The endothelin antagonist BQ123 reduces pulmonary vascular resistance after surgical intervention for congenital heart disease.
OBJECTIVE
Postoperative pulmonary hypertension in children after surgical intervention for congenital heart disease has been attributed to failure of the pulmonary endothelium to provide adequate vasodilation. Although we have shown that the impaired vasodilatory component attributable to the l-arginine-nitric oxide pathway is almost completely reversible, a nonrestorable component persists, implying an additional vasoconstrictive mechanism in postoperative pulmonary endothelial dysfunction. In this study of children after surgical intervention for congenital heart disease, we measured endothelin-1 levels and used BQ123, a selective endothelin-A receptor antagonist, together with inhaled nitric oxide to discriminate dysfunctional pulmonary endothelial vasodilation from endothelin-mediated pulmonary vasoconstriction.


METHODS
All children were examined early after surgical intervention in the intensive care unit. Pulmonary vascular resistance (with respiratory mass spectrometry), as well as arterial and venous endothelin-1 levels (measured by means of a quantitative enzyme-linked immunosorbent assay), were determined in 7 children (age range, 3.3-13.7 months; median age, 6.3 months) with intracardiac shunting defects at baseline and during ventilation with a fraction of inspired oxygen of 0.65, with additional BQ123 (0.1 mg/kg infused over 20 minutes), and with inhaled nitric oxide (20 ppm).


RESULTS
Pulmonary vascular resistance decreased from 7.7 +/- 3.4 at baseline to 6.1 +/- 2.8 Woods units. m(-2) (P =.022) at a fraction of inspired oxygen of 0.65 and to 4.7 +/- 2.7 Woods units. m(-2) (P =.013) during BQ123 infusion. Inhaled nitric oxide had no further effect on pulmonary vascular resistance. Left atrial endothelin-1 levels (1.35-5.12 pg/mL; mean, 2.4 pg/mL) correlated significantly with the decrease in pulmonary vascular resistance in response to BQ123 infusion (r(2) = 0.89, P =.003).


CONCLUSIONS
Postoperative elevation of pulmonary vascular resistance in children after surgical intervention for congenital heart disease is responsive to endothelin-A blockade with BQ123. Increased levels of endothelin-1 predict the response to this therapy, which might become an important addition to the clinical armamentarium in postoperative pulmonary hypertensive disease.
Cardiac Intensive Care Unit, Department of Vascular Biology and Pharmacology, and Cardiothoracic Unit, Great Ormond Street Hospital, London, United Kingdom.
Ingram
I
Schulze-Neick
Jia
J
Li
Jayne A
JA
Reader
Lara
L
Shekerdemian
Andrew N
AN
Redington
Daniel J
DJ
Penny
D000293:Adolescent; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002315:Cardiopulmonary Bypass; D002648:Child; D002669:Child Welfare; D002675:Child, Preschool; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000601:surgery*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007223:Infant; D007229:Infant Welfare; D007262:Infusions, Intravenous; D008131:London; D008168:Lung / Q000098:blood supply*; D009569:Nitric Oxide / Q000008:administration & dosage; D010100:Oxygen / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011667:Pulmonary Veins / Q000187:drug effects / Q000502:physiology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects / Q000502:physiology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D009569:Nitric Oxide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D010100:Oxygen