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01.04.2007 | Experimental

Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

verfasst von: Bettina Temmesfeld-Wollbrück, Bernhard Brell, István Dávid, Martin Dorenberg, Jörn Adolphs, Bernd Schmeck, Norbert Suttorp, Stefan Hippenstiel

Erschienen in: Intensive Care Medicine | Ausgabe 4/2007

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Abstract

Objective

Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival.

Design

Prospective randomized controlled animal study.

Subjects

Male Sprague–Dawley rats (270 g).

Interventions

We used 4.8 × 10³ U/kg of Staphylococcus aureus α-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 μg/kg per hour. Adrenomedullin was started 1 h after α-toxin administration.

Measurement and results

Infusion of α-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. α-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after α-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 μg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement.

Conclusions

These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.

Nur mit Berechtigung zugänglich

Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554PubMedCrossRef

Hinshaw LB (1996) Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med 24:1072–1078PubMedCrossRef

Volk T, Kox WJ (2000) Endothelium function in sepsis. Inflamm Res 49:185–198PubMedCrossRef

Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101:3765–3777PubMedCrossRef

Orfanos SE, Mavrommati I, Korovesi I, Roussos C (2004) Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med 30:1702–1714PubMedCrossRef

Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo H, Fujimura Y, Yoshioka A, Masui K, Doi N, Murao Y, Miyamoto S (1999) Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med 160:132–136PubMed

Shindo T, Kurihara H, Maemura K, Kurihara Y, Kuwaki T, Izumida T, Minamino N, Ju KH, Morita H, Oh-hashi Y, Kumada M, Kangawa K, Nagai R, Yazaki Y (2000) Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature. Circulation 101:2309–2316PubMed

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 30:2729–2735PubMedCrossRef

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 236:625–633PubMedCrossRef

10.

Cui X, Wu R, Zhou M, Dong W, Ulloa L, Yang H, Wang H, Tracey KJ, Simms HH, Wang P (2005) Adrenomedullin and its binding protein attenuate the proinflammatory response after hemorrhage. Crit Care Med 33:391–398PubMedCrossRef

11.

Sata M, Kakoki M, Nagata D, Nishimatsu H, Suzuki E, Aoyagi T, Sugiura S, Kojima H, Nagano T, Kangawa K, Matsuo H, Omata M, Nagai R, Hirata Y (2000) Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. Hypertension 36:83–88PubMed

12.

Westphal M, Stubbe H, Bone HG, Daudel F, Vocke S, Van Aken H, Booke M (2002) Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. Biochem Biophys Res Commun 296:134–138PubMedCrossRef

13.

De Matteo R, May CN (2003) Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide. Br J Pharmacol 140:1414–1420PubMedCrossRef

14.

Stangl V, Dschietzig T, Bramlage P, Boye P, Kinkel HT, Staudt A, Baumann G, Felix SB, Stangl K (2000) Adrenomedullin and myocardial contractility in the rat. Eur J Pharmacol 408:83–89PubMedCrossRef

15.

Parkes DG, May CN (1997) Direct cardiac and vascular actions of adrenomedullin in conscious sheep. Br J Pharmacol 120:1179–1185PubMedCrossRef

16.

Charles CJ, Jardine DL, Nicholls MG, Richards AM (2005) Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep. J Endocrinol 187:275–281PubMedCrossRef

17.

Hippenstiel S, Witzenrath M, Schmeck B, Hocke A, Krisp M, Krull M, Seybold J, Seeger W, Rascher W, Schutte H, Suttorp N (2002) Adrenomedullin reduces endothelial hyperpermeability. Circ Res 91:618–625PubMedCrossRef

18.

Brell B, Temmesfeld-Wollbruck B, Altzschner I, Frisch E, Schmeck B, Hocke AC, Suttorp N, Hippenstiel S (2005) Adrenomedullin reduces Staphylococcus aureus alpha-toxin-induced rat ileum microcirculatory damage. Crit Care Med 33:819–826PubMedCrossRef

19.

Lowy FD (1998) Staphylococcus aureus infections. N Engl J Med 339:520–532PubMedCrossRef

20.

Seeger W, Birkemeyer RG, Ermert L, Suttorp N, Bhakdi S, Duncker HR (1990) Staphylococcal alpha-toxin-induced vascular leakage in isolated perfused rabbit lungs. Lab Invest 63:341–349PubMed

21.

Grimminger F, Rose F, Sibelius U, Meinhardt M, Potzsch B, Spriestersbach R, Bhakdi S, Suttorp N, Seeger W (1997) Human endothelial cell activation and mediator release in response to the bacterial exotoxins Escherichia coli hemolysin and staphylococcal alpha-toxin. J Immunol 159:1909–1916PubMed

22.

Brell B, Hippenstiel S, David I, Pries AR, Habazettl H, Schmeck B, Suttorp N, Temmesfeld-Wollbruck B (2005) Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus aureus alpha-toxin–an intravital microscopic study on an isolated rat ileum. Crit Care Med 33:2810–2816PubMedCrossRef

23.

Sibelius U, Grandel U, Buerke M, Mueller D, Kiss L, Kraemer HJ, Braun-Dullaeus R, Haberbosch W, Seeger W, Grimminger F (2000) Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation. Circulation 101:78–85PubMed

24.

Temmesfeld-Wollbruck B, Szalay A, Mayer K, Olschewski H, Seeger W, Grimminger F (1998) Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine. Am J Respir Crit Care Med 157:1586–1592PubMed

25.

Cabrales P, Acero C, Intaglietta M, Tsai AG (2003) Measurement of the cardiac output in small animals by thermodilution. Microvasc Res 66:77–82PubMedCrossRef

26.

Patterson CE, Rhoades RA, Garcia JG (1992) Evans blue dye as a marker of albumin clearance in cultured endothelial monolayer and isolated lung. J Appl Physiol 72:865–873PubMedCrossRef

27.

Falk S, Goggel R, Heydasch U, Brasch F, Muller KM, Wendel A, Uhlig S (1999) Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation. Am J Respir Crit Care Med 160:1734–1742PubMed

28.

Forgacs B, Eibl G, Faulhaber J, Kahrau S, Buhr H, Foitzik T (2000) Effect of fluid resuscitation with and without endothelin A receptor blockade on hemoconcentration and organ function in experimental pancreatitis. Eur Surg Res 32:162–168PubMedCrossRef

29.

Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317PubMedCrossRef

30.

Richards MJ, Edwards JR, Culver DH, Gaynes RP (1999) Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. Crit Care Med 27:887–892PubMedCrossRef

31.

Soderquist B, Colgue-Navarro P, Blomquist L, Olcén P, Holmberg H, Möllby R (1993) Staphylococcal alpha-toxin in septicaemic patients; detection in serum, antibody response and production in isolated strain. Serodiagn Immunother Infect Dis 5:139–144CrossRef

32.

Li S, Arvidson S, Mollby R (1997) Variation in the agr-dependent expression of alpha-toxin and protein A among clinical isolates of Staphylococcus aureus from patients with septicaemia. FEMS Microbiol Lett 152:155–161PubMedCrossRef

33.

Kernodle DS, Voladri RK, Menzies BE, Hager CC, Edwards KM (1997) Expression of an antisense hla fragment in Staphylococcus aureus reduces alpha-toxin production in vitro and attenuates lethal activity in a murine model. Infect Immun 65:179–184PubMed

34.

Patel AH, Nowlan P, Weavers ED, Foster T (1987) Virulence of protein A-deficient and alpha-toxin-deficient mutants of Staphylococcus aureus isolated by allele replacement. Infect Immun 55:3103–3110PubMed

35.

Blomqvist L, Appelgren LE, Thelestam M (1987) Distribution of 3H-labeled staphylococcal alpha-toxin and a toxin fragment in mice. Infect Immun 55:1906–1913PubMed

36.

Lortie M, Gauthier B, Plante GE (1994) Renal reperfusion injury: sequential changes in function and regional albumin extravasation. Microvasc Res 48:295–302PubMedCrossRef

37.

Suttorp N, Hessz T, Seeger W, Wilke A, Koob R, Lutz F, Drenckhahn D (1988) Bacterial exotoxins and endothelial permeability for water and albumin in vitro. Am J Physiol 255:C368–C376PubMed

38.

Bhakdi S, Tranum-Jensen J (1991) Alpha-toxin of Staphylococcus aureus. Microbiol Rev 55:733–751PubMed

39.

40.

Ross GR, Yallampalli C (2007) Vascular hyper-responsiveness to adrenomedullin during pregnancy is associated with increased generation of cyclic nucleotides in rat mesenteric artery. Biol Reprod 76:118–123PubMedCrossRef

41.

Okamura T, Ayajiki K, Kangawa K, Toda N (1997) Mechanism of adrenomedullin-induced relaxation in isolated canine retinal arteries. Invest Ophthalmol Vis Sci 38:56–61PubMed

42.

Caron KM, Smithies O (2001) Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene. Proc Natl Acad Sci USA 98:615–619PubMedCrossRef

43.

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377PubMedCrossRef

Titel: Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock
verfasst von: Bettina Temmesfeld-Wollbrück
Bernhard Brell
István Dávid
Martin Dorenberg
Jörn Adolphs
Bernd Schmeck
Norbert Suttorp
Stefan Hippenstiel
Publikationsdatum: 01.04.2007
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 4/2007
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0561-y

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Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock