The endothelin receptor antagonist, bosentan, in combination with the cyclooxygenase inhibitor, diclofenac, counteracts pulmonary hypertension in porcine endotoxin shock

M Wanecek, A Rudehill, A Hemsén, J M Lundberg, E Weitzberg
Critical Care Medicine 1997, 25 (5): 848-57

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.

DESIGN: Prospective, controlled trial.

SETTING: Animal laboratory at a large university medical center.

SUBJECTS: Twelve domestic pigs, weighing 17.5 to 27 kg.

INTERVENTIONS: 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).

MEASUREMENTS AND MAIN 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.


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"