BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. A possible role for endothelin in endotoxin-induced pulmonary hypertension in sheep was investigated by studying animals given intravenous endotoxin with and without pretreatment with BMS182874. BMS182874 administration alone caused a reduction in pulmonary artery pressure (P[PA]) and systemic arterial pressure (P[SA]). Endotoxin alone caused an acute, nearly threefold increase in P(PA) which was followed, from 2-5 h after endotoxin, by a sustained but less severe increase in P(PA). These changes were accompanied by a threefold increase in lung lymph flow and dramatic increases in plasma and lung lymph thromboxane B2 concentrations. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in P(PA) and completely blocked the late sustained pulmonary hypertension (p < 0.05), while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level. We theorize that BMS182874 attenuates the early endotoxin-induced pulmonary hypertension by counteracting the effects of thromboxane, since previous studies demonstrated that the early acute rise in P(PA) is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin.

To further define the role of platelet-activating factor (PAF) in endotoxin-induced lung dysfunction, we examined the effect of ABT-299, a specific and potent PAF-receptor antagonist, on the response to endotoxemia in six chronically instrumented awake sheep. We administered Escherichia coli endotoxin (0.5 microg/kg) intravenously with or without pretreatment with ABT-299 while monitoring mean pulmonary arterial pressure (Ppa), mean systemic arterial pressure (Psa), dynamic compliance of the lungs (Cdyn), and functional residual capacity (FRC). Endotoxin administration caused pulmonary hypertension, reduced Cdyn, leukopenia, and hypoxemia while having no significant effect on Psa or FRC. Administration of ABT-299 did not affect any of the measured variables at baseline. Pretreatment with ABT-299 attenuated the peak Ppa seen after endotoxin administration but had minimal effects on endotoxin-induced changes in Cdyn, white blood cell count, or alveolar-to-arterial oxygen difference. ABT-299 was shown to completely block the pulmonary hypertension and reduction in Cdyn seen after intravenous administration of exogenous PAF. We conclude that PAF does not play an essential role in the sheep's response to endotoxin.

No abstract