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Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock.

Iskit AB, Senel I, Sokmensuer C, Guc MO

Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey. alperi@hacettepe.edu.tr

The role of endothelin peptides was evaluated on survival and organ injury in a model of polymicrobial sepsis, induced by caecal ligation and puncture with particular emphasis on the timing of the administration of its blocker bosentan in Swiss albino mice (20-40 g). The cardiovascular response pattern in this experimental model was characterized by an early, "hyperdynamic" phase starting at 5 h, followed by a late but "hypodynamic" phase that commence after 20 h, provided that the animals are "resuscitated" by injecting 1 ml of saline i.p. at the end of the surgery. However, if saline resuscitation is omitted, then only hypodynamic pattern is observed starting at 5 h without any hyperdynamic phase. Thus, mice were first allocated into saline-resuscitated or unresuscitated groups and endothelin receptor antagonist bosentan (30 mg kg(-1), i.p., either 5 or 20 h after caecal ligation and puncture) was then administered. The control animals received the solvent of bosentan (i.e., saline: %0.9 NaCl, w/v). The survival rates in each group (n=14) were recorded over the following 144 h. In unresuscitated mice, the overall survival at 144 h was 14.3% in controls while bosentan treatment at 5 h (78.6%, P=0.0018) or 20 h (64.3%, P=0.0183) have both significantly improved the survival. However, in saline-resuscitated mice, bosentan administered at 20 h has significantly improved the survival (71.4%, P=0.0213) while its administration at 5 h has yielded exactly the same percent of survival (i.e., 21.4%) as observed in control animals. The beneficial effects of bosentan in preventing the tissue injury due to caecal ligation and puncture were also observed histopathologically in liver, spleen and kidney. Therefore, we concluded that the blockade of endothelin receptors by using bosentan during the later (hypodynamic) stages of septic shock is a promising therapeutic manoeuvre.

Published 13 December 2004 in Eur J Pharmacol, 506(1): 83-8.
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