Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 371, Issue 1, pp 34–43

Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia

  • Chin-Wei Chiao
  • Shoei-Sheng Lee
  • Chin-Chen Wu
  • Ming-Jai Su
Original Article


This study addressed the question of whether thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and α-1 adrenoceptor antagonistic activity, has protective effects in endotoxaemic rats and we attempted to elucidate the mechanisms contributing to such protective effects. Injection of rats with endotoxin (E. coli lipopolysaccharide, LPS) induced severe hypotension and tachycardia as well as vascular hyporeactivity to noradrenaline. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO·) and superoxide anion (O2·) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxaemia for 240 min resulted in a bell-shaped time course for the change of serum tumour necrosis factor-α (TNF-α) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-α level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxaemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS-treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-α, NO· and O2· production.


Lipopolysaccharide Thaliporphine Nitric oxide Superoxide anion Tumour necrosis factor-α Survival rate Multiple organ injury 


  1. Arthur MJ, Kowalski-Saunders P, Wright R (1988) Effect of endotoxin on release of reactive oxygen intermediates by rat hepatic macrophages. Gastroenterology 95:1588–1594Google Scholar
  2. Barron RL (1993) Pathophysiology of septic shock and implications for therapy. Clin Pharm 12:829–845Google Scholar
  3. Bautista AP, Meszaros K, Bojta J, Spitzer JJ (1990) Superoxide anion generation in the liver during the early stage of endotoxemia in rats. J Leukoc Biol 48:123–128Google Scholar
  4. Beckman JS, Crow JP (1993) Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans 21:330–334Google Scholar
  5. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624PubMedGoogle Scholar
  6. Bernard GR, Vincent JL, Laterre PF (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709CrossRefPubMedGoogle Scholar
  7. Crespo E, Macias M, Pozo D, Escames G, Martin M, Vives F, Guerrero JM, Acuna-Castroviejo D (1999) Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 13:1537–1546Google Scholar
  8. Doebber TW, Wu MS, Robbins JC, Choy BM, Chang MN, Shen TY (1985) Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Commun 127:799–808Google Scholar
  9. Fleming I, Dambacher T, Busse R (1992) Endothelium-derived kinins account for the immediate response of endothelial cells to bacterial lipopolysaccharide. J Cardiovasc Pharmacol 20 (Suppl 12):S135–S138Google Scholar
  10. Guinaudeau H, Leboeuf M, Cave A (1975) Aporphine alkaloids. J Nat Prod 38:275–338Google Scholar
  11. Harlan JM (1987) Neutrophil-mediated vascular injury. Acta Med Scand 715 (Suppl.):123–129Google Scholar
  12. Heard SO, Perkins MW, Fink MP (1992) Tumor necrosis factor-alpha causes myocardial depression in guinea pigs. Crit Care Med 20:523–527Google Scholar
  13. Hung LM, Lee SS, Chen JK, Huang SS, Su MJ (2001) Thaliporphine protects ischemic and ischemic-reperfused rat heart via an NO-dependent mechanism. Drug Dev Res 52:446–453CrossRefGoogle Scholar
  14. Kameswara Rao NS, Lee SS (2000) Preparation of thaliporphine and lirioferine from glaucine by treatment with hydrogen bromide. J Chin Chem Soc 47:1227–1230Google Scholar
  15. Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, Wildhirt SM, Schulz R (2002) Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol 283:H1108–H1115Google Scholar
  16. McCallum RE, Berry LJ (1973) Effects of endotoxin on gluconeogenesis, glycogen synthesis, and liver glycogen synthase in mice. Infect Immun 7:642–654Google Scholar
  17. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  18. Oberholzer A, Oberholzer C, Moldawer LL (2002) Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit Care Med 30 (Suppl 1): S58–S63CrossRefGoogle Scholar
  19. Okusa MD (2002) The inflammatory cascade in acute ischemic renal failure. Nephron 90:133–138CrossRefGoogle Scholar
  20. Parks DA, Bulkley GB, Granger DN (1983) Role of oxygen free radicals in shock, ischemia, and organ preservation. Surgery 94:428–432Google Scholar
  21. Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477CrossRefPubMedGoogle Scholar
  22. Peavy DL, Fairchild EJ (1986) Evidence for lipid peroxidation in endotoxin-poisoned mice. Infect Immun 52:613–616Google Scholar
  23. Rackow EC, Astiz ME (1991) Pathophysiology and treatment of septic shock. JAMA 266:548–554CrossRefGoogle Scholar
  24. Saito S, Nakano M (1996) Nitric oxide production by peritoneal macrophages of Mycobacterium bovis BCG-infected or non-infected mice: regulatory role of T lymphocytes and cytokines. J Leukoc Biol 59:908–915Google Scholar
  25. Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR (1997) Epidemiology of sepsis syndrome in 8 academic medical centers. Academic medical center consortium sepsis project working group. JAMA 278:234–240CrossRefGoogle Scholar
  26. Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10:2247–2258PubMedGoogle Scholar
  27. Stadler J, Bentz BG, Harbrecht BG, Di Silvio M, Curran RD, Billiar TR, Hoffman RA, Simmons RL (1992) Tumor necrosis factor alpha inhibits hepatocyte mitochondrial respiration. Ann Surg 216:539–546Google Scholar
  28. Su MJ, Chang YM, Chi JF, Lee SS (1994) Thaliporphine, a positive inotropic agent with a negative chronotropic action. Eur J Pharmacol 254:141–150CrossRefGoogle Scholar
  29. Sugino K, Dohi K, Yamada K, Kawasaki T (1987) The role of lipid peroxidation in endotoxin-induced hepatic damage and the protective effect of antioxidants. Surgery 101:746–752Google Scholar
  30. Szabo C, Mitchell JA, Thiemermann C, Vane JR (1993) Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol 108:786–792Google Scholar
  31. Teng CM, Yu SM, Lee SS, Ko FN, Su MJ, Huang TF (1993) Vasoconstricting effect in rat aorta caused by thaliporphine isolated from the plant Neolitsea konishii K. Eur J Pharmacol 233:7–12CrossRefGoogle Scholar
  32. Thiemermann C (1994) The role of the l-arginine: nitric oxide pathway in circulatory shock. Adv Pharmacol 28:45–79Google Scholar
  33. Uchikura K, Wada T, Hoshino S, Nagakawa Y, Aiko T, Bulkley GB, Klein AS, Sun Z (2004) Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species. Am J Physiol 287:G620–G626Google Scholar
  34. van der Vliet A, Cross CE (2000) Oxidants, nitrosants, and the lung. Am J Med 109:398–421CrossRefGoogle Scholar
  35. Waage A, Aasen AO (1992) Different role of cytokine mediators in septic shock related to meningococcal disease and surgery/polytrauma. Immunol Rev 127:221–230Google Scholar
  36. Wang S, Leonard SS, Castranova V, Vallyathan V, Shi X (1999) The role of superoxide radical in TNF-alpha induced NF-κB activation. Ann Clin Lab Sci 29:192–199Google Scholar
  37. Wu CC, Chiao CW, Hsiao G, Chen A, Yen MH (2001) Melatonin prevents endotoxin-induced circulatory failure in rats. J Pineal Res 30:147–156CrossRefGoogle Scholar
  38. Yu SM, Lee SS, Chou H, Teng CM (1993) Contractile effects caused by thaliporphine in the guinea-pig ileum. Eur J Pharmacol 234:121–123CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Chin-Wei Chiao
    • 1
  • Shoei-Sheng Lee
    • 2
  • Chin-Chen Wu
    • 3
  • Ming-Jai Su
    • 1
  1. 1.Institute of Pharmacology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  2. 2.Department of Pharmacy, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  3. 3.Department of PharmacologyNational Defence Medical CentreTaipeiTaiwan

Personalised recommendations