Am. J. Respir. Crit. Care Med., Vol 157, No. 1, Jan 1998, 81-88.
Role of endothelin in endotoxin-induced sustained pulmonary hypertension in sheep [In Process Citation]
JR Snapper, JS Thabes, PL Lefferts and W Lu
Center for Lung Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650, USA.
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.
