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Vol. 103, No. 2, 2005
Issue release date: February 2005
Cardiology 2005;103:92–100

Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

Azab A.N. · Kobal S. · Rubin M. · Kaplanski J.
aDepartment of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, and bDepartment of Cardiology, Soroka University Medical Center, Beer-Sheva, Israel

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Prostanoids and cytokines are known to play a pivotal role in the mechanisms leading to endotoxin-induced cardiovascular failure. We investigated the effect of nimesulide (NIM), a selective cyclooxygenase-2 (COX-2) inhibitor, on the cardiovascular alterations occurring during endotoxemia, and on prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in endotoxemic rats. NIM significantly reduced endotoxin-induced elevation of plasma and myocardial levels of TNF-α, but not those of IL-1β. Searching for the mechanism underlying the anti-TNF-α effect of NIM, it was found that the drug reduced nuclear factor kappa B activation through diminished nuclear levels of p-65 accompanied by a protective effect against the cardiovascular alterations and mortality seen during endotoxemia. In addition, the inhibitory effect of NIM on endotoxin-induced elevation in plasma and hypothalamic levels of PGE2 was noteworthy, and this may suggest that the large amounts of PGE2 observed during endotoxemia are mainly produced via COX-2.

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  1. Sriskandan S, Cohen J: The pathogenesis of septic shock. J Infect 1995;30:201–206.
  2. Beutler B, Kruys V: Lipopolysaccharide signal transduction, regulation of tumor necrosis factor biosynthesis, and signaling by tumor necrosis factor itself. J Cardiovasc Pharmacol 1995;25:S1–S8.

    External Resources

  3. Van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJ, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990;322:1622–1627.
  4. Van der Poll T, Lowry SF: Tumor necrosis factor in sepsis: Mediator of multiple organ failure or essential part of host defense? Shock 1995;3:1–12.
  5. Chernow B, Rainey TG, Lake CR: Endogenous and exogenous catecholamines in critical care medicine. Crit Care Med 1982;10:409–416.
  6. Hollenberg SM, Tangora JJ, Piotrowski MJ, Easington C, Parrillo JE: Impaired microvascular vasoconstrictive responses to vasopressin in septic rats. Crit Care Med 1997;25:869–873.
  7. Masferrer JL, Zweifel BS, Seibert K, Needleman P: Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest 1990;86:1375–1379.
  8. Chemo A, Fraifeld V, Abramovich L, Sod-Moriah UA, Kaplanski J: Tolerance to lipopolysaccharide is not related to the ability of the hypothalamus to produce prostaglandin E2. Life Sci 1997;61:813–818.
  9. Feuerstein G, Hallenbeck JM: Prostaglandins, leukotrienes, and platelet-activating factor in shock. Annu Rev Pharmacol Toxicol 1987;27:301–313.
  10. Hocherl K, Dreher F, Kurtz A, Bucher M: Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure. Hypertension 2002;40:947–953.
  11. Leach M, Hamilton LC, Olbrich A, Wray GM, Thiemermann C: Effects of inhibitors of the activity of cyclooxygenase-2 on the hypotension and multiple organ dysfunction caused by endotoxin – a comparison with dexamethasone. Br J Pharmacol 1998;124:586–592.
  12. Ruetten H, Thiemermann C: Combination immunotherapy which neutralises the effects of TNF alpha and IL-1 beta attenuates the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat. J Physiol Pharmacol 1997;48:605–621.
  13. Kapadia S, Lee J, Torre-Amione G, Birdsall HH, Ma TS, Mann DL: Tumor necrosis factor alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995;96:1042–1052.
  14. Parker J, Adams HR: Development of myocardial dysfunction in endotoxin shock. Am J Physiol 1985;248:H818–H826.
  15. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995;273:934–941.
  16. Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, Zwingelstein C, Lesslauer W, Leighton A: p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis, and septic shock. JAMA 1997;277:1531–1538.
  17. Cohen J, Carlet J: INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor α in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 1996;24:1431–1440.
  18. Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal Nogare A, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light RB, Poole L, Allred R, Constant J, Pennington J, Porter S: Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 1998;351:929–933.
  19. Abraham E, Laterre PF, Garbino J, Pingleton S, Butler T, Dugernier T, Margolis B, Kudsk K, Zimmerli W, Anderson P, Reynaert M, Lew D, Lesslauer W, Passe S, Cooper P, Burdeska A, Modi M, Leighton A, Salgo M, Van der Auwera P; Lenercept Study Group: Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001;29:503–510.
  20. Azab AN, Fraifeld V, Kaplanski J: Nimesulide prevents lipopolysaccharide induced elevation in plasma tumor necrosis factor α in rats. Life Sci 1998;63:323–327.

    External Resources

  21. Azab AN, Kaplanski J: A reduction of tumor necrosis factor α in paw exudate of lipopolysaccharide treated rats by nimesulide. Life Sci 2001;68:1667–1675.
  22. Pizzaro TT, Malinowska K, Kovocs EJ, Clancy J, Robinson JA, Piccinini LA: Induction of TNF α and TNF β gene expression in rat cardiac transplants during allograft rejection. Transplantation 1993;56:399–404.
  23. Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL: Tumor necrosis factor α and tumor necrosis factor receptors in the failing human heart. Circulation 1996;93:704–711.
  24. D’Acquisto F, Iuvone T, Rombola L, Sautebin L, Di Rosa M, Carnuccio R: Involvement of NF-κB in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages. FEBS Lett 1997;418:175–178.
  25. Arons MM, Wheeler AP, Bernard GR, Christman BW, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson W, Wright P, Dupont WD, Swindell BB: Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 1999;27:699–707.
  26. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB: The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 1997;336:912–918.
  27. Haupt MT, Jastremski MS, Clemmer TP, Metz CA, Goris GB: Effect of ibuprofen in patients with severe sepsis – a randomized, double-blind, multicenter study. Crit Care Med 1991;19:1339–1347.
  28. Leeper-Woodford SK, Carey D, Byrne K, Walsh C, Fisher B, Sugerman HJ, Fowler AA: Histamine receptor antagonists, cyclooxygenase blockade, and tumor necrosis factor during acute septic insult. Shock 1998;9:89–94.
  29. Matsumuri A, Yamada T, Suzuki H, Matoba Y, Sasayama S: Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 1994;72:561–566.
  30. Li D, Li Z, Liu M, Du X, Ding W, Zhang J, Mehta JL: Kinetics of tumor necrosis factor α in plasma and the cardioprotective effect of monoclonal antibody to tumor necrosis factor α in acute myocardial infarction. Am Heart J 1999;137:1145–1152.
  31. Suffredini AF, Fromm RE, Parker MM, Brenner M, Covacs JA, Wesley RA, Parrillo JE: The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989;321:280–287.
  32. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A: Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–664.
  33. Ferreira SH: The role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral analgesics. Drugs 1993;46(suppl 1):1–9.
  34. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP: The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA 1995;273:117–123.
  35. Wenzel RP: Anti-endotoxin monoclonal antibodies: A second look. N Engl J Med 1992;326:1151–1153.
  36. Almqvist PM, Ekstrom B, Kuenzing M, Haglund U, Schartz SI: Increased survival of endotoxin-injected dogs treated with methylprednisolone, naloxone, and ibuprofen. Circ Shock 1984;14:129–136.
  37. Kojima M, Morisaki T, Izuhara K, Uchiyama A, Matsunari Y, Katano M, Tanaka M: Lipopolysaccharide increases cyclooxygenase-2 expression in a colon carcinoma cell line through nuclear factor-κB activation. Oncogene 2000;19:1225–1231.
  38. Stuhlmeier KM, Li H, Kao JJ: Ibuprofen – new explanation for old phenomenon. Biochem Pharmacol 1999;57:313–320.
  39. Shao J, Fujiwara T, Kadowaki Y, Fukazawa T, Waku T, Itoshima T, Yamatsuji T, Nishizaki M, Roth JA, Tanaka N: Overexpression of the wild-type p53 gene inhibits NF-κB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells. Oncogene 2000;19:726–736.
  40. Yamamoto Y, Gaynor RB: Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J Clin Invest 2001;107:135–142.
  41. Motomura K, Sakai H, Isobe H, Nawata H: Effects of retinoids on the production of tumour necrosis factor-alpha and nitric oxide by lipopolysaccharide-stimulated rat Kupffer cell in vitro: Evidence for participation of retinoid X receptor signaling pathway. Cell Biochem Funct 1997;15:95–101.
  42. Wang S, Lantz RC, Rider ED, Chen GJ, Breceda V, Hays AM, Robledo RF, Tollinger BJ, Dinesh SV, Witten ML: A free radical scavenger (Lazaroid U75412E) attenuates tumor necrosis factor-alpha generation in a rabbit model of smoke-induced lung injury. Respiration 1997;64:358–363.
  43. Davis R, Brogden RN: Nimesulide: An update of its pharmacodynamics and pharmacokinetics properties, and therapeutic efficacy. Drugs 1994;48:431–454.
  44. Karin M, Cao Y, Greten FR, Li ZW: NF-κB in cancer – from innocent bystander to major culprit. Nat Rev Cancer 2002;2:301–310.

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