Inhaled nitric oxide increases endothelin-1 levels: a potential cause of rebound pulmonary hypertension.
OBJECTIVE
Inhaled nitric oxide (iNO) is front-line therapy for pulmonary hypertension after repair of congenital heart disease. However, little clinical data exists regarding the effects of iNO on regulators of pulmonary vascular resistance. An imbalance between primary vasodilators, such as NO, and vasoconstrictors, such as endothelin-1 (ET-1), has been implicated in rebound pulmonary hypertension upon iNO withdrawal. The objective of this study was to determine whether iNO therapy alters plasma ET-1 levels.


METHODS
This is a prospective study involving pediatric and adult patients at risk for pulmonary hypertension.


METHODS
Pediatric patients were in the cardiac intensive care unit and adult patients were in a tertiary-care hospital.


METHODS
Group 1 included children with congenital heart disease requiring iNO for treatment of pulmonary hypertension after cardiopulmonary bypass (n = 15), group 2 was adults receiving iNO (n = 10), and group 3 included children at risk for pulmonary hypertension after bypass that did not require iNO (n = 8).


METHODS
Dosages of iNO were 2-60 ppm. The duration of therapy ranged from 23 to 188 hrs in group 1 and 29 to 108 hrs in group 2.


RESULTS
Arterial blood was obtained for the measurement of ET-1 levels before and during iNO therapy and 24 hrs after iNO withdrawal. Group 1 mean ET-1 levels increased to 127% of baseline by 12 hrs of iNO, remained elevated at 48 hrs (p < .05), then decreased to 71% of iNO levels 24 hrs after withdrawal (p < .01). Group 2 ET-1 levels increased to 147%, and 137% of baseline at 12 and 24 hrs of iNO therapy, then fell to 68% of baseline within 24 hrs of discontinuing iNO. ET-1 levels in group 3 decreased after surgery (p < .05).


CONCLUSIONS
These data suggest that iNO increased plasma ET-1 levels, which subsequently decreased when iNO was discontinued. Increased circulating ET-1 levels might contribute to rebound pulmonary hypertension upon iNO withdrawal.
Pearl
Jeffrey M
JM
Division of Cardiothoracic Surgery, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. pearj0@chmcc.org
Nelson
David P
DP
Raake
Jenni L
JL
Manning
Peter B
PB
Schwartz
Steven M
SM
Koons
Lisa
L
Shanley
Thomas P
TP
Wong
Hector R
HR
Duffy
Jodie Y
JY
D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D019332:Endothelin-1 / Q000097:blood*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology*; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology
D019332:Endothelin-1; D014665:Vasodilator Agents; D009569:Nitric Oxide