Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 Jun;118(3):617–626. doi: 10.1111/j.1476-5381.1996.tb15446.x

Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock.

E Weitzberg 1, A Hemsén 1, A Rudehill 1, A Modin 1, M Wanecek 1, J M Lundberg 1
PMCID: PMC1909693  PMID: 8762086

Abstract

1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. Pulmonary and systemic haemodynamics as well as splenic, renal and intestinal blood flows were measured continuously. Release and synthesis of ET-1 and Big ET-1 were also measured. 2. Only three of the six pigs in the control group survived 3 h of LPS infusion while in the bosentantreated group all six pigs were alive at that time. A biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) was seen in control pigs. Pretreatment with bosentan did not influence the first peak but markedly attenuated the second, more prolonged increase in MPAP and PVR. The second dose of bosentan completely restored these parameters to pre-LPS levels. The LPS-induced changes in mean arterial blood pressure, heart rate and systemic vascular resistance were similar in both groups, while cardiac output (CO) was significantly higher in the bosentan-treated group. The second bosentan dose increased CO and splenic and intestinal blood flow without further lowering of blood pressure. 3. Bosentan caused an increase of the basal arterial plasma levels of ET-1-like immunoreactivity (LI), from 16.8 +/- 1.3 pM to 49.6 +/- 10.0 pM (n = 6, P < 0.01). However, the rate of the increase of ET-1 levels during the LPS infusion was not affected by bosentan. Repeated administration of bosentan during LPS infusion caused an additional increase of ET-1-LI levels. Neither the basal levels of Big ET-LI nor the LPS induced 8 fold increase in Big ET-LI were changed by bosentan. The level of preproET-1 mRNA in the lung was increased about 3 fold after 4.5 h of LPS treatment. This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.

Full text

PDF
626

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai H., Hori S., Aramori I., Ohkubo H., Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature. 1990 Dec 20;348(6303):730–732. doi: 10.1038/348730a0. [DOI] [PubMed] [Google Scholar]
  2. Badr K. F., Murray J. J., Breyer M. D., Takahashi K., Inagami T., Harris R. C. Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney. Elucidation of signal transduction pathways. J Clin Invest. 1989 Jan;83(1):336–342. doi: 10.1172/JCI113880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  4. Cernacek P., Stewart D. J. Immunoreactive endothelin in human plasma: marked elevations in patients in cardiogenic shock. Biochem Biophys Res Commun. 1989 Jun 15;161(2):562–567. doi: 10.1016/0006-291x(89)92636-3. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Clozel M., Breu V., Gray G. A., Kalina B., Löffler B. M., Burri K., Cassal J. M., Hirth G., Müller M., Neidhart W. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther. 1994 Jul;270(1):228–235. [PubMed] [Google Scholar]
  7. Clozel M., Gray G. A., Breu V., Löffler B. M., Osterwalder R. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun. 1992 Jul 31;186(2):867–873. doi: 10.1016/0006-291x(92)90826-7. [DOI] [PubMed] [Google Scholar]
  8. Frelin C., Guedin D. Why are circulating concentrations of endothelin-1 so low? Cardiovasc Res. 1994 Nov;28(11):1613–1622. doi: 10.1093/cvr/28.11.1613. [DOI] [PubMed] [Google Scholar]
  9. GOODFRIEND T. L., LEVINE L., FASMAN G. D. ANTIBODIES TO BRADYKININ AND ANGIOTENSIN: A USE OF CARBODIIMIDES IN IMMUNOLOGY. Science. 1964 Jun 12;144(3624):1344–1346. doi: 10.1126/science.144.3624.1344. [DOI] [PubMed] [Google Scholar]
  10. Gardiner S. M., Kemp P. A., March J. E., Bennett T. Effects of bosentan (Ro 47-0203), an ETA-, ETB-receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats. Br J Pharmacol. 1994 Jul;112(3):823–830. doi: 10.1111/j.1476-5381.1994.tb13153.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hahn A. W., Resink T. J., Scott-Burden T., Powell J., Dohi Y., Bühler F. R. Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. Cell Regul. 1990 Aug;1(9):649–659. doi: 10.1091/mbc.1.9.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hardie E. M., Olson N. C. Prostaglandin and thromboxane levels during endotoxin-induced respiratory failure in pigs. Prostaglandins Leukot Med. 1987 Aug;28(3):255–265. doi: 10.1016/0262-1746(87)90115-6. [DOI] [PubMed] [Google Scholar]
  13. Haynes W. G., Webb D. J. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994 Sep 24;344(8926):852–854. doi: 10.1016/s0140-6736(94)92827-4. [DOI] [PubMed] [Google Scholar]
  14. Hemsén A. Biochemical and functional characterization of endothelin peptides with special reference to vascular effects. Acta Physiol Scand Suppl. 1991;602:1–61. [PubMed] [Google Scholar]
  15. Hjemdahl P. Catecholamine measurements in plasma by high-performance liquid chromatography with electrochemical detection. Methods Enzymol. 1987;142:521–534. doi: 10.1016/s0076-6879(87)42065-x. [DOI] [PubMed] [Google Scholar]
  16. Itoh Y., Yanagisawa M., Ohkubo S., Kimura C., Kosaka T., Inoue A., Ishida N., Mitsui Y., Onda H., Fujino M. Cloning and sequence analysis of cDNA encoding the precursor of a human endothelium-derived vasoconstrictor peptide, endothelin: identity of human and porcine endothelin. FEBS Lett. 1988 Apr 25;231(2):440–444. doi: 10.1016/0014-5793(88)80867-6. [DOI] [PubMed] [Google Scholar]
  17. Karet F. E., Kuc R. E., Davenport A. P. Novel ligands BQ123 and BQ3020 characterize endothelin receptor subtypes ETA and ETB in human kidney. Kidney Int. 1993 Jul;44(1):36–42. doi: 10.1038/ki.1993.210. [DOI] [PubMed] [Google Scholar]
  18. Katoh T., Chang H., Uchida S., Okuda T., Kurokawa K. Direct effects of endothelin in the rat kidney. Am J Physiol. 1990 Feb;258(2 Pt 2):F397–F402. doi: 10.1152/ajprenal.1990.258.2.F397. [DOI] [PubMed] [Google Scholar]
  19. Kon V., Yoshioka T., Fogo A., Ichikawa I. Glomerular actions of endothelin in vivo. J Clin Invest. 1989 May;83(5):1762–1767. doi: 10.1172/JCI114079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Leeper-Woodford S. K., Carey P. D., Byrne K., Fisher B. J., Blocher C., Sugerman H. J., Fowler A. A., 3rd Ibuprofen attenuates plasma tumor necrosis factor activity during sepsis-induced acute lung injury. J Appl Physiol (1985) 1991 Sep;71(3):915–923. doi: 10.1152/jappl.1991.71.3.915. [DOI] [PubMed] [Google Scholar]
  21. Lerman A., Edwards B. S., Hallett J. W., Heublein D. M., Sandberg S. M., Burnett J. C., Jr Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991 Oct 3;325(14):997–1001. doi: 10.1056/NEJM199110033251404. [DOI] [PubMed] [Google Scholar]
  22. Löffler B. M., Breu V., Clozel M. Effect of different endothelin receptor antagonists and of the novel non-peptide antagonist Ro 46-2005 on endothelin levels in rat plasma. FEBS Lett. 1993 Oct 25;333(1-2):108–110. doi: 10.1016/0014-5793(93)80384-7. [DOI] [PubMed] [Google Scholar]
  23. Maemura K., Kurihara H., Morita T., Oh-hashi Y., Yazaki Y. Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury. Gerontology. 1992;38 (Suppl 1):29–35. doi: 10.1159/000213360. [DOI] [PubMed] [Google Scholar]
  24. Miyauchi T., Yanagisawa M., Tomizawa T., Sugishita Y., Suzuki N., Fujino M., Ajisaka R., Goto K., Masaki T. Increased plasma concentrations of endothelin-1 and big endothelin-1 in acute myocardial infarction. Lancet. 1989 Jul 1;2(8653):53–54. doi: 10.1016/s0140-6736(89)90303-6. [DOI] [PubMed] [Google Scholar]
  25. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  26. Moreland S., McMullen D. M., Delaney C. L., Lee V. G., Hunt J. T. Venous smooth muscle contains vasoconstrictor ETB-like receptors. Biochem Biophys Res Commun. 1992 Apr 15;184(1):100–106. doi: 10.1016/0006-291x(92)91163-k. [DOI] [PubMed] [Google Scholar]
  27. Ohta K., Hirata Y., Imai T., Kanno K., Emori T., Shichiri M., Marumo F. Cytokine-induced release of endothelin-1 from porcine renal epithelial cell line. Biochem Biophys Res Commun. 1990 Jun 15;169(2):578–584. doi: 10.1016/0006-291x(90)90370-3. [DOI] [PubMed] [Google Scholar]
  28. Oishi R., Nonoguchi H., Tomita K., Marumo F. Endothelin-1 inhibits AVP-stimulated osmotic water permeability in rat inner medullary collecting duct. Am J Physiol. 1991 Dec;261(6 Pt 2):F951–F956. doi: 10.1152/ajprenal.1991.261.6.F951. [DOI] [PubMed] [Google Scholar]
  29. Parker M. M., Parrillo J. E. Septic shock. Hemodynamics and pathogenesis. JAMA. 1983 Dec 23;250(24):3324–3327. [PubMed] [Google Scholar]
  30. Pernow J., Hemsén A., Lundberg J. M. Increased plasma levels of endothelin-like immunoreactivity during endotoxin administration in the pig. Acta Physiol Scand. 1989 Oct;137(2):317–318. doi: 10.1111/j.1748-1716.1989.tb08756.x. [DOI] [PubMed] [Google Scholar]
  31. Pernow J., Hemsén A., Lundberg J. M. Tissue specific distribution, clearance and vascular effects of endothelin in the pig. Biochem Biophys Res Commun. 1989 Jun 15;161(2):647–653. doi: 10.1016/0006-291x(89)92648-x. [DOI] [PubMed] [Google Scholar]
  32. Radermacher P., Santak B., Becker H., Falke K. J. Prostaglandin E1 and nitroglycerin reduce pulmonary capillary pressure but worsen ventilation-perfusion distributions in patients with adult respiratory distress syndrome. Anesthesiology. 1989 Apr;70(4):601–606. doi: 10.1097/00000542-198904000-00008. [DOI] [PubMed] [Google Scholar]
  33. Radermacher P., Santak B., Wüst H. J., Tarnow J., Falke K. J. Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with ARDS. Intensive Care Med. 1990;16(4):227–232. doi: 10.1007/BF01705156. [DOI] [PubMed] [Google Scholar]
  34. Rinaldo J. E., Rogers R. M. Adult respiratory-distress syndrome: changing concepts of lung injury and repair. N Engl J Med. 1982 Apr 15;306(15):900–909. doi: 10.1056/NEJM198204153061504. [DOI] [PubMed] [Google Scholar]
  35. Sakurai T., Yanagisawa M., Takuwa Y., Miyazaki H., Kimura S., Goto K., Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature. 1990 Dec 20;348(6303):732–735. doi: 10.1038/348732a0. [DOI] [PubMed] [Google Scholar]
  36. Stewart D. J., Levy R. D., Cernacek P., Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991 Mar 15;114(6):464–469. doi: 10.7326/0003-4819-114-6-464. [DOI] [PubMed] [Google Scholar]
  37. Sugiura M., Inagami T., Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun. 1989 Jun 30;161(3):1220–1227. doi: 10.1016/0006-291x(89)91372-7. [DOI] [PubMed] [Google Scholar]
  38. Svartholm E., Bergqvist D., Hedner U., Ljungberg J., Haglund U. Thromboxane A2-receptor blockade and prostacyclin in porcine Escherichia coli shock. Arch Surg. 1989 Jun;124(6):669–672. doi: 10.1001/archsurg.1989.01410060031006. [DOI] [PubMed] [Google Scholar]
  39. Weitzberg E., Ahlborg G., Lundberg J. M. Differences in vascular effects and removal of endothelin-1 in human lung, brain, and skeletal muscle. Clin Physiol. 1993 Nov;13(6):653–662. doi: 10.1111/j.1475-097x.1993.tb00480.x. [DOI] [PubMed] [Google Scholar]
  40. Weitzberg E., Ahlborg G., Lundberg J. M. Long-lasting vasoconstriction and efficient regional extraction of endothelin-1 in human splanchnic and renal tissues. Biochem Biophys Res Commun. 1991 Nov 14;180(3):1298–1303. doi: 10.1016/s0006-291x(05)81336-1. [DOI] [PubMed] [Google Scholar]
  41. Weitzberg E., Lundberg J. M., Rudehill A. Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock. 1991 Apr;33(4):222–227. [PubMed] [Google Scholar]
  42. Weitzberg E., Lundberg J. M., Rudehill A. Inhibitory effects of diclofenac on the endotoxin shock response in relation to endothelin turnover in the pig. Acta Anaesthesiol Scand. 1995 Jan;39(1):50–59. doi: 10.1111/j.1399-6576.1995.tb05592.x. [DOI] [PubMed] [Google Scholar]
  43. Weitzberg E., Rudehill A., Lundberg J. M. Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxin shock. Eur J Pharmacol. 1993 Mar 16;233(1):85–94. doi: 10.1016/0014-2999(93)90352-i. [DOI] [PubMed] [Google Scholar]
  44. Weitzberg E., Rudehill A., Modin A., Lundberg J. M. Porcine intrinsic pulmonary and systemic vascular tone is endothelin-dependent. Acta Physiol Scand. 1994 Dec;152(4):433–434. doi: 10.1111/j.1748-1716.1994.tb09827.x. [DOI] [PubMed] [Google Scholar]
  45. Woodcock E. A., Land S. Interaction between vasopressin and endothelin in renal papillary tubules: uncoupling following cell isolation and culture. Clin Exp Pharmacol Physiol. 1992 May;19(5):384–387. doi: 10.1111/j.1440-1681.1992.tb00478.x. [DOI] [PubMed] [Google Scholar]
  46. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  47. de Nucci G., Thomas R., D'Orleans-Juste P., Antunes E., Walder C., Warner T. D., Vane J. R. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9797–9800. doi: 10.1073/pnas.85.24.9797. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES