Agents and Actions

, Volume 26, Issue 3–4, pp 292–300

Pharmacological evaluation of rat paw oedema induced byBothrops jararaca venom

  • H. A. Trebien
  • J. B. Calixto
Inflammation and Immunomodulation


The mechanism involved in the genesis of the rat paw oedema caused by intraplantar (IPL) injection ofBothrops jararaca venom (BJV) has been investigated. IPL injection of BJV (1 to 30 μg/paw) caused a dose- and time-related oedematogenic effect. Oedema was maximal within 1 h after BJV injection, was partially reduced at 6 h and disappeared completely within 24 h. No systemic effect was observed. Previous heating of BJV at 100°C for 3 to 30 min caused a significant inhibition (25%) of its oedematogenic activity. Daily IPL injections of BJV (10 μg/paw) for 4 days attenuated BJV-induced oedema (26%), but did not influence oedema-induced by PAF-acether, serotonin (5-HT) and histamine (His), indicating the absence of cross desensitization. In the paw desensitized by daily IPL injections of PAF-acether, BJV induced a full oedematogenic response also indicating absence of cross desensitization. Different groups of drugs including α1- and α2-adrenoceptor antagonists (prazosin and yohimbine), inhibitors of both cyclo- and lipo-oxygenase (indomethacin, nordihydroguaiaretic acid), inhibitors of phospholiase A2 (dexamethasone and mepacrine) caused marked inhibition of BJV-induced rat paw oedema, whereas antagonists of 5-HT, PAF-acether and H1-histamine receptors were less effective. Pre-treatment with a β-adrenoceptor antagonist, a Ca2+ channel blocker and a H2-histamine antagonist failed to affect BJV-induced oedema. Pre-treatment of the animals with captopril did not interfere with BJV-induce oedema, suggesting that kinins are not insolved in the genesis of oedema. Association of BJV with 5-HT and PAF did not potentiate the BJV-induced oedema. It is concluded that BJV-induced rat paw oedema appears to be mediated primarily by cycloxygenase and lipoxygenase eicosanoid products and activation of α1- and α2-adrenoceptors, while HIS, 5-HT and PAF-acether appear to exert minor roles.


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  1. [1]
    S. A. Minton Jr.,Snakes and snake venoms. InVenom diseases, pp. 107–108, Thomas Springfield 1974.Google Scholar
  2. [2]
    F. R. Mandelbaum, A. P. Reichel and M. T. Assakura,Isolation and characterization of a proteolitic enzyme from the venom of the snake Bothrops jararaca (jararaca). Toxicon20, 955–972 (1982).CrossRefPubMedGoogle Scholar
  3. [3]
    C. P. S. Amaral, O. A. da Silva, P. Godoy and D. Miranda,Renal cortical necrosis following Bothrops jararaca and B. jararacussu snake bite, Toxicon23, 877–885 (1985).CrossRefPubMedGoogle Scholar
  4. [4]
    I. L. Bonta,Microvascular lesions as a target of antiinflammatory and certain other drugs. Acta Physiol Pharmacol. Neerl.15, 188–222 (1969).PubMedGoogle Scholar
  5. [5]
    B. B. Vargaftig, N. Bhargava and I. L. Bonta,Haemorrhagic and permeability increasing effects of “Bothrops jararaca” and other Crotalidae venoms as related to amine or kinin release. Agents and Actions4, 163–168 (1974).PubMedGoogle Scholar
  6. [6]
    R. C. Shaeffer, R. W. Carlson and M. H. Weil,Effects of antivenin and corticosteroid analogs on rattlesnake venom shock in the rat. J. Pharmacol. Exp. Ther.211, 409–414 (1979a).PubMedGoogle Scholar
  7. [7]
    R. C. Shaeffer, T. R. Pattabhiraman, R. W. Carlson, F. E. Russel and M. H. Weil,Cardiovascular failure produced by a peptide from the venom of the Southern pacific rattlesnake Crotalus viridis helleri, Toxicon17, 447–453 (1979b).CrossRefPubMedGoogle Scholar
  8. [8]
    A. Ohsaka,hemorrhagic necrotizing and oedema forming effects in snake venom. InSnake Venoms, Handbook of Experimental Pharamcology, vol. 52. (C. Y. Lee Ed.) p. 480, Springer, Berlin, 1979.Google Scholar
  9. [9]
    S. Leyck, E. Etschemberg, C. Handding and J. Winkihnan,A new model of acute inflammation: Cobra venom factor induced paw oedema. Agents and Actions73, 437–438 (1983).Google Scholar
  10. [10]
    E. Lomonte,Edema forming activity of Bushmater (Lachesis muta stenophrys) and Central American rattlesnake (Crotalus durissus durissus) venoms and neutralization by a polivalent antivenom. Toxicon23, 173–176 (1985).CrossRefPubMedGoogle Scholar
  11. [11]
    B. S. Vishwanath, R. M. Kini and T. V. Gowda,Characterization of three edema-inducing phospholipase A 2-enzymes from Habu (Trimeresurus flavovidis) venom and their interaction with the alkaloid aristolochic acid. Toxicon25, 501–515 (1987).CrossRefPubMedGoogle Scholar
  12. [12]
    B. J. Hawgood,Physiological and pharmacological effects of rattlesnake venoms. InRathe snake venoms. Their actions and treatment. (Ed. Anthony I. Tu) pp. 121–162, Marrel Akker Inc., New York 1983.Google Scholar
  13. [13]
    A. M. Rothschild and Z. Rothschild,Liberation of pharmacologically active substances by snake venoms. InSnake Venoms. Handbook of Experimental Pharmacology, vol. 52. (Ed. C. Y. Lee) pp. 591–628, Springer, Berlin 1979.Google Scholar
  14. [14]
    M. Rocha e Silva, W. T. Beraldo and G. Rosenfeld,Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma by snake venoms and by trypsin. Am. J. Physiol.156, 261–273 (1949).Google Scholar
  15. [15]
    S. H. Ferreira,A bradykinin-potentiating factor (BPF) present in the venom of B. jararaca. Br. J. Pharmac.24, 163–165 (1965).Google Scholar
  16. [16]
    C. V. Winder, J. Max and M. A. Beem,Rapid foot volume measurements on unanesthetized rats and the question of a phenylbutazone effect on anaphylactoid oedema. Arch. Int. pharmacodyn.112, 147–182 (1957).Google Scholar
  17. [17]
    C. A. Winter, E. A. Risley and G. W. Nuss,Carrageenan induced oedema in the hind paw of the rat as an assay for anti-inflammatory drugs. Proc. Soc. Exp. Biol. Med.111, 544–547 (1962).Google Scholar
  18. [18]
    U. Hamberg and M. Rocha e Silva,Release of bradykinin as related to the esterase activity of trypsin and of the venom of Bothrops jararaca, Experientia13, 489 (1957).PubMedGoogle Scholar
  19. [19]
    R. S. B. Cordeiro, M. A. Martins, P. M. R. Silva, H. C. Castro Faria Neto, J. R. C. Castanheira and B. B. Vargaftig,Desensitization to PAF-induced rat paw oedema by repeated intraplantar injections. Life Sci.39, 1871–1878 (1986).CrossRefPubMedGoogle Scholar
  20. [20]
    P. Crunkhorn and S. C. R. Meacok,Mediators of the inflammation induced in the rat paw by carrageenin. Br. J. Pharmac.42, 392–402 (1971).Google Scholar
  21. [21]
    M. Di Rosa, J. P. Giroud and D. A. Willoughby,Studies of the mediators of the acute inflammatory responses induced in rats in differents sites by carrageenin and turpentine. J. Pathology.104, 15–29 (1971).CrossRefGoogle Scholar
  22. [22]
    J. Garcia Leme, L. Hamamura, M. P. Leite and M. Rocha e Silva.Pharmacological analysis of the acute inflammatory process induced in the rat's paw by local injection of carrageenin and by heating. Br. J. Pharmac.48, 88–96 (1973).Google Scholar
  23. [23]
    K. Stochla and S. Maslinski,Carrageenin-induced oedema in the rat paw-histamine participations. Agents and Actions. 12, 201–202 (1982).CrossRefPubMedGoogle Scholar
  24. [24]
    J. P. Bolam, N. P. C. Elliot, A. W. Ford-hutchinson and M. J. H. Smith,Histamine, 5-hydroxytryptamine, kinins and the anti-inflammatory activity of human plasma fraction in carrageenan induced paw oedma in the rat. J. Pharm. Pharmac.26, 434–440 (1974).Google Scholar
  25. [25]
    T. Mikami and K. Miyasaka,Effects of several in the antiinflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin-induced pleurisy.95, 1–12 (1983).Google Scholar
  26. [26]
    M. M. Goldenberg and R. D. Meurer,A pharmacologic analysis of the action of platelet-activating factor in the reaction of hind-paw edema in the rat. Prostaglandins.28, 271–277 (1984).CrossRefPubMedGoogle Scholar
  27. [27]
    K. F. Swingle and M. J. Reiter,Inhibition of Paf-acetherinduced edema of the rat's paw. Agents and Actions.18, 359–365 (1986).PubMedGoogle Scholar
  28. [28]
    M. J. DiMartino, D. E. Griswold, B. A. Berkowitz, G. Poste and N. Hanna,Pharmacologic characterization of the antiinflammatory properties of a new dual inhibitor of lipooxigenase and cyclo-oxygenase. Agents and Actions20, 113–123 (1987).PubMedGoogle Scholar
  29. [29]
    T. J. Williams,Interactions between prostaglandins, leukotrienes and other mediators of inflammation. Br. Med. Bull.39, 239–242 (1983).PubMedGoogle Scholar
  30. [30]
    S. D. Brain and T. J. Williams,Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br. J. Pharmac.86, 855–860 (1985).Google Scholar
  31. [31]
    D. Haworth, J. R. M. Heron and F. Carey,Rat paw hyperalgesia and oedema in response to NMDA Naja naja phospholipase A2. Br. J. Pharmac.93, 145P (1988).Google Scholar
  32. [32]
    A. M. Boctor, C. Burke and M. E. Hovinga,Arachidonic acid-induced pleurisy (ARIP): An in vivo medel for testing 5-lipoxygenase inhibition. Meth Find Exptl Clin Pharmacol.9, 793–797 (1987).Google Scholar
  33. [33]
    S. J. Foster, M. E. McCormik and A. Howarth,The contribution of cyclooxygenase products to acute inflammation in the rat. Agents and Actions17, 358–359 (1985).Google Scholar
  34. [34]
    A. Blackham, A. A. Norris, and A. M. WoodsModels for evaluating the anti-inflammatory effects of inhibitors of arachidonic acid metabolism. J. Pharm. Pharmac.37, 787–793 (1985).Google Scholar
  35. [35]
    J. A. Salmon, P. M. Simmons and S. Moncada,The effects of BW755CC and other anti-inflammatory drugs on eicosanoid concentrations and leukocyte accumalation in experimentallyinduced acute inflammation. J. Pharm. Pharmac.35, 808–813 (1983).Google Scholar
  36. [36]
    M. T. Zanin and S. H. Ferreira,Relationship between oedema and plasma exudation in rat paw carrageenan inflammation. Agents and Actions8, 606–609 (1978).PubMedGoogle Scholar
  37. [37]
    P. Braquet, L. Touqui, T. Y. Shen and B. B. Vargaftig,Perspectives in platelet-activating factor research, Pharmacol. Rev.39, 97–145 (1987).PubMedGoogle Scholar
  38. [38]
    A. L. A. Boura and A. P. Svolmanis,Converting enzyme inhibition in the rat paw by captopril is accompained by potentiation of carrageenan-induced inflammation. J. Pharm. Dyn.7, 372–377 (1984).Google Scholar
  39. [39]
    H. Suda, H. Yamauchi and T. Iso,Potentiative effect of angiotensin converting enzyme inhibitor on carrageenan oedema in rats and the role of tissue kininogen. J. Pharm. Dyn.7, 372–377 (1984).Google Scholar
  40. [40]
    J. B. Calixto, M. Nicolau and R. A. Yunes,The selective antagonism of bradykinin action on isolated rat uterus by crude Mandevilla velutina extract. Br. J. Pharmac.85, 729–731 (1985).Google Scholar
  41. [41]
    J. B. Calixto, M. Nicolau, M. G. Pizzolatti and R. A. Yunes,Kinin antagonist activity of compounds from Mandevilla velutina in the isolated rat uterus. Br. J. Pharmac.91, 199–204 (1987).Google Scholar
  42. [42]
    J. B. Calixto and R. A. Yunes,Effects of a crude extract of Mandevilla velutina on bradykinin and [Des-Arg 9]-BK-induced contraction of isolated rabbit vessels. Br. J. Pharmac.85, 937–941 (1986).Google Scholar
  43. [43]
    J. B. Calixto, M. Nicolau, H. Trebien, M. G. O. Henrique, V. B. Weg, R. S. B. Cordeiro and R. A. Yunes,Antiedematogenic actions of a hydroalcoholic crude water-alcohol extract of Mandevilla velutina. Brazilian J. Med. Biol. Res.19, 575A (1986).Google Scholar
  44. [44]
    M. Nicolau, J. B. Calixto, M. L. Bittencourt, M. N. Beins, R. S. B. Cordeiro, M. G. O. Henrique, V. B. Weg and R. A. Yunes,Effect of Mandevilla velutina crude extracts in cutaneous rat vascular permeability and mouse carrageenan induced pleurisy. Proceedings of the French Branzilian Symposium of Chemistry and Pharmacology of Natural Substance in Inflammation, Allergy and Thrombosis. Rio de Janeiro 1986.Google Scholar

Copyright information

© Birkhäuser Verlag 1989

Authors and Affiliations

  • H. A. Trebien
    • 1
  • J. B. Calixto
    • 1
  1. 1.Department of Pharmacology CCBUniversidade Federal de Santa CatarinaFlorianópolisBrasil

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