Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus -: Implications for infants with patent ductus arteriosus

Background-Oxygen (O-2)-sensitive K+ channels mediate acute O-2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O-2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O-2 constriction in preterm DA is reduced expression and function of O-2-sensitive, voltage-gated (Kv) channels. Methods and Results-Preterm rabbit DA rings have reduced O-2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O-2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O-2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O-2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O-2 constriction in human DAs. Conclusions-These data demonstrate a central role for developmentally regulated DASMC O-2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O-2 responsiveness, including persistent DA.