• E A Triplett, K T Kruse-Elliott, A P Hart, B R Schram, P S MacWilliams, A J Cooley, M K Clayton, and B J Darien.
• Department of Medical Science, School of Veterinary Medicine, University of Wisconsin, Madison 53706, USA.
• Shock. 1996 Nov 1; 6 (5): 357-64.

AbstractCytokines and eicosanoids are well documented important mediators of endotoxemia. Bicyclic imidazoles are a novel class of nonsteroidal anti-inflammatory compounds that display unique pharmacological profiles by reducing cytokine production and arachidonic acid metabolism. In this study, we evaluated the ability of the bicyclic imidazole, SK&F 86002, to attenuate endotoxin-induced cardiopulmonary dysfunction. Pigs were randomly assigned to one of four groups: LPS (n = 5), given .5 microgram/kg/h 055:B5 Escherichia coli lipopolysaccharide (LPS) intravenously (i.v.) for 6 h; saline (n = 5); SK&F 86002 (n = 3), given 50 mg/kg SK&F 86002 orally 30 min prior to anesthesia; and SK&F 86002 + LPS (n = 5). Administration of LPS resulted in cardiopulmonary dysfunction characterized by decreased stroke volume and arterial oxygen tension, and increased room air alveolar-arterial oxygen gradient, pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure. Additionally, LPS administration was associated with leukopenia and increased pulmonary myeloperoxidase activity. Pretreatment with SK&F 86002 attenuated LPS induced hypotension, hypoxemia and bronchoconstriction and blocked the pulmonary hypertension. SK&F 86002 blocked the LPS-induced increase in myeloperoxidase activity, indicating a reduction in pulmonary neutrophil infiltration, but had no effect on systemic leukopenia. Pretreatment with SK&F 86002 significantly attenuated LPS-induced increases in plasma thromboxane B2 and tumor necrosis factor-alpha. We hypothesize that ameliorating effects of SK&F 86002 in this endotoxin model of cardiopulmonary dysfunction are related to inhibition of cytokine and eicosanoid biosynthesis.

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