Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1

McMullan, D. Michael, Janine M. Bekker, Michael J. Johengen, Karen Hendricks-Munoz, Rene Gerrets, Stephen M. Black, and Jeffrey R. Fineman. Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1. Am J Physiol Heart Circ Physiol 280: H777–H785, 2001.—Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicletreated control lambs and six PD-156707 (an ET_A receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 ± 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET- 1, endothelin-converting enzyme-1α, and ET_A and ETB receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (–5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET_A receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.