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(Circulation Research. 2002;91:478.)
© 2002 American Heart Association, Inc.

Integrative Physiology

O₂ Sensing in the Human Ductus Arteriosus

Regulation of Voltage-Gated K⁺ Channels in Smooth Muscle Cells by a Mitochondrial Redox Sensor

Evangelos D. Michelakis, Ivan Rebeyka, XiChen Wu, Ali Nsair, Bernard Thébaud, Kyoko Hashimoto, Jason R.B. Dyck, Al Haromy, Gwyneth Harry, Amy Barr, Stephen L. Archer

From the Cardiology Division and the Vascular Biology Group, Department of Medicine (E.D.M., X.W., A.N., B.T., K.H., J.R.B.D., A.H., G.H., S.L.A.), the Division of Cardiac Surgery (I.R.), the Cardiovascular Research Group (A.B.), and the Department of Physiology (S.L.A.), University of Alberta, Alberta, Canada.

Correspondence to Stephen L. Archer, MD, Heart and Stroke Chair in Cardiovascular Research, Chair, Cardiology Division, Dept of Medicine, University of Alberta, WMC 2C2.36, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. E-mail sarcher{at}cha.ab.ca

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O₂ constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O₂ alters the function of an O₂ sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H₂O₂), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K⁺ channels, Kv). O₂ constriction was evaluated in 26 human DAs (12 female, aged 9±2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O₂ cause similar constriction and K⁺ current inhibition (I_K). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O₂ and 4-AP constriction in DA rings and reduced O₂- and 4-AP–sensitive I_K in DASMCs. Remodeled DAMSCs are depolarized and express less O₂-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK_Ca). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O₂. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I_K and reversing constriction to O₂, but not phenylephrine. O₂ increases, whereas hypoxia and ETC inhibitors decrease H₂O₂ production by altering mitochondrial membrane potential (m). H₂O₂, like O₂, inhibits I_K and depolarizes DASMCs. We conclude that O₂ controls human DA tone by modulating the function of the mitochondrial ETC thereby varying m and the production of H₂O₂, which regulates DASMC Kv channel activity and DA tone.

Key Words: Kv2.1 • Kv1.5 • mitochondrial membrane potential • redox • hydrogen peroxide

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