Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 328, Issue 1, pp 9–15 | Cite as

Inhibition of compound 48/80 — induced vascular protein leakage by pretreatment with capsaicin and a substance P antagonist

  • A. Saria
  • X. Hua
  • G. Skofitsch
  • J. M. Lundberg


  1. 1.

    Intravenous injection of compound 48/80 (1 mg×kg−1) induced an acute increase in vascular permeability to plasma proteins in various organs of rats.

  2. 2.

    The compound 48/80 response was partly inhibited by histamine H1 and H2 receptor blockade in the urinary bladder and in the duodenum, but not in the trachea, the oesophagus, the ureter and the paw skin. Blockade of 5-hydroxytryptamine receptors with methysergide led to a reduction of the permeability response in the oesophagus and in the urinary bladder, leaving responses in other organs unchanged.

  3. 3.

    Pretreatment of neonatal rats with capsaicin almost abolished the 48/80 response in all organs except in the duodenum. Pretreatment of rats with [D-Arg1, D-Trp7,9, Leu11]-substance P, a substance P antagonist, also caused a partial inhibition of the permeability response to compound 48/80 in several organs.

  4. 4.

    Topical administration of compound 48/80 (1 mg×ml−1) onto the tracheal mucosa induced local Evans blue extravasation. This response was resistant to pretreatment with histamine receptor antagonists, but was largely inhibited after neonatal capsaicin pretreatment. Topical administration of compound 48/80 (1 mg×ml−1 or 10 mg×ml−1) into the eye did not cause visible Evans blue extravasation in the conjunctiva, nor any signs of pain reaction as indicated by the absence of the wiping response, usually seen upon noxious chemical stimuli in the eye.

  5. 5.

    In guinea-pigs, 10 mg×kg−1 compound 48/80 i.v. were required to induce vascular protein leakage in different organs. This response was blocked by pretreatment with H1 and H2 receptor antagonists, but only slightly reduced after systemic capsaicin pretreatment of guinea-pigs.

  6. 6.

    Pretreatment of rats with compound 48/80 for 3 consecutive days lead to an almost complete depletion of histamine in the paw skin and to a partial depletion of histamine in the trachea. In the lung and in the duodenum, however, histamine concentrations remained unchanged. Simultaneously, there was an about 25%–30% reduction of substance P concentrations in the paw skin and in the trachea, but not in the lung or in the spinal cord. In compound 48/80 pretreated rats, there was no change of the permeability response to intravenous substance P, nor any change of the behavioural nociceptive response upon topical capsaicin application in the eye.

  7. 7.

    It is concluded that intravenous compound 48/80 administration induces an acute increase in vascular permeability in various organs of rats mainly via a histamine independent activation of capsaicin sensitive, most probably substance P containing sensory neurones. In guineapigs, the permeability response to intravenous compound 48/80 is mainly caused by histamine, acting both directly and indirectly via sensory neurones. Pretreatment of rats with compound 48/80 causes, besides histamine depletion from mast cells, a reduction of substance P in sensory nerves. This may reflect a long lasting stimulation of sensory nerve endings by mast cell constituents or a direct action of compound 48/80 on sensory nerves.


Key words

Compound 48/80 Vascular permeability Capsaicin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alberty J, Takkunen R (1957) Der Anteil von Histamin an der anaphylaktischen und der durch einen chemischen Histaminfreisetzer hervorgerufenen vasculären Hautreaktion. Arch Allergy 10:285–304Google Scholar
  2. Arvier PT, Chahl LA, Ladd RJ (1977) Modification by capsaicin and compound 48/80 of dye leakage induced by irritants in the rat. Br J Pharmacol 59:61–68Google Scholar
  3. Beaven MA (1982) Factors regulating availability of histamine at tissue receptors. In: Ganellin CR, Parsons ME (eds) Pharmacology of histamine receptors, Wright PSG, Bristol, London, Boston, pp 103–145Google Scholar
  4. Chang MM, Leeman SE (1970) Isolation of a sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. J Biol Chem 245:4784–4790Google Scholar
  5. Donnerer J, Lembeck F (1983) Heat loss reaction to capsaicin through a peripheral side of action. Br J Pharmacol 79:719–723Google Scholar
  6. Fitzgerald M (1983) Capsaicin and sensory neurones. A review. Pain 15:109–130Google Scholar
  7. Gamse R (1982) Capsaicin and nociception in the rat and mouse. Possible role of substance P. Naunyn-Schmiedeberg's Arch Pharmacol 320:205–216Google Scholar
  8. Gamse R, Holzer P, Lembeck F (1980) Decrease of substance P in primary afferent neurones and impairment of neurogenic plasma extravasation by capsaicin. Br J Pharmacol 68:207–213Google Scholar
  9. Gamse R, Leeman SE, Holzer P, Lembeck F (1981) Differential effects of capsaicin on the content of somatostatin, substance P, and neurotensin in the nervous system of the rat. Naunyn-Schmiedeberg's Arch Pharmacol 317:140–148Google Scholar
  10. Goth A (1978) On the general problem of the release of histamine. In: Rocha e Silva M (ed) Histamine and anti-histaminics. Handb exp Pharmacol, vol 18/2. Springer Verlag, Berlin Heidelberg New York, pp 57–74Google Scholar
  11. Jancsó N, Jancsó-Gábor A, Szolcsányi J (1967) Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol Chemother. 31:138–151Google Scholar
  12. Jancsó G, Király E, Jancsó-Gábor A (1977) Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature 270:741–743Google Scholar
  13. Jancsó G, Király E, Jancsó-Gábor A (1980) Chemosensitive pain fibres and inflammation. Int J Tissue React 11:57–66Google Scholar
  14. Kangawa K, Minamino N, Fukuda A, Matsuo H (1983) Neuromedin K: A novel mammalian tachykinin identified in porcine spinal cord. Biochem Biophys Res Commun 114:533–540Google Scholar
  15. Lembeck F, Holzer P (1979) Substance P as neurogenic mediator of antidromic vasodilatation and plasma extravasation. Naunyn-Schmiedeberg's Arch Pharmacol 310:175–183Google Scholar
  16. Levi R, Owen DAA, Przeciakowski J (1982) Actions of histamine on the heart and vasculature. In: Ganellin CR, Parson ME (eds) Pharmacology of histamine receptors. Wright and Sons, Bristol, UK, pp 236–297Google Scholar
  17. Lundberg JM, Saria A (1983) Capsaicin-induced desensitization of the airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature 302:251–253Google Scholar
  18. Lundberg JM, Brodin E, Hua X, Saria A (1984a) Vascular permeability changes and smooth muscle contraction in the relation to capsaicin-sensitive substance P afferents in the guinea-pig. Acta Physiol Scand 120:217–227Google Scholar
  19. Lundberg JM, Brodin E, Saria A (1983a) Effects and distribution of capsaicin-sensitive substance P neurons with special reference to the trachea and lungs. Acta Physiol Scand 119:243–252Google Scholar
  20. Lundberg JM, Saria A, Brodin E, Rosell S, Folkers K (1983b) A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea-pig. Proc Natl Acad Sci USA 80:1120–1124Google Scholar
  21. Mandahl A, Bill A (1984) Effects of the substance P antagonist (D-Arg1, D-Pro2, D-Trp7,9, Leu11)-SP on the miotic response to substance P, antidromic trigeminal nerve stimulation, capsaicin, prostaglandin E1, compound 48/80 and histamine. Acta Physiol Scand 120:27–35Google Scholar
  22. Miles AA, Miles EM (1952) Vascular reactions to histamine, histamine liberator and leucotaxine in the skin of guinea-pigs. J Physiol 118:228–257Google Scholar
  23. Mota J, Vugman J (1956) Action of compound 48/80 on the mast cells and histamine content of guinea-pig tissues. Br J Pharmacol 11:304–312Google Scholar
  24. Nawa H, Hirose T, Takashima H, Inayama S, Nakanishi S (1983) Nucleotide sequence of cloned cDNAs for two types of bovine brain substance P precursor. Nature 306:32–36Google Scholar
  25. Olgart L, Gazelius B (1978) Inhibition of compound 48/80-induced intradental sensory nerve activity by disodium chromoglycate and serotonin antagonists. Acta Physiol Scand 104:415–421Google Scholar
  26. Owen DAA, Poy E, Woodward DF (1980) Evaluation of the role of histamine H1- and H2 receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation. Br J Pharmacol 69:615–623Google Scholar
  27. Paton WDM (1951) Compound 48/80: A potent histamine liberator. Br J Pharmacol 6:499–508Google Scholar
  28. Rosell S, Björkroth U, Folkers K (1983) Subpopulations of substance P (SP) receptors and separate eledoisin receptors. In: Skrabanek P, Powell D (eds) Substance P. Boole Press, Dublin, pp 61–62Google Scholar
  29. Saria A, Lundberg JM (1983) Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues. J Neurosci Methods 8:41–49 (1983)Google Scholar
  30. Saria A, Lundberg JM, Skofitsch G, Lembeck F (1983a) Vascular protein leakage in various tissues induced by substance P, capsaicin, bradykinin, serotonin, histamine and by antigen challenge. Naunyn-Schmiedeberg's Arch Pharmacol 324:212–218Google Scholar
  31. Saria A, Lundberg JM, Hua X, Lembeck F (1983b) Sensory control of vascular permeability and capsaicin induced substance P release from the guinea-pig ureter. Neurosci Lett 41:167–172Google Scholar
  32. Smith AN (1958) The experimental production of gastric ulcers by histamine releasing substances. Br J Surg 46:157–164Google Scholar
  33. Skofitsch G, Saria A, Holzer P, Lembeck F (1981) Determination of histamine by high performance liquid chromatography after condensation with o-phthaldialdehyde. J Chromatogr 226:53–59Google Scholar
  34. Theodorsson-Norheim E, Brodin E, Norheim I, Rosell S (1984) Antisera raised against eledoisin and kassinin detect immunoreactive material in rat tissue extracts: Tissue distribution and chromatographic characterization. Regul Pept, in pressGoogle Scholar
  35. Uvnäs B (1978) The mechanism of histamine release from mast cells. In: Rocha e Silva M (ed) Histamine and anti-histamines. Handb exp Pharmacol, vol 18/2. Springer Verlag, Berlin Heidelberg New York, pp 75–92Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • A. Saria
    • 1
  • X. Hua
    • 2
  • G. Skofitsch
    • 1
  • J. M. Lundberg
    • 2
  1. 1.Department of Experimental and Clinical PharmacologyUniversity of GrazGrazAustria
  2. 2.Department of PharmacologyKarolinska InstitutetStockholmSweden

Personalised recommendations