THE ENDOTHELIN RECEPTOR ANTAGONIST, BOSENTAN, IN COMBINATION WITH THECYCLOOXYGENASE INHIBITOR, DICLOFENAC, COUNTERACTS PULMONARY-HYPERTENSION IN PORCINE ENDOTOXIN-SHOCK

Objective: To prevent endotoxin induced pulmonary hypertension in the pig with a combination of a nonpeptide mixed endothelin receptor antag onist, bosentan, and a cyclooxygenase inhibitor, diclofenac. Design: P rospective, controlled trial. Setting: Animal laboratory at a large un iversity medical center. Subjects: Twelve domestic pigs, weighing 17.5 to 27 kg. Interventions: Endotoxin shock was induced by intravenous i nfusion of Escherichia coli lipopolysaccharide endotoxin (15 mu g/kg/h r). Six pigs receiving only endotoxin served as controls. Six pigs wer e pretreated with intravenous bolus injections of bosentan (5 mg/kg) a nd 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. Arter ial and mixed venous blood samples were collected regularly for determ ination of Big endothelin-1-like immunoreactivity, endothelin-1-like i mmunoreactivity, norepinephrine, and blood gases. The bosentan/diclofe nac pretreatment per se significantly decreased mean pulmonary arteria l pressure (p < .001), pulmonary vascular resistance index (p < .001), and mean arterial blood pressure (p < .001), but cardiac index did no t change. Splenic blood flow increased (p < .01) while renal blood flo w decreased (p < .001). In addition, intestinal blood flow decreased s lightly (p < .05). In the control group, only three animals survived t he 3 hrs of endotoxin infusion, while all pretreated animals survived. The biphasic increase in mean pulmonary arterial pressure and pulmona ry vascular resistance index seen in control animals during endotoxemi a was markedly attenuated in animals pretreated with the bosentan/dicl ofenac combination. The pretreated group generally showed a favorable hemodynamic course, with a relatively higher cardiac index, stroke vol ume index, and splenic and renal blood flow. In control animals, a pro nounced metabolic acidosis developed during endotoxin infusion. A rela tively higher arterial plasma concentration of endothelin-1-like immun oreactivity was reached in pretreated animals, while the Big endotheli n-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-trea ted animals. Conclusions: The combination of bosentan and diclofenac i nduced systemic and pulmonary vasodilation in the intrinsic state. Dur ing endotoxin shock, this drug combination efficiently counteracts pul monary hypertension and improves cardiac performance and splenic and r enal blood flow. These favorable circulatory effects may have resulted in a reduction of both sympathetic nervous system activation and meta bolic acidosis. Thus, we conclude that the endothelin receptors partic ipate in intrinsic regulation of vascular tone in the anesthetized pig . During endotoxin shock, blockade of these receptors, as well as inhi bition of the cyclooxygenase enzymes, contributes to a less adverse ef fect on the systemic and pulmonary circulation.