Developmental Absence of the O 2 Sensitivity of L-Type Calcium Channels in Preterm Ductus Arteriosus Smooth Muscle Cells Impairs O 2 Constriction Contributing to Patent Ductus Arteriosus

Patent ductus arteriosus (PDA) complicates the hospital course of premature infants. Impaired oxygen (O 2 )-induced vasoconstriction in preterm ductus arteriosus (DA) contributes to PDA and results, in part, from decreased function/expression of O 2 -sensitive, voltage-gated potassium channels (Kv) in DA smooth muscle cells (DASMCs). This paradigm suggests that activation of the voltage-sensitive L-type calcium channels (Ca L ), which increases cytosolic calcium ([Ca 2+ ] i ), is a passive consequence of membrane depolarization. However, effective Kv gene transfer only partially matures O 2 responsiveness in preterm DA. Thus, we hypothesized that Ca L are directly O 2 sensitive and that immaturity of Ca L function in preterm DA contributes to impaired O 2 constriction. We show that preterm rabbit DA rings have reduced O 2 - and 4-aminopyridine (Kv blocker)–induced constriction. Preterm rabbit DASMCs have reduced O 2 -induced whole-cell calcium current (I Ca ) and [Ca 2+ ] i . BAY K8644, a Ca L activator, increased O 2 constriction, I Ca , and [Ca 2+ ] i in preterm DASMCs to levels seen at term but had no effect on human and rabbit term DA. Preterm rabbit DAs have decreased γ and increased α subunit protein expression. We conclude that the Ca L in term rabbit and human DASMCs is directly O 2 sensitive. Functional immaturity of Ca L O 2 sensitivity contributes to impaired O 2 constriction in premature DA and can be reversed by BAY K8644.