart J 131:994–998PubMedCrossRefGoogle Scholar
  44. 44.
    Richards AM, Doughty R, Nicholls MG, et al (2001) Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol 37:1781–1787PubMedCrossRefGoogle Scholar
  45. 45.
    Richards AM, Nicholls MG, Yandle TG, et al (1998) Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 97:1921–1929PubMedGoogle Scholar
  46. 46.
    Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM (2002) Long-term adrenomedullin administration in experimental heart failure. Hypertension 40:667–672PubMedCrossRefGoogle Scholar
  47. 47.
    Rademaker MT, Charles CJ, Lewis LK, et al (1997) Beneficial hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure. Circulation 96:1983–1990PubMedGoogle Scholar
  48. 48.
    Nagaya N, Satoh T, Nishikimi T, et al (2000) Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure. Circulation 101:498–503PubMedGoogle Scholar
  49. 49.
    Oya H, Nagaya N, Furuichi S, et al (2000) Comparison of intravenous adrenomedullin with atrial natriuretic peptide in patients with congestive heart failure. Am J Cardiol 86:94–98PubMedCrossRefGoogle Scholar
  50. 50.
    Nagaya N, Goto Y, Satoh T, et al (2002) Intravenous adrenomedullin in myocardial function and energy metabolism in patients after myocardial infarction. J Cardiovasc Pharmacol 39: 754–760PubMedCrossRefGoogle Scholar
  51. 51.
    Angus DC, Pereira CA, Silva E (2006) Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets 6:207–212PubMedGoogle Scholar
  52. 52.
    Fowler DE, Wang P (2002) The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein. Int J Mol Med 9:443–449PubMedGoogle Scholar
  53. 53.
    Westphal M, Daudel F, Bone HG, et al (2004) New approach to an ovine model of hypodynamic endotoxaemia. Eur J Anaesthesiol 21:625–631PubMedCrossRefGoogle Scholar
  54. 54.
    Shoemaker WC, Appel PL, Kram HB, Bishop MH, Abraham E (1993) Temporal hemodynamic and oxygen transport patterns in medical patients. Septic shock. Chest 104:1529–1536Google Scholar
  55. 55.
    Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D (1994) Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 330:1717–1722PubMedCrossRefGoogle Scholar
  56. 56.
    Wang P, Zhou M, Ba ZF, Cioffi WG, Chaudry IH (1998) Up-regulation of a novel potent vasodilatory peptide adrenomedullin during polymicrobial sepsis. Shock 10:118–122PubMedCrossRefGoogle Scholar
  57. 57.
    Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH (1998) The pivotal role of adrenomedullin in producing hyperdynamic circulation during the early stage of sepsis. Arch Surg 133:1298–1304PubMedCrossRefGoogle Scholar
  58. 58.
    Hirata Y, Mitaka C, Sato K, et al (1996) Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab 81:1449–1453PubMedCrossRefGoogle Scholar
  59. 59.
    Nishio K, Akai Y, Murao Y, et al (1997) Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit Care Med 25:953–957PubMedCrossRefGoogle Scholar
  60. 60.
    Ueda S, Nishio K, Minamino N, et al (1999) Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med 160:132–136PubMedGoogle Scholar
  61. 61.
    Shindo T, Kurihara H, Maemura K, et al (2000) Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature. Circulation 101:2309–2316PubMedGoogle Scholar
  62. 62.
    Wang P, Yoo P, Zhou M, Cioffi WG, Ba ZF, Chaudry IH (1999) Reduction in vascular responsiveness to adrenomedullin during sepsis. J Surg Res 85:59–65PubMedCrossRefGoogle Scholar
  63. 63.
    Cui Y, Ji Y, Wu R, Zhou M, Wang P (2006) Adrenomedullin binding protein-1 is downregulated during polymicrobial sepsis in the rat. Int J Mol Med 17:925–929PubMedGoogle Scholar
  64. 64.
    Yang S, Zhou M, Chaudry IH, Wang P (2002) 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 236:625–633PubMedCrossRefGoogle Scholar
  65. 65.
    Gonzalez-Rey E, Chorny A, Varela N, Robledo G, Delgado M (2006) Urocortin and adrenomedullin prevent lethal endotoxemia by down-regulating the inflammatory response. Am J Pathol 168:1921–1930PubMedCrossRefGoogle Scholar
  66. 66.
    Zhou M, Ba ZF, Chaudry IH, Wang P (2002) Adrenomedullin binding protein-1 modulates vascular responsiveness to adrenomedullin in late sepsis. Am J Physiol Regul Integr Comp Physiol 283:R553–560PubMedGoogle Scholar
  67. 67.
    Li YY, Wong LY, Cheung BM, Hwang IS, Tang F (2005) Differential induction of adrenomedullin, interleukins and tumour necrosis factor-alpha by lipopolysaccharide in rat tissues in vivo. Clin Exp Pharmacol Physiol 32:1110–1118PubMedCrossRefGoogle Scholar
  68. 68.
    Kubo A, Minamino N, Isumi Y, et al (1998) Production of adrenomedullin in macrophage cell line and peritoneal macrophage. J Biol Chem 273:16730–16738PubMedCrossRefGoogle Scholar
  69. 69.
    Isumi Y, Kubo A, Katafuchi T, Kangawa K, Minamino N (1999) Adrenomedullin suppresses interleukin-1beta-induced tumor necrosis factor-alpha production in Swiss 3T3 cells. FEBS Lett 463:110–114PubMedCrossRefGoogle Scholar
  70. 70.
    Wong LY, Cheung BM, Li YY, Tang F (2005) Adrenomedullin is both proinflammatory and antiinflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line. Endocrinology 146:1321–1327PubMedCrossRefGoogle Scholar
  71. 71.
    Bone RC (1996) Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 24:1125–1128PubMedCrossRefGoogle Scholar
  72. 72.
    Yang S, Zhou M, Fowler DE, Wang P (2002) Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines. Crit Care Med 30:2729–2735PubMedCrossRefGoogle Scholar
  73. 73.
    Wang P, Ba ZF, Chaudry IH (1994) Nitric oxide. To block or enhance its production during sepsis? Arch Surg 129:1137–1142; discussion 1142–1133PubMedGoogle Scholar
  74. 74.
    Zhou M, Wang P, Chaudry IH (1997) Endothelial nitric oxide synthase is downregulated during hyperdynamic sepsis. Biochim Biophys Acta 1335:182–190PubMedGoogle Scholar
  75. 75.
    Hotchkiss RS, Swanson PE, Freeman BD, et al (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27:1230–1251PubMedCrossRefGoogle Scholar
  76. 76.
    Hotchkiss RS, Chang KC, Swanson PE, et al (2000) Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1:496–501PubMedCrossRefGoogle Scholar
  77. 77.
    Kato H, Shichiri M, Marumo F, Hirata Y (1997) Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. Endocrinology 138:2615–2620PubMedCrossRefGoogle Scholar
  78. 78.
    Troughton RW, Lewis LK, Yandle TG, Richards AM, Nicholls MG (2000) Hemodynamic, hormone, and urinary effects of adrenomedullin infusion in essential hypertension. Hypertension 36:588–593PubMedGoogle Scholar
  79. 79.
    Westphal M, Sander J, Van Aken H, Ertmer C, Stubbe HD, Booke M (2006) [Role of adrenomedullin in the pathogenesis and treatment of cardiovascular dysfunctions and sepsis]. Anaesthesist 55:171–178PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media Inc. 2007

Authors and Affiliations

  • C. Ertmer
    • 1
  • H. Van Aken
    • 1
  • M. Westphal
    • 1
  1. 1.Department of Anesthesiology and Intensive CareUniversity HospitalMuensterGermany

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