Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5'-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension.
OBJECTIVE
To examine the role of endogenous nitric oxide (NO) and endothelin-1 (ET-1) in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) and to determine whether inhaled NO, currently under investigation as a new therapy for PPHN, affects plasma concentrations of these vasoactive mediators.


METHODS
Circulating ET-1 and cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay in 15 healthy term newborn infants and 46 newborn infants with PPHN enrolled in a randomized, controlled trial of inhaled NO. These concentrations were followed up longitudinally and compared between the NO and the conventionally treated group.


RESULTS
Concentrations of ET-1 were significantly higher and cGMP concentrations significantly lower in infants with PPHN compared with healthy newborn infants (median ET-1, 28 vs 11 pmol/L; p = 0.0001; median cGMP, 35 vs 61 pmol/ml; p = 0.0001, respectively). ET-1 concentrations showed an upward trend at 1 and 24 hours of treatment and a subsequent decline at recovery in both subgroups of patients, with the most pronounced decrease in the NO group. cGMP concentrations increased significantly only in the NO group, with a peak at 1 hour of treatment (median, 61 pmol/ml). As the dose of NO decreased, cGMP concentrations declined. In contrast, conventionally treated infants manifested no change in cGMP concentrations from baseline until recovery, when a significant decrease was noted (median decrease of 13 pmol/ml; p = 0.002). We did not find a significant difference between ET-1 and cGMP concentrations in infants who required extracorporeal membrane oxygenation compared with those who did not.


CONCLUSIONS
PPHN is associated with increased ET-1 and decreased cGMP plasma concentrations, which may contribute to the pathogenesis of the disease. Inhaled NO appears to modulate these mediators during the disease process, suggesting an interaction between ET-1 and NO in vivo.
Christou
H
H
Joint Program in Neonatology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Adatia
I
I
Van Marter
L J
LJ
Kane
J W
JW
Thompson
J E
JE
Stark
A R
AR
Wessel
D L
DL
Kourembanas
S
S
D000280:Administration, Inhalation; D006152:Cyclic GMP / Q000097:blood*; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000502:physiology; D010547:Persistent Fetal Circulation Syndrome / Q000097:blood / Q000188:drug therapy*
D019332:Endothelin-1; D009569:Nitric Oxide; D006152:Cyclic GMP