title: The endothelin receptor antagonist, bosentan, in combination with the cyclooxygenase inhibitor, diclofenac, counteracts pulmonary hypertension in porcine endotoxin shock.
abstract: OBJECTIVE
  To prevent endotoxin-induced pulmonary hypertension in the pig with a combination of a nonpeptide mixed endothelin receptor antagonist, bosentan, and a cyclooxygenase inhibitor, diclofenac.
  
  
  METHODS
  Prospective, controlled trial.
  
  
  METHODS
  Animal laboratory at a large university medical center.
  
  
  METHODS
  Twelve domestic pigs, weighing 17.5 to 27 kg.
  
  
  METHODS
  Endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide endotoxin (15 micrograms/kg/hr). Six pigs receiving only endotoxin served as controls. Six pigs were pretreated with intravenous bolus injections of bosentan (5 mg/kg) and diclofenac (3 mg/kg) followed by a continuous bosentan infusion (2.5 mg/kg/hr).
  
  
  RESULTS
  Systemic hemodynamics and regional circulation were measured using ultrasonic flow probes. Arterial and mixed venous blood samples were collected regularty for determination of Big endothelin-1-like immunoreactivity, endothelin-1-like immunoreactivity, norepinephrine, and blood gases. The bosentan/diclofenac pretreatment per se significantly decreased mean pulmonary arterial pressure (p < .001), pulmonary vascular resistance index (p < .001), and mean arterial blood pressure (p < .001), but cardiac index did not change. Splenic blood flow increased (p < .01) while renal blood flow decreased (p < .001). In addition, intestinal blood flow decreased slightly (p < .05). In the control group, only three animals survived the 3 hrs of endotoxin infusion, while all pretreated animals survived. The biphasic increase in mean pulmonary arterial pressure and pulmonary vascular resistance index seen in control animals during endotoxemia was markedly attenuated in animals pretreated with the bosentan/diclofenac combination. The pretreated group generally showed a favorable hemodynamic course, with a relatively higher cardiac index, stroke volume index, and splenic and renal blood flow. In control animals, a pronounced metabolic acidosis developed during endotoxin infusion. A relatively higher arterial plasma concentration of endothelin-1-like immunoreactivity was reached in pretreated animals, while the Big endothelin-1-like immunoreactivity plasma increase was similar in both groups. Arterial concentrations of norepinephrine were significantly (p < .01) higher in control animals when compared with diclofenac/bosentan-treated animals.
  
  
  CONCLUSIONS
  The combination of bosentan and diclofenac induced systemic and pulmonary vasodilation in the intrinsic state. During endotoxin shock, this drug combination efficiently counteracts pulmonary hypertension and improves cardiac performance and splenic and renal blood flow. These favorable circulatory effects may have resulted in a reduction of both sympathetic nervous system activation and metabolic acidosis. Thus, we conclude that the endothelin receptors participate in intrinsic regulation of vascular tone in the anesthetized pig. During endotoxin shock, blockade of these receptors, as well as inhibition of the cyclooxygenase enzymes, contributes to a less adverse effect on the systemic and pulmonary circulation.
authors.affiliation: Department of Anesthesiology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Wanecek
authors.forename: A
authors.initials: A
authors.lastname: Rudehill
authors.forename: A
authors.initials: A
authors.lastname: Hemsén
authors.forename: J M
authors.initials: JM
authors.lastname: Lundberg
authors.forename: E
authors.initials: E
authors.lastname: Weitzberg
mesh_terms: D000818:Animals; D000077300:Bosentan; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D012079:Renal Circulation / Q000187:drug effects; D012772:Shock, Septic / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine
chemical_list: D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D004008:Diclofenac; D000077300:Bosentan