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

Bernard Thebaud; Xi-Chen Wu; Hidemi Kajimoto; Sandra Bonnet; Kyoko Hashimoto; Evangelos D. Michelakis; Stephen L. Archer

doi:10.1203/PDR.0b013e31815ed059

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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

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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

Bernard Thebaud, Xi-Chen Wu, Hidemi Kajimoto, Sandra Bonnet, Kyoko Hashimoto, Evangelos D. Michelakis and Stephen L. Archer

Pediatric research, Vol.63(2), pp.176-181

02/01/2008

DOI: 10.1203/PDR.0b013e31815ed059

PMID: 18091358

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Abstract

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 ([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 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 [Ca2+](i). BAY K8644, a Ca-L activator, increased O-2 constriction, I-Ca, and [Ca2+](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 a 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.

Life Sciences & Biomedicine

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Title: Subtitle: 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
Creators: Bernard Thebaud - University of Alberta
Xi-Chen Wu - University of Alberta
Hidemi Kajimoto - University of Alberta
Sandra Bonnet - University of Alberta
Kyoko Hashimoto - University of Alberta
Evangelos D. Michelakis - University of Alberta
Stephen L. Archer - University of Chicago
Resource Type: Journal article
Publication Details: Pediatric research, Vol.63(2), pp.176-181
DOI: 10.1203/PDR.0b013e31815ed059
PMID: 18091358
NLM abbreviation: Pediatr Res
ISSN: 0031-3998
Publisher: INT PEDIATRIC RESEARCH FOUNDATION, INC
Number of pages: 6
Grant note: R01HL071115 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) NIH-R01-HL071115 / NHLBI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Language: English
Date published: 02/01/2008
Academic Unit: Cardiology; Stead Family Department of Pediatrics
Record Identifier: 9984961114402771

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