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Adrenomedullin and cardiovascular responses in sepsis

Adrenomedullin and cardiovascular responses in sepsis. TU Jie March 19, 2004. Introduction. Sepsis, septic shock: the major cause of high mortality in intensive care units Adrenomedullin (ADM or AM): produced in abnormally large quantities.

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Adrenomedullin and cardiovascular responses in sepsis

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  1. Adrenomedullinand cardiovascular responses in sepsis TU Jie March 19, 2004

  2. Introduction • Sepsis, septic shock: the major cause of high mortality in intensive care units • Adrenomedullin (ADM or AM): produced in abnormally large quantities

  3. Molecular structure of AM: 52-amino acid peptide, first reported in 1993 Distribution of AM: plasma, heart, lung, kidney, stomach, endothelial cells, smooth muscles, epithelial cells …

  4. Molecular structure of AM: 52-amino acid peptide, first reported in 1993 • Distribution of AM: plasma, heart, lung, kidney, stomach, endothelial cells, smooth muscles, epithelial cells …

  5. Functions of AM: endocrine factor as well as a local autocrine and paracrine factor with cardiovascular and renal actions be of particular interest in pathophysiology of sepsis

  6. AM receptor and AM-binding protein • the existence of AM binding sites in blood vessels, heart, lung, spleen, liver … • two AM receptor subtypes: CGRP-like receptor and AM specific receptor

  7. RAMP1/CRLR=CGRP recptor RAMP2/CRLR=AM receptor RAMP3/CRLR ?AM receptor • RAMPs: a novel family of single transmembrane proteins, three isoforms • CRLR: calcitonin-receptor-like receptor, an orphan recptor with seven transmembrane domains • the function of RAMP/CRLR complex (depending on the expression of RAMP)

  8. AM binding protein: 120 and/or 140 kDa in mammalian blood • AMBP-1: identical to human complement factor H • AMBP-1 may affect the function and bioactivity of AM • The circulating level of AMBP-1 during sepsis: remains unknown

  9. Nishio K, Akai Y, Murao Y et al. Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock: Crit Care Med. 1997, 25(6):953-7 Zhou M, Chaudry IH, Wang P. Adrenomedullin is upregulated in the heart and aorta during the early and late stages of sepsis. Biochim Biophys Acta. 1999 , 24;1453(2):273-83. Upregulation of AM in sepsis Plasma concentration of adrenomedullin in patients with septic shock and in control patients. **p <0.01 between groups. Changes in cardiac ADM levels at 5 and 20 h after cecal ligation and puncture (CLP) or sham-operation (sham). *P<0.05 versus the respective sham.

  10. LPS: stimulating AM production Jean Marc Hyvelin, Qixian Shan, Jean Pierre Bourreau. Adrenomedullin: a cardiac depressant factor in septic shock.J Card Surg, 2002, 17(4):328-35

  11. Matheson PJ, Mays MP, Hurt RTet al. Adrenomedullin is increased in the portal circulation during chronic sepsis in rats. Am J Surg, 2003, 186 (5):519-25 Acute Escherichia coli bacteremia stimulated adrenomedullin tissue levels in the lung, spleen, and small intestine. *P < 0.05 versus saline controls.

  12. Time course of the effects of IL-1ß ( ) and TNF ( ) on the secretion of ir-AM in cultured cardiac myocytes (A) and nonmyocytes (B). Control ( ) indicates basal secretion. *P < 0.05; ***P < 0.001 (compared with the control). Takeshi Horio, Toshio Nishikimi, Fumiki Yoshihara et al. Production and Secretion of Adrenomedullin in Cultured Rat Cardiac Myocytes and Nonmyocytes: Stimulation by Interleukin-1ß and Tumor Necrosis Factor-a. Endocrinology, 1998, 139(11): 4576-80 • Proinflammatory cytokines (e.g. TNF-a, IL-1b): participating in the overproduction of AM Quantitative analysis of AM transcripts in cultured cardiac myocytes (A) and nonmyocytes (B) with or without treatment with IL-1ß or TNF . Open bars, Control; solid bars, IL-1ß; hatched bars, TNF. *P < 0.05; **P < 0.01; ***P < 0.001 (compared with the control).

  13. The role of AM in the hemodynamic alterations during sepsis • AM increases in cardiovascular system during sepsis • a biphasic hemodynamic response during the progession of sepsis

  14. Correlations between the plasma concentration of adrenomedullin and cardiac index, stroke volume index, systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) in patients with septic shock. Nishio Kenji, Akai Yasuhiro, Murao Yoshinori et al. Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Critical care medicine, 1997, 25(6): 953-957 • Upregulation of AM in proportion to the severity of hyperdynamic state of septic shock

  15. on smoonth muscle cells Ca2+ cAMP Vascular relaxation on endothelial cells NO Intracellular signaling transduction of AM • Vasodilatory actions

  16. Actions on the heart 1. the negative inotropic effect: NO/sGC/cGMP pathway Effects of AM on myocyte contraction and intracellular calcium. Modification of effect of AM by methylene (Meth.) blue Influence of L-NMMA on negative inotropic effect of AM

  17. Hiroshi Ikenouchi, Kenji Kangawa, Hisayuki Matsuo et al. Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes. Circulation, 1997, 95(9), 2318-2324 Effects of AM on intracellular cGM

  18. Szokodi I, Kinnunen P, Tavi P et al. Evidence for cAMP-independent mechanisms mechanisms mediating the effects of adrenomedullin, a new inotropic peptide. Circulation, 1998, 97(11): 1062-1070 2. the positive inotropic effect: (1) cAMP-independent mechanism • A A, Effect of ADM and PAMP on developed tension (DT) in isolated perfused, paced rat hearts; B, Effect of ADM alone or in combination with CGRP8–37, a CGRP receptor antagonist, on DT in isolated perfused, paced rat hearts. A, Effect of ADM alone or in combination with H-89, a protein kinase A inhibitor, on developed tension (DT) in isolated perfused, paced rat hearts; B, Effect of ADM and isoproterenol (ISO) on cAMP levels of the perfused hearts.

  19. (2) cAMP-dependent pathway (2) Dose-dependent effects of adrenomedullin on the force of rat papillary muscle. Dose-dependent effects of adrenomedullin on intracellular cAMP level in rat papillary muscle. Ihara T, Ikeda U, Tate Y et al. Positive inotropic effects of adrenomedullin on rat papillary muscle. Eur. J. Pharmacol, 2000, 309: 167-172

  20. Shivani Mittra, Jean- Marc Hyvelin, Qixian Shan et al. Role of cyclo-oxygenase in the ventricular effects of adrenomedullin Is adrenomedullin a double-edged sword in sepsis? American Journal of Physiology, 2004 (accepted) 3. a dual inotropic effect of AM: • A. Positive effect B. negative effect of ADM on Ca2+ transient • Positive and negative effect of ADM on cell shortening in response to electrical-field stimulation in normal myocytes at 30 mins and at >1 hour. • Pretreatment with ADM (22-52) abolished both the effects. *P< 0.05 vs control; P< 0.05 vs ADM (1-52) group.

  21. Shivani Mittra, Jean- Marc Hyvelin, Qixian Shan et al. Role of cyclo-oxygenase in the ventricular effects of adrenomedullin Is adrenomedullin a double-edged sword in sepsis? American Journal of Physiology, 2004 (accepted) 4.the negative effect of AM on the LPS-treated rat isolated myocytes • The amplitude of the calcium transient elicited in myocytes isolated from LPS treated rats by electrical-field stimulation was significantly decreased as compared to transients obtained in myocytes isolated from control rats. ADM(22-52) abolished this effect of LPS on the myocytes; • B. In LPS- treated cells the cell shortening was markedly decreased and incubation with of ADM (22-52) or anti-ADM (rat)-IgG restored the cell contractility

  22. Shivani Mittra, Jean- Marc Hyvelin, Qixian Shan et al. Role of cyclo-oxygenase in the ventricular effects of adrenomedullin. Is adrenomedullin a double-edged sword in sepsis? American Journal of Physiology, 2004 (accepted) Effect of indomethacin (A, C), SC-236 (A, C), tranylcypromine (B, D) and SQ 29548 (B, D) on decreased Ca2+ transient (A, B) and cell shortening (C, D) in LPS treated rat ventricular myocytes. *P< 0.05 vs control; P< 0.05 vs LPS treated cells.

  23. Modulation of AM in sepsis • an anti-inflammatory factor • Early producion of AM prolongs the hyperdynamic and hypercardiovascular response during sepsis • Protective against circulation collapse, organ damage

  24. Future area of research • Whether AM downregulates proinflammatory cytokines • Whether AM gene delivery prolongs the hyperdynamic response in sepsis • Whether one the mechanisms responsible for the protective effects by AM is due to an increase in endothelium-derived NO release

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