Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep.
OBJECTIVE
To evaluate the cardiopulmonary effects of the novel endothelin receptor antagonist tezosentan in endotoxin-induced lung injury in sheep and to assess the dose response to tezosentan and endothelin-1 in healthy sheep.


METHODS
Prospective, randomized, controlled experimental study.


METHODS
University animal laboratory.


METHODS
Twenty-one yearling sheep.


METHODS
Seventeen awake, chronically instrumented sheep were subjected to intravenous infusion of Ringer's lactate for 24 hrs. The animals were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide group (n = 7) receiving an intravenous infusion of Escherichia coli lipopolysaccharide 15 ng x kg x min, and a tezosentan group (n = 7) subjected to lipopolysaccharide and, from 4 hrs, an intravenous injection of tezosentan 3 mg/kg followed by infusion of 1 mg x kg x hr. In addition, four healthy sheep, exposed to an intravenous infusion of endothelin-1 at 20 ng x kg x min, after 1 hr received tezosentan in stepwise increasing doses of 0.5, 1, and 2 mg x kg x hr that were maintained for 1 hr each. After a 4-hr recovery, the sheep received infusions of tezosentan at the same dose rates as a pretreatment to endothelin-1.


RESULTS
In the sham-operated sheep, all cardiopulmonary variables remained unchanged. Lipopolysaccharide caused pulmonary hypertension, increased extravascular lung water index, and induced arterial hypoxemia. Tezosentan decreased the increments in pulmonary vascular resistance and extravascular lung water index by as much as 60% and 70%, respectively. In parallel, tezosentan ameliorated arterial hypoxemia, increased cardiac index, attenuated the decrease in stroke volume index, and reduced systemic vascular resistance. Compared with the lipopolysaccharide group, tezosentan further increased plasma concentrations of endothelin-1. In healthy animals, the administration of endothelin-1 induced systemic and pulmonary hypertension, increased extravascular lung water index, and evoked bradycardia and a decrease in cardiac index. These changes were attenuated by tezosentan infused at 1 and 2 mg x kg x hr.


CONCLUSIONS
In an ovine model of endotoxin-induced lung injury, tezosentan ameliorates pulmonary hypertension, lung edema, cardiac dysfunction, and arterial hypoxemia. Tezosentan counteracts the hemodynamic effects of endothelin-1 in a dose-dependent manner.
Kuklin
Vladimir N
VN
Departments of Anesthesiology, Faculty of Medicine, University of Tromsø, Norway. lars.bjertnaes@unn.no
Kirov
Mikhail Y
MY
Evgenov
Oleg V
OV
Sovershaev
Mikhail A
MA
Sjöberg
Jonas
J
Kirova
Svetlana S
SS
Bjertnaes
Lars J
LJ
D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D015633:Extravascular Lung Water / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides; D011446:Prospective Studies; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D012756:Sheep; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D008070:Lipopolysaccharides; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan