Advertisement

Inflammation

pp 1–10 | Cite as

Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats

  • M. C. G. Leite-Avalca
  • F. T. Staats
  • D. Verona
  • P. de Souza
  • M. C. Almeida
  • J. E. Silva-Santos
  • A. R. ZampronioEmail author
ORIGINAL ARTICLE
  • 52 Downloads

Abstract

Sepsis is a life-threatening condition with high mortality rates that is caused by dysregulation of the host response to infection. We previously showed that treatment with the cannabinoid CB1 receptor antagonist rimonabant reduced mortality rates in animals with sepsis that was induced by cecal ligation and puncture (CLP). This improvement in the survival rate appeared to be related to an increase in arginine vasopressin (AVP) levels 12 h after CLP. The present study investigated the effects of rimonabant on organ dysfunction, hematologic parameters, and vascular reactivity in male Wistar rats with sepsis induced by CLP. Intraperitoneal treatment with rimonabant (10 mg/kg, 4 h after CLP) abolished the increase in the plasma levels of lactate, lactate dehydrogenase, glucose, and creatinine kinase MB without altering hematological parameters (i.e., leukopenia and a reduction of platelet counts). CLP increased plasma levels of nitrate/nitrite (NOx) and induced vasoconstriction in the tail artery. The treatment of CLP rats with rimonabant did not alter NOx production but reduced the vasoconstriction. Rimonabant also attenuated the hyperreactivity to AVP induced by CLP without affecting hyporesponsiveness to phenylephrine in aortic rings. These results suggest that rimonabant reduces organ dysfunction during sepsis, and this effect may be related to AVP signaling in blood vessels. This effect may have contributed to the higher survival rate in rimonabant-treated septic animals.

KEY WORDS

CB1 receptor antagonist sepsis rimonabant organ dysfunction 

Notes

Acknowledgments

The authors thank MSc. Tatiane M.B.B. Telles for the help with the analysis in the Municipal Laboratory of Curitiba.

Funding

This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Grant # 473194/2012-0.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were approved by the institution’s Ethical Committee for Animal Use and were in accordance with Brazilian and EU Directive 2010/63/EU Guidelines for Animal Care. All efforts were made to minimize the number of animals used and their suffering.

References

  1. 1.
    Wiersinga, W.J., S.J. Leopold, D.R. Cranendonk, and T. van der Poll. 2014. Host innate immune responses to sepsis. Virulence 5 (1): 36–44.CrossRefGoogle Scholar
  2. 2.
    Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, R.S. Hotchkiss, M.M. Levy, J.C. Marshall, G.S. Martin, S.M. Opal, G.D. Rubenfeld, T. van der Poll, J.L. Vincent, and D.C. Angus. 2016. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315 (8): 801–810.CrossRefGoogle Scholar
  3. 3.
    Bakker, J., M.W. Nijsten, and T.C. Jansen. 2013. Clinical use of lactate monitoring in critically ill patients. Annals of Intensive Care 3 (1): 12.CrossRefGoogle Scholar
  4. 4.
    Duman, A., A. Akoz, M. Kapci, M. Ture, S. Orun, K. Karaman, and K.A. Turkdogan. 2016. Prognostic value of neglected biomarker in sepsis patients with the old and new criteria: predictive role of lactate dehydrogenase. The American Journal of Emergency Medicine 34 (11): 2167–2171.CrossRefGoogle Scholar
  5. 5.
    Zhang, L., et al. 2015. Poly (ADP-ribose) synthetase inhibitor has a heart protective effect in a rat model of experimental sepsis. International Journal of Clinical and Experimental Pathology 8 (9): 9824–9835.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lafreniere, J.D., and C. Lehmann. 2017. Parameters of the endocannabinoid system as novel biomarkers in sepsis and septic shock. Metabolites 7 (4): pii: E55.Google Scholar
  7. 7.
    Maccarrone, M., I. Bab, T. Bíró, G.A. Cabral, S.K. Dey, V. di Marzo, J.C. Konje, G. Kunos, R. Mechoulam, P. Pacher, K.A. Sharkey, and A. Zimmer. 2015. Endocannabinoid signaling at the periphery: 50 years after THC. Trends in Pharmacological Sciences 36 (5): 277–296.CrossRefGoogle Scholar
  8. 8.
    Sarker, K.P., S. Obara, M. Nakata, I. Kitajima, and I. Maruyama. 2000. Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Letters 472 (1): 39–44.CrossRefGoogle Scholar
  9. 9.
    Villanueva, A., S.M. Yilmaz, W.R. Millington, R.A. Cutrera, D.G. Stouffer, L.H. Parsons, J.F. Cheer, and C. Feleder. 2009. Central cannabinoid 1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area. Shock 32 (6): 614–620.CrossRefGoogle Scholar
  10. 10.
    Pacher, P., and G. Kunos. 2013. Modulating the endocannabinoid system in human health and disease--successes and failures. The FEBS Journal 280 (9): 1918–1943.CrossRefGoogle Scholar
  11. 11.
    Zampronio, A.R., J.B. Kuzmiski, C.M. Florence, S.J. Mulligan, and Q.J. Pittman. 2010. Opposing actions of endothelin-1 on glutamatergic transmission onto vasopressin and oxytocin neurons in the supraoptic nucleus. The Journal of Neuroscience 30 (50): 16855–16863.CrossRefGoogle Scholar
  12. 12.
    Leite-Avalca, M.C., et al. 2016. Involvement of central endothelin ETA and cannabinoid CB1 receptors and arginine vasopressin release in sepsis induced by cecal ligation and puncture in rats. Shock 46 (3): 290–296.CrossRefGoogle Scholar
  13. 13.
    Rattmann, Y.D., S.M. Malquevicz-Paiva, M. Iacomini, and L.M.C. Cordeiro. 2013. Galactofuranose-rich polysaccharides from Trebouxia sp. induce inflammation and exacerbate lethality by sepsis in mice. Phytochemistry 94: 206–210.CrossRefGoogle Scholar
  14. 14.
    Fernandes, D., et al. 2006. Nitric oxide-dependent reduction in soluble guanylate cyclase functionality accounts for early lipopolysaccharide-induced changes in vascular reactivity. Molecular Pharmacology 69 (3): 983–990.PubMedGoogle Scholar
  15. 15.
    Gordon, C.J. 1990. Thermal biology of the laboratory rat. Physiology & Behavior 47 (5): 963–991.CrossRefGoogle Scholar
  16. 16.
    Karnatovskaia, L.V., and E. Festic. 2012. Sepsis: a review for the neurohospitalist. Neurohospitalist 2 (4): 144–153.CrossRefGoogle Scholar
  17. 17.
    Brooks, H.F., C.K. Osabutey, R.F. Moss, P.L.R. Andrews, and D.C. Davies. 2007. Caecal ligation and puncture in the rat mimics the pathophysiological changes in human sepsis and causes multi-organ dysfunction. Metabolic Brain Disease 22 (3–4): 353–373.CrossRefGoogle Scholar
  18. 18.
    Yang, W.L., and G. Ma. 2016. Combined administration of human ghrelin and human growth hormone attenuates organ injury and improves survival in aged septic rats. Molecular Medicine 22: 1.CrossRefGoogle Scholar
  19. 19.
    Zhou, L., M. Gao, Z. Xiao, J. Zhang, X. Li, and A. Wang. 2015. Protective effect of astaxanthin against multiple organ injury in a rat model of sepsis. The Journal of Surgical Research 195 (2): 559–567.CrossRefGoogle Scholar
  20. 20.
    Maitra, S.R., M.M. Wojnar, and C.H. Lang. 2000. Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock 13 (5): 379–385.CrossRefGoogle Scholar
  21. 21.
    Sharma, A.C., S.J. Motew, S. Farias, K.J. Alden, H.B. Bosmann, W.R. Law, and J.L. Ferguson. 1997. Sepsis alters myocardial and plasma concentrations of endothelin and nitric oxide in rats. Journal of Molecular and Cellular Cardiology 29 (5): 1469–1477.CrossRefGoogle Scholar
  22. 22.
    Osuchowski, M.F., J. Connett, K. Welch, J. Granger, and D.G. Remick. 2009. Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis. Critical Care Medicine 37 (5): 1567–1573.CrossRefGoogle Scholar
  23. 23.
    Cohen, J. 2002. The immunopathogenesis of sepsis. Nature 420 (6917): 885–891.CrossRefGoogle Scholar
  24. 24.
    Katchan, V., P. David, and Y. Shoenfeld. 2016. Cannabinoids and autoimmune diseases: A systematic review. Autoimmunity Reviews 15 (6): 513–528.CrossRefGoogle Scholar
  25. 25.
    Ho, J.T., M.J. Chapman, S. O’Connor, S. Lam, J. Edwards, G. Ludbrook, J.G. Lewis, and D.J. Torpy. 2010. Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levels. Clinical Endocrinology 73 (3): 413–420.CrossRefGoogle Scholar
  26. 26.
    Vincent, J.L. 1998. Cardiovascular alterations in septic shock. The Journal of Antimicrobial Chemotherapy 41 (Suppl A): 9–15.CrossRefGoogle Scholar
  27. 27.
    Lorente, J.A., et al. 1993. L-arginine pathway in the sepsis syndrome. Critical Care Medicine 21 (9): 1287–1295.CrossRefGoogle Scholar
  28. 28.
    Bernardelli, A.K., et al. 2016. Vasoplegia in sepsis depends on the vascular system, vasopressor, and time-point: a comparative evaluation in vessels from rats subjected to the cecal ligation puncture model. Canadian Journal of Physiology and Pharmacology 94 (11): 1227–1236.Google Scholar
  29. 29.
    OBrien, J.M., Jr., et al. 2007. Sepsis. The American Journal of Medicine 120 (12): 1012–1022.CrossRefGoogle Scholar
  30. 30.
    Bennett, T., R.P. Mahajan, J.E. March, P.A. Kemp, and S.M. Gardiner. 2004. Regional and temporal changes in cardiovascular responses to norepinephrine and vasopressin during continuous infusion of lipopolysaccharide in conscious rats. British Journal of Anaesthesia 93 (3): 400–407.CrossRefGoogle Scholar
  31. 31.
    Barrett, L.K., N.N. Orie, V. Taylor, R.P. Stidwill, L.H. Clapp, and M. Singer. 2007. Differential effects of vasopressin and norepinephrine on vascular reactivity in a long-term rodent model of sepsis. Critical Care Medicine 35 (10): 2337–2343.CrossRefGoogle Scholar
  32. 32.
    Kienbaum, P., C. Prante, N. Lehmann, A. Sander, A. Jalowy, and J. Peters. 2008. Alterations in forearm vascular reactivity in patients with septic shock. Anaesthesia 63 (2): 121–128.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • M. C. G. Leite-Avalca
    • 1
  • F. T. Staats
    • 1
  • D. Verona
    • 1
  • P. de Souza
    • 2
  • M. C. Almeida
    • 3
  • J. E. Silva-Santos
    • 2
  • A. R. Zampronio
    • 1
    • 4
    Email author
  1. 1.Department of Pharmacology, Biological Sciences SectionFederal University of ParanáCuritibaBrazil
  2. 2.Department of PharmacologyFederal University of Santa CatarinaFlorianópolisBrazil
  3. 3.Center for Natural and Human SciencesFederal University of ABCSão Bernardo do CampoBrazil
  4. 4.Departamento de Farmacologia, Centro PolitécnicoUniversidade Federal do ParanáCuritibaBrazil

Personalised recommendations