Developmental absence of the O2 sensitivity of L-type calcium channels in preterm ductus arteriosus smooth muscle cells impairs O2 constriction contributing to patent ductus arteriosus.
Patent ductus arteriosus (PDA) complicates the hospital course of premature infants. Impaired oxygen (O2)-induced vasoconstriction in preterm ductus arteriosus (DA) contributes to PDA and results, in part, from decreased function/expression of O2-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 (CaL), which increases cytosolic calcium ([Ca2+]i), is a passive consequence of membrane depolarization. However, effective Kv gene transfer only partially matures O2 responsiveness in preterm DA. Thus, we hypothesized that CaL are directly O2 sensitive and that immaturity of CaL function in preterm DA contributes to impaired O2 constriction. We show that preterm rabbit DA rings have reduced O2- and 4-aminopyridine (Kv blocker)-induced constriction. Preterm rabbit DASMCs have reduced O2-induced whole-cell calcium current (ICa) and [Ca2+]i. BAY K8644, a CaL activator, increased O2 constriction, ICa, and [Ca]i in preterm DASMCs to levels seen at term but had no effect on human and rabbit term DA. Preterm rabbit DAs have decreased gamma and increased alpha subunit protein expression. We conclude that the CaL in term rabbit and human DASMCs is directly O2 sensitive. Functional immaturity of CaL O2 sensitivity contributes to impaired O2 constriction in premature DA and can be reversed by BAY K8644.
Thébaud
Bernard
B
Department of Pediatrics, Division of Neonatology, University of Alberta, Edmonton, T6G 2J3, AB, Canada.
Wu
Xi-Chen
XC
Kajimoto
Hidemi
H
Bonnet
Sandra
S
Hashimoto
Kyoko
K
Michelakis
Evangelos D
ED
Archer
Stephen L
SL
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004373:Ductus Arteriosus / Q000378:metabolism*; D004374:Ductus Arteriosus, Patent / Q000209:etiology; D004594:Electrophysiology; D006801:Humans; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010100:Oxygen / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011817:Rabbits; D014661:Vasoconstriction
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D010100:Oxygen; D002118:Calcium