ROLE OF ENDOTHELIN IN ENDOTOXIN-INDUCED SUSTAINED PULMONARY-HYPERTENSION IN SHEEP

BMS182874, an endothelin receptor antagonist, blocks the effects of ex ogenously administered endothelins in chronically instrumented awake s heep. A possible role for endothelin in endotoxin-induced pulmonary hy pertension in sheep was investigated by studying animals given intrave nous 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 a n 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 f low and dramatic increases in plasma and lung lymph thromboxane B-2 co ncentrations. 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 d ose response curve for U46619, a prostaglandin H-2 analogue, to the ri ght. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the rec eptor level. We theorize that BMS182874 attenuates the early endotoxin -induced pulmonary hypertension by counteracting the effects of thromb oxane, since previous studies demonstrated that the early acute rise i n P-PA is caused by thromboxane. The late sustained pulmonary hyperten sion of endotoxemia, on the other hand, appears to be mediated by endo thelin.