TY - JOUR
T1 - Inhaled nitric oxide-induced rebound pulmonary hypertension
T2 - Role for endothelin-1
AU - Mcmullan, D. Michael
AU - Bekker, Janine M.
AU - Johengen, Michael J.
AU - Hendricks-Munoz, Kaken
AU - Gerrets, Rene
AU - Black, Stephen M.
AU - Fineman, Jeffrey R.
PY - 2001/2
Y1 - 2001/2
N2 - 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 vehicle-treated control lambs and six PD-156707 (an ETA 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 Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn.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 pre-proET-1, endothelin-converting enzyme-1α, and ETA 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 ETA 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.
AB - 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 vehicle-treated control lambs and six PD-156707 (an ETA 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 Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn.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 pre-proET-1, endothelin-converting enzyme-1α, and ETA 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 ETA 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.
KW - Endothelin receptor
KW - Endothelium-derived factors
KW - Pulmonary heart disease
KW - Pulmonary hypertension of the newborn
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U2 - 10.1152/ajpheart.2001.280.2.h777
DO - 10.1152/ajpheart.2001.280.2.h777
M3 - Article
C2 - 11158977
AN - SCOPUS:0034996074
SN - 0363-6135
VL - 280
SP - H777-H785
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2 49-2
ER -