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Cardiopulmonary dysfunction during porcine endotoxin shock is effectively counteracted by the endothelin receptor antagonist bosentan

Endothelin 1, an endothelium derived peptide, is the most potent vasoconstrictor known. In experimental endotoxin models as well as in human septic shock, a three- to fourfold elevation of plasma levels of endothelin-1-like immunoreactivity is seen [1]. In a porcine endotoxin shock model, the mixed non-peptide endothelin receptor antagonist bosentan [2] was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen related variables and plasma levels of endothelin-1-like immunoreactivity were compared to a control group only receiving endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Further, bosentan restored cardiac index to pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery and acid base balance, and since mean arterial blood pressure was unaffected, reduced systemic vascular resistance. Endotoxemia increased plasma levels of endothelin-1-like immunoreactivity (from 14 ± 1 to 37 ± 2 pmol/l) and tumor necrosis factor-alpha, the former being further increased by bosentan (from 37 ± 2 to 180 ± 30 pmol/l).

Effects of endotoxin infusion, started at T0 h and bosentan, administered after 2 h of endotoxemia (T2 h), in pigs (n = 8) compared to control pigs (n = 8) not receiving bosentan. Groups are compared at T0 h, T2 h and T5 h. *P < 0.05 and ***P < 0.001 for differences between groups in time-matched between-group contrasts.

In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during established shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment to reverse a deteriorated cardiopulmonary state during septic shock.

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Waneek, M., Oldner, A., Rudehill, A. et al. Cardiopulmonary dysfunction during porcine endotoxin shock is effectively counteracted by the endothelin receptor antagonist bosentan. Crit Care 1, P078 (1997). https://doi.org/10.1186/cc70

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Keywords

  • Septic Shock
  • Pulmonary Hypertension
  • Cardiac Index
  • Bosentan
  • Acid Base Balance