• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of brjpharmLink to Publisher's site
Br J Pharmacol. Dec 1995; 116(8): 3191–3198.
PMCID: PMC1909185

Role for intracellular platelet-activating factor in the circulatory failure in a model of gram-positive shock.

Abstract

1. This study investigates the effects of two structurally different antagonists of platelet-activating factor (PAF), BN52021 and WEB2086, on the circulatory and renal failure elicited by lipoteichoic acid (LTA) from Staphylococcus aureus (an organism without endotoxin) in anaesthetized rats. 2. Administration of LTA (10 mg kg-1, i.v.) caused hypotension and vascular hyporeactivity to noradrenaline (1 microgram kg-1, i.v.) WEB2086 (5 mg kg-1, i.v., 20 min before and 150 min after LTA) inhibited the delayed fall in mean arterial blood pressure (at 300 min: 99 +/- 6 mmHg vs. 75 +/- 6 mmHg, P < 0.01) and prevented the decrease in pressor response to noradrenaline (at 300 min: 36 +/- 5 mmHg min vs. 17 +/- 5 mmHg min, P < 0.01). Surprisingly, BN52021 (20 mg kg-1, i.v., 20 min before and 150 min after LTA) neither prevented the hypotension (74 +/- 6 mmHg) nor the vascular hyporeactivity (21 +/- 5 mmHg min). However, BN52021 inhibited the hypotension to injections of PAF as well as the circulatory failure elicited by lipopolysaccharides (10 mg kg-1, i.v.). 3. LTA caused an increase in plasma concentration of creatinine from 39 +/- 5 microM (sham-operated) to 70 +/- 8 microM and urea from 4.7 +/- 0.1 to 13.1 +/- 1.6 mM. The renal failure elicited by LTA was significantly inhibited by WEB2086 (creatinine: 45 +/- 4 microM and urea: 5.7 +/- 0.7 mM), but not by BN52021. 4. The induction of nitric oxide synthase activity in lungs by LTA was attenuated by WEB2086 from 98 +/- 17 to 40 +/- 15 pmol L-citrulline 30 min-1 mg-1 protein (P < 0.01), but not by BN52021 (148 +/- 21 pmol L-citrulline 30 min-1 mg-1 protein). Similarly, WEB2086, but not BN52021, inhibited the increase in plasma nitrite concentration associated with the delayed circulatory failure caused by LTA. The release of tumour necrosis factor-alpha (TNF-alpha) after injection of LTA was not attenuated by WEB2086. 5. The induction of nitrite release by cultured macrophages activated with LTA (10 micrograms ml-1 for 24 h) was inhibited by 74 +/- 4% by WEB2086 (3 x 10(-4) M), but not by BN52021, indicating that only WEB2086 acts on intracellular PAF receptors. 6. Thus, the intracellular release of PAF contributes to the circulatory and renal failure and induction of nitric oxide synthase elicited by LTA in anaesthetized rats. The difference between the two structurally different PAF antagonists in our septic shock models using either LTA or lipopolysaccharide (LPS), shows the importance of models for Gram-positive sepsis in the elucidation of the pathophysiology of septic shock and for the evaluation of potential drugs.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aiura K, Gelfand JA, Burke JF, Thompson RC, Dinarello CA. Interleukin-1 (IL-1) receptor antagonist prevents Staphylococcus epidermidis-induced hypotension and reduces circulating levels of tumor necrosis factor and IL-1 beta in rabbits. Infect Immun. 1993 Aug;61(8):3342–3350. [PMC free article] [PubMed]
  • Bone RC. Gram-positive organisms and sepsis. Arch Intern Med. 1994 Jan 10;154(1):26–34. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating factor research. Pharmacol Rev. 1987 Jun;39(2):97–145. [PubMed]
  • Casals-Stenzel J. Protective effect of WEB 2086, a novel antagonist of platelet activating factor, in endotoxin shock. Eur J Pharmacol. 1987 Mar 17;135(2):117–122. [PubMed]
  • Chang SW, Feddersen CO, Henson PM, Voelkel NF. Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats. J Clin Invest. 1987 May;79(5):1498–1509. [PMC free article] [PubMed]
  • Chang SW, Fernyak S, Voelkel NF. Beneficial effect of a platelet-activating factor antagonist, WEB 2086, on endotoxin-induced lung injury. Am J Physiol. 1990 Jan;258(1 Pt 2):H153–H158. [PubMed]
  • De Kimpe SJ, Hunter ML, Bryant CE, Thiemermann C, Vane JR. Delayed circulatory failure due to the induction of nitric oxide synthase by lipoteichoic acid from Staphylococcus aureus in anaesthetized rats. Br J Pharmacol. 1995 Mar;114(6):1317–1323. [PMC free article] [PubMed]
  • DeVuono J, Panos C. Effect of L-form Streptococcus pyogenes and of lipoteichoic acid on human cells in tissue culture. Infect Immun. 1978 Oct;22(1):255–265. [PMC free article] [PubMed]
  • Dinarello CA. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J Infect Dis. 1991 Jun;163(6):1177–1184. [PubMed]
  • Doebber TW, Wu MS, Robbins JC, Choy BM, Chang MN, Shen TY. Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Commun. 1985 Mar 29;127(3):799–808. [PubMed]
  • Dos Santos OF, Boim MA, Barros EJ, Schor N. Role of platelet activating factor in gentamicin and cisplatin nephrotoxicity. Kidney Int. 1991 Oct;40(4):742–747. [PubMed]
  • Fischer W. Physiology of lipoteichoic acids in bacteria. Adv Microb Physiol. 1988;29:233–302. [PubMed]
  • Fletcher JR, DiSimone AG, Earnest MA. Platelet activating factor receptor antagonist improves survival and attenuates eicosanoid release in severe endotoxemia. Ann Surg. 1990 Mar;211(3):312–316. [PMC free article] [PubMed]
  • Floch A, Bousseau A, Hetier E, Floc'h F, Bost PE, Cavero I. RP 55778, a PAF receptor antagonist, prevents and reverses LPS-induced hemoconcentration and TNF release. J Lipid Mediat. 1989 Nov-Dec;1(6):349–360. [PubMed]
  • Freudenberg MA, Galanos C. Tumor necrosis factor alpha mediates lethal activity of killed gram-negative and gram-positive bacteria in D-galactosamine-treated mice. Infect Immun. 1991 Jun;59(6):2110–2115. [PMC free article] [PubMed]
  • Iñarrea P, Gomez-Cambronero J, Pascual J, Ponte MC, Hernando L, Sánchez-Crespo M. Synthesis of PAF-acether and blood volume changes in gram-negative sepsis. Immunopharmacology. 1985 Feb;9(1):45–52. [PubMed]
  • Julou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, Stoclet JC. Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway. Am J Physiol. 1990 Oct;259(4 Pt 2):H1038–H1043. [PubMed]
  • Karkar AM, Koshino Y, Cashman SJ, Dash AC, Bonnefoy J, Meager A, Rees AJ. Passive immunization against tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats. Clin Exp Immunol. 1992 Nov;90(2):312–318. [PMC free article] [PubMed]
  • Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun. 1990 Nov 15;172(3):1132–1138. [PubMed]
  • Kita T, Tanaka N, Nagano T. The immunocytochemical localization of tumour necrosis factor and leukotriene in the rat kidney after treatment with lipopolysaccharide. Int J Exp Pathol. 1993 Oct;74(5):471–479. [PMC free article] [PubMed]
  • Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J. 1994 Mar 1;298(Pt 2):249–258. [PMC free article] [PubMed]
  • Koltai M, Guinot P, Hosford D, Braquet PG. Platelet-activating factor antagonists: scientific background and possible clinical applications. Adv Pharmacol. 1994;28:81–167. [PubMed]
  • Koltai M, Hosford D, Braquet P. PAF-induced amplification of mediator release in septic shock: prevention or downregulation by PAF antagonists. J Lipid Mediat. 1993 Mar-Apr;6(1-3):183–198. [PubMed]
  • Lopez Diez F, Nieto ML, Fernandez-Gallardo S, Gijon MA, Sanchez Crespo M. Occupancy of platelet receptors for platelet-activating factor in patients with septicemia. J Clin Invest. 1989 May;83(5):1733–1740. [PMC free article] [PubMed]
  • López-Farré A, Bernabeu F, Gómez-Garre D, Ramon y Cajal S, Braquet P, López-Novoa JM. Platelet-activating factor antagonists treatment protects against postischemic acute renal failure in rats. J Pharmacol Exp Ther. 1990 Apr;253(1):328–333. [PubMed]
  • Lynch JM, Henson PM. The intracellular retention of newly synthesized platelet-activating factor. J Immunol. 1986 Oct 15;137(8):2653–2661. [PubMed]
  • Marcheselli VL, Rossowska MJ, Domingo MT, Braquet P, Bazan NG. Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex. J Biol Chem. 1990 Jun 5;265(16):9140–9145. [PubMed]
  • Moore JM, Earnest MA, DiSimone AG, Abumrad NN, Fletcher JR. A PAF receptor antagonist, BN 52021, attenuates thromboxane release and improves survival in lethal canine endotoxemia. Circ Shock. 1991 Sep;35(1):53–59. [PubMed]
  • Natanson C, Danner RL, Elin RJ, Hosseini JM, Peart KW, Banks SM, MacVittie TJ, Walker RI, Parrillo JE. Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock. J Clin Invest. 1989 Jan;83(1):243–251. [PMC free article] [PubMed]
  • Ogata M, Matsumoto T, Koga K, Takenaka I, Kamochi M, Sata T, Yoshida S, Shigematsu A. An antagonist of platelet-activating factor suppresses endotoxin-induced tumor necrosis factor and mortality in mice pretreated with carrageenan. Infect Immun. 1993 Feb;61(2):699–704. [PMC free article] [PubMed]
  • Pignol B, Hénane S, Sorlin B, Rola-Pleszczynski M, Mencia-Huerta JM, Braquet P. Effect of long-term treatment with platelet-activating factor on IL-1 and IL-2 production by rat spleen cells. J Immunol. 1990 Aug 1;145(3):980–984. [PubMed]
  • Poubelle PE, Gingras D, Demers C, Dubois C, Harbour D, Grassi J, Rola-Pleszczynski M. Platelet-activating factor (PAF-acether) enhances the concomitant production of tumour necrosis factor-alpha and interleukin-1 by subsets of human monocytes. Immunology. 1991 Feb;72(2):181–187. [PMC free article] [PubMed]
  • Qi M, Jones SB. Contribution of platelet activating factor to hemodynamic and sympathetic responses to bacterial endotoxin in conscious rats. Circ Shock. 1990 Oct;32(2):153–163. [PubMed]
  • Rabinovici R, Yue TL, Farhat M, Smith EF, 3rd, Esser KM, Slivjak M, Feuerstein G. Platelet activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha) interactions in endotoxemic shock: studies with BN 50739, a novel PAF antagonist. J Pharmacol Exp Ther. 1990 Oct;255(1):256–263. [PubMed]
  • Sánchez Crespo M, Fernández-Gallardo S. Pharmacological modulation of PAF: a therapeutic approach to endotoxin shock. J Lipid Mediat. 1991 Sep-Oct;4(2):127–143. [PubMed]
  • Stewart AG, Dubbin PN, Harris T, Dusting GJ. Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3215–3219. [PMC free article] [PubMed]
  • Szabó C, Wu CC, Mitchell JA, Gross SS, Thiemermann C, Vane JR. Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide. Circ Res. 1993 Dec;73(6):991–999. [PubMed]
  • Takada H, Kawabata Y, Arakaki R, Kusumoto S, Fukase K, Suda Y, Yoshimura T, Kokeguchi S, Kato K, Komuro T, et al. Molecular and structural requirements of a lipoteichoic acid from Enterococcus hirae ATCC 9790 for cytokine-inducing, antitumor, and antigenic activities. Infect Immun. 1995 Jan;63(1):57–65. [PMC free article] [PubMed]
  • Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol. 1990 Jul 17;182(3):591–595. [PubMed]
  • Torley LW, Pickett WC, Carroll ML, Kohler CA, Schaub RE, Wissner A, DeJoy SQ, Oronsky AL, Kerwar SS. Studies of the effect of a platelet-activating factor antagonist, CL 184,005, in animal models of gram-negative bacterial sepsis. Antimicrob Agents Chemother. 1992 Sep;36(9):1971–1977. [PMC free article] [PubMed]
  • Wakabayashi G, Gelfand JA, Jung WK, Connolly RJ, Burke JF, Dinarello CA. Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli. J Clin Invest. 1991 Jun;87(6):1925–1935. [PMC free article] [PubMed]
  • Wicken AJ, Knox KW. Bacterial cell surface amphiphiles. Biochim Biophys Acta. 1980 May 27;604(1):1–26. [PubMed]
  • Yue TL, Farhat M, Rabinovici R, Perera PY, Vogel SN, Feuerstein G. Protective effect of BN 50739, a new platelet-activating factor antagonist, in endotoxin-treated rabbits. J Pharmacol Exp Ther. 1990 Sep;254(3):976–981. [PubMed]
  • Zingarelli B, Squadrito F, Ioculano M, Altavilla D, Bussolino F, Campo GM, Caputi AP. Platelet activating factor interaction with tumor necrosis factor and myocardial depressant factor in splanchnic artery occlusion shock. Eur J Pharmacol. 1992 Nov 3;222(1):13–19. [PubMed]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...