Abstract
Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10−6–10−4 M) and diethylamine NONOate (10−7–10−5 M) induced dose-dependent relaxation of oxygen-constricted DA (−52 ± 4% and −51 ± 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 × 10−5 M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (−30 ± 2% and −27 ± 4%, respectively). Oxygen inhibition of whole-cell K+ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase–derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery.
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Abbreviations
- 4-AP:
-
4-aminopyridine
- BKCa:
-
large conductance calcium-sensitive potassium channels
- cGMP:
-
3′ 5′-cyclic GMP
- DA:
-
ductus arteriosus
- DASMC:
-
DA smooth muscle cells
- DEANO:
-
diethylamine NONOate
- Em:
-
membrane potential
- IBTX:
-
iberiotoxin
- IK:
-
whole-cell potassium current
- NO:
-
nitric oxide
- O2:
-
oxygen
- ODQ:
-
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- PDE-5:
-
type 5 phosphodiesterase
- PG:
-
prostaglandin
- sGC:
-
soluble guanylate cyclase
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Acknowledgements
The authors thank Alex Bolivar, Steve Joy, and Dr. Lakshmi Puttagunta for excellent technical assistance.
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B.T. is supported by the Canadian Institutes for Health Research, and by the Alberta Heritage Foundation for Medical Research, a grant from the French Ministry for Foreign Affairs, the Fondation pour la Recherche Médicale and the Société Française de Médecine Périnatale. E.M. and S.L.A. are both supported by the Alberta Heritage Foundation for Medical Research, the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Canada, and the Canadian Foundation for Innovation.
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Thébaud, B., Michelakis, E., Wu, XC. et al. Sildenafil Reverses O2 Constriction of the Rabbit Ductus Arteriosus by Inhibiting Type 5 Phosphodiesterase and Activating BKCa Channels. Pediatr Res 52, 19–24 (2002). https://doi.org/10.1203/00006450-200207000-00006
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DOI: https://doi.org/10.1203/00006450-200207000-00006
