title: Sildenafil reverses O2 constriction of the rabbit ductus arteriosus by inhibiting type 5 phosphodiesterase and activating BK(Ca) channels.
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 x 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.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Evangelos
authors.initials: E
authors.lastname: Michelakis
authors.forename: Xi-chen
authors.initials: XC
authors.lastname: Wu
authors.forename: Gwenyth
authors.initials: G
authors.lastname: Harry
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004373:Ductus Arteriosus / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010100:Oxygen / Q000097:blood; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013450:Sulfones; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D024681:Potassium Channels, Calcium-Activated; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP; D010100:Oxygen