Advertisement

BioDrugs

, Volume 7, Issue 2, pp 107–118 | Cite as

Implications of Cytokine Inhibition for the Drug Therapy of Heart Failure

  • Akira Matsumori
Biopharmaceuticals
  • 16 Downloads

Summary

Cytokines are being increasingly recognised as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. In our murine model of congestive heart failure resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. Vesnarinone inhibited the increase in natural killer cell activity and production of tumour necrosis factor-α (TNFα) in this animal model. Vesnarinone also inhibited the production of various cytokines by peripheral blood and by endothelial cells.

These findings provide evidence that vesnarinone plays an important role in the regulation of cytokine production, and suggest that the reduction of cytokine release may contribute to the beneficial effects of the drug for the treatment of heart failure. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.

Keywords

Heart Failure Myocarditis Natural Killer Cell Activity Rolipram Phosphodiesterase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

This work was supported, in part, by a Research Grant from the Ministry of Health and Welfare and a Grant-in-Aid for Development Scientific Research and for General Scientific Research from the Ministry of Education, Science and Culture, Japan.

Referencesd

  1. 1.
    Cohn JN. Current therapy of the failing heart. Circulation 1988; 78: 1099–1107PubMedCrossRefGoogle Scholar
  2. 2.
    Benotti JR, Grossman W, Braunwald E, et al. Hemodynamic assessment of amrinone: a new inotropic agent. N Engl J Med 1978; 299: 1373–7PubMedCrossRefGoogle Scholar
  3. 3.
    Packer M, Leier CV. Survival in congestive heart failure during treatment with drugs with positive inotropic actions. Circulation 1987; 75Suppl. IV: 55–63Google Scholar
  4. 4.
    Massie B, Bourassa M, DiBianco R, et al. Long-term oral administration of amrinone for congestive heart failure: lack of efficacy in a multicenter controlled trial. Circulation 1985; 71: 963–71PubMedCrossRefGoogle Scholar
  5. 5.
    Petein M, Levine B, Cohn JN. Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19,205) in patients with congestive heart failure. Circulation 1986; 73Suppl. III: 203–36Google Scholar
  6. 6.
    Uretsky BF, Jessup M, Konstam MA, et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: lack of benefit compared with placebo. Circulation 1990; 82: 774–80PubMedCrossRefGoogle Scholar
  7. 7.
    Dies F, Krell MJ, Whitlow P, et al. Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure. Circulation 1986; 74Suppl. II: 38Google Scholar
  8. 8.
    Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1–6Google Scholar
  9. 9.
    Katz AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation 1986; 73: 184–90Google Scholar
  10. 10.
    Iijima T, Taira N. Membrane current changes responsible for the positive inotropic effects of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 1987; 240: 657–62PubMedGoogle Scholar
  11. 11.
    Sasayama S, Inoue M, Asanoi H, et al. Acute hemodynamic effects of a new inotropic agent, OPC-8212, on severe congestive heart failure. Heart Vessels 1986; 2: 23–8PubMedCrossRefGoogle Scholar
  12. 12.
    Sasayama S, OPC-8212 Multicenter Research Group. A placebo-controlled, randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure. Cardiovasc Drugs Ther 1990; 4: 419–26CrossRefGoogle Scholar
  13. 13.
    Feldman AM, Vesnarinone Study Group. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 1993; 329: 149–55PubMedCrossRefGoogle Scholar
  14. 14.
    Sasayama S. What do the newer inotropic drugs have to offer? Cardiovasc Drugs Ther 1992; 6: 15–8PubMedCrossRefGoogle Scholar
  15. 15.
    Bertolet BD, White BG, Pepine CJ. Neutropenia occurring during treatment with vesnarinone. Am J Cardiol 1994; 74: 968–70PubMedCrossRefGoogle Scholar
  16. 16.
    Gulick T, Pieper ST, Murphy MA, et al. A new method for assessment of cultured cardiac myocyte contractility detects immune factor-mediated inhibition of (β-adrenergic responses. Circulation 1991; 84: 313–21PubMedCrossRefGoogle Scholar
  17. 17.
    Gulick T, Chung ML, Pieper SJ, et al. Interleukin-1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci USA 1989; 86: 6753–7PubMedCrossRefGoogle Scholar
  18. 18.
    Balligand JL, Ungureanu D, Kelly RA, et al. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage conditioned medium. J Clin Invest 1993; 91: 2314–9PubMedCrossRefGoogle Scholar
  19. 19.
    Beck AC, Ward JH, Hammond EH, et al. Cardiomyopathy associated with high-dose interleukin-2 (IL-2) therapy. West J Med 1991; 158: 293–6Google Scholar
  20. 20.
    Sobotka PA, McMannis J, Fisher RI, et al. Effects of interleukin-2 on cardiac function in the isolated rat heart. J Clin Invest 1990; 86: 845–50PubMedCrossRefGoogle Scholar
  21. 21.
    Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–9PubMedCrossRefGoogle Scholar
  22. 22.
    Brady AJB, Poole-Wilson PA, Harding SE, et al. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263: 1963–6Google Scholar
  23. 23.
    Yokoyama T, Vaca L, Rossen RD, et al. Cellular basis for the negative inotropic effects of tumor necrosis factor-α in the adult mammalian heart. J Clin Invest 1993; 92: 2303–12PubMedCrossRefGoogle Scholar
  24. 24.
    Levine B, Kalman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323: 236–41PubMedCrossRefGoogle Scholar
  25. 25.
    Matsumori A, Yamada T, Suzuki H, et al. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 1994; 72: 561–6PubMedCrossRefGoogle Scholar
  26. 26.
    Katz SD, Rao R, Berman JW, et al. Pathophysiological correlates of increased serum tumor necrosis factor in patients with congestive heart failure: relation to nitric oxide-dependent vasodilation in the forearm circulation. Circulation 1994; 90: 12–6PubMedCrossRefGoogle Scholar
  27. 27.
    Ikeda U, Ohkawa F, Seino Y, et al. Serum interleukin-6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol 1992; 24: 579–584PubMedCrossRefGoogle Scholar
  28. 28.
    Latini R, Bianchi M, Correale E, et al. Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin-1 receptor antagonist. J Cardiovasc Pharmacol 1994; 23: 1–6PubMedGoogle Scholar
  29. 29.
    Ghezzi P, Dinarello CA, Bianchi M, et al. Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells. Cytokine 1991; 3: 189–94PubMedCrossRefGoogle Scholar
  30. 30.
    Yamauchi-Takihara K, Ihara Y, Ogata A, et al. Hypoxic stress induces cardiac myocyte-derived interleukin-6. Circulation 1995; 91: 1520–4PubMedCrossRefGoogle Scholar
  31. 31.
    Lantz M, Thysell H, Nilsson E, et al. On the binding of tumor necrosis factor (TNF) to heparin and the release in vivo of the TNF-binding protein I by heparin. J Clin Invest 1991; 88: 2026–31PubMedCrossRefGoogle Scholar
  32. 32.
    Kapadia S, Torre-Amione G, Yokoyama T, et al. Soluble binding proteins modulate the negative inotropic properties of TNF-α in vitro. Am J Physiol 1995; 268: H517–25PubMedGoogle Scholar
  33. 33.
    Bromberg JS, Chavin KD, Kunkel SL. Anti-tumor necrosis factor antibodies suppress cell-mediated immunity in vivo. J Immunol 1992; 148: 3412–7PubMedGoogle Scholar
  34. 34.
    Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell 1994; 76: 253–62PubMedCrossRefGoogle Scholar
  35. 35.
    Matsumori A, Kawai C. An experimental model for congestive heart failure after encephalomyocarditis virus myocarditis in mice. Circulation 1982; 65: 1230–5PubMedCrossRefGoogle Scholar
  36. 36.
    Matsumori A, Kawai C. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation 1982; 66: 355–60PubMedCrossRefGoogle Scholar
  37. 37.
    Matsumori A. Lessons from animal experiments in myocarditis. Herz 1992; 17: 107–11PubMedGoogle Scholar
  38. 38.
    Matsumori A. Animal models: pathological findings and therapeutic considerations. In: Banatvala JE, editor. Viral infection of the heart. London: Edward Arnold, 1993: 110–37Google Scholar
  39. 39.
    Kyu B, Matsumori A, Sato Y, et al. Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation 1992; 86: 522–30PubMedCrossRefGoogle Scholar
  40. 40.
    Matsumori A, Yamada T, Kawai C. Immunomodulating therapy in viral myocarditis: effects of tumor necrosis factor, interleukin-2 and anti-interleukin-2 receptor antibody in an animal model. Eur Heart J 1991; 12Suppl. D: 203–5PubMedGoogle Scholar
  41. 41.
    Yamada T, Matsumori A, Sasayama S. Therapeutic effects of anti-tumor necrosis factor-α antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus. Circulation 1994; 89: 846–51PubMedCrossRefGoogle Scholar
  42. 42.
    Matsui S, Matsumori A, Matoba Y, et al. Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone: suppression of natural killer cell activity and tumor necrosis factor-α production. J Clin Invest 1994; 94: 1212–7PubMedCrossRefGoogle Scholar
  43. 43.
    Chordera A, Feller K. Some aspects of pharmacokinetic and biotransformation differences in humans and mammal animals. Int J Clin Pharmacol Biopharm 1978; 16: 357–60Google Scholar
  44. 44.
    Matsumori A, Shioi T, Yamada T, et al. Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure. Circulation 1994; 89: 955–8PubMedCrossRefGoogle Scholar
  45. 45.
    Sato Y, Matsumori A, Sasayama S. Inotropic agent vesnarinone inhibits cytokine production and E-selectin expression in human umbilical vein endothelial cells. J Mol Cell Cardiol 1995; 27: 2265–73PubMedCrossRefGoogle Scholar
  46. 46.
    Matsui S, Matsumori A, Sasayama S. Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia. Life Sci 1994; 55: 1735–41PubMedCrossRefGoogle Scholar
  47. 47.
    Hurme M. Modulation of interleukin 1β production by cyclic AMP in human monocytes. FEBS Lett 1990; 263: 35–7PubMedCrossRefGoogle Scholar
  48. 48.
    Serkkola E, Hurme M, Palkama T. Prolonged elevation of intracellular cyclic AMP activated interleukin-1 production of human peripheral blood monocytes. Scand J Immunol 1992; 35: 203–8PubMedCrossRefGoogle Scholar
  49. 49.
    Liu S, Schreur KD. G-protein-mediated suppression of L-type Ca2+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am J Physiol 1995; 268: C339–49PubMedGoogle Scholar
  50. 50.
    Libby P, Warner SJ, Friedman GB. Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest 1988; 81: 487–98PubMedCrossRefGoogle Scholar
  51. 51.
    Essayan DM, Huang S-K, Undem BJ, et al. Modulation of antigen- and mitogen-induced proliferative responses of peripheral blood mononuclear cells by nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors. J Immunol 1994; 153; 3408–16PubMedGoogle Scholar
  52. 52.
    Matsumori A, Ono K, Sato Y, et al. Differential modulation of cytokine production by drugs: implication for therapy in heart failure. J Mol Cell Cardiol. In pressGoogle Scholar
  53. 53.
    Winlaw DS, Smythe GA, Keogh AM, et al. Nitric oxide production and heart failure. Lancet 1994; 344: 373–4PubMedCrossRefGoogle Scholar
  54. 54.
    De Belder AJ, Radomski MW, Why HJF, et al. Nitric oxide synthase activities in human myocardium. Lancet 1993; 341: 84–5PubMedCrossRefGoogle Scholar
  55. 55.
    Matsumori A, Okada I, Shioi T, et al. Inotropic agents differentially inhibit the induction of nitric oxide synthase by endotoxin in cultured macrophages. Life Sci 1996; 59: PL121–5PubMedCrossRefGoogle Scholar
  56. 56.
    Kubo SH, Gollub S, Bourge R, et al. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Circulation 1992; 85: 942–9PubMedCrossRefGoogle Scholar
  57. 57.
    Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996; 335: 1107–14PubMedCrossRefGoogle Scholar
  58. 58.
    Wang W, Matsumori A, Yamada T, et al. Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis: a possible mechanism through inhibition of nitric oxide production. Circulation. In pressGoogle Scholar

Copyright information

© Adis International Limited 1997

Authors and Affiliations

  • Akira Matsumori
    • 1
  1. 1.Department of Cardiovascular MedicineKyoto University Graduate School of Medicine, Third Division Department of Internal Medicine, Kyoto University HospitalSakyo-ku, KyotoJapan

Personalised recommendations