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 end othelin-1 (ET-1) in the pathogenesis of persistent pulmonary hypertens ion of the newborn (PPHN) and to determine whether inhaled NO, current ly under investigation as a new therapy for PPHN, affects plasma conce ntrations 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 in fants 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: Concentr ations of ET-1 were significantly higher and cGMP concentrations signi ficantly lower in infants with PPHN compared with healthy newborn infa nts (median ET-1, 28 vs 11 pmol/L; p = 0.0001; median cGMP, 35 vs 61 p mol/ml; p = 0.0001, respectively). ET-1 concentrations showed an upwar d trend at 1 and 24 hours of treatment and a subsequent decline at rec overy 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 contras t, conventionally treated infants manifested no change in cGMP concent rations from baseline until recovery, when a significant decrease was noted (median decrease of 13 pmol/ml; p = 0.002). We did not find a si gnificant difference between ET-1 and cGMP concentrations in infants w ho required extracorporeal membrane oxygenation compared with those wh o did not. Conclusions: PPHN is associated with increased ET-1 and dec reased cGMP plasma concentrations, which may contribute to the pathoge nesis of the disease. Inhaled NO appears to modulate these mediators d uring the disease process, suggesting an interaction between ET-1 and NO in vivo.