title: Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition.
abstract: Fetal to maternal blood flow matching in the placenta, necessary for optimal fetal blood oxygenation, may occur via hypoxic fetoplacental vasoconstriction (HFPV). We hypothesized that HFPV is mediated by K(+) channel inhibition in fetoplacental vascular smooth muscle, as occurs in several other O(2)-sensitive tissues. With the use of an isolated human placental cotyledon perfused at a constant flow rate, we found that hypoxia reversibly increased perfusion pressure by >20%. HFPV was unaffected by cyclooxygenase or nitric oxide synthase inhibition. HFPV and 4-aminopyridine, an inhibitor of voltage-dependent K(+) (K(v)) channels, increased pressure in a nonadditive manner, suggesting they act via a common mechanism. Iberiotoxin, a large conductance Ca(2+)-sensitive K(+) (BK(Ca)) channel inhibitor, had little effect on normoxic pressure. Immunoblotting and RT-PCR showed expression of several putative O(2)-sensitive K(+) channels in peripheral fetoplacental vessels. In patch-clamp experiments with smooth muscle cells isolated from peripheral fetoplacental arteries, hypoxia reversibly inhibited K(v) but not BK(Ca) or ATP-dependent currents. We conclude that human fetoplacental vessels constrict in response to hypoxia. This response is largely mediated by hypoxic inhibition of K(v) channels in the smooth muscle of small fetoplacental arteries.
authors.affiliation: Department of Physiology, Charles University Second Medical School, 15000 Prague 5, Czech Republic. vaclav.hampl@lfmotol.cuni.cz
authors.forename: Václav
authors.initials: V
authors.lastname: Hampl
authors.forename: Jana
authors.initials: J
authors.lastname: Bíbová
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Stranák
authors.forename: Xichen
authors.initials: X
authors.lastname: Wu
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006935:Hypercapnia / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010920:Placenta / Q000098:blood supply* / Q000502:physiology*; D021041:Placental Circulation / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012016:Reference Values; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine; D019001:Nitric Oxide Synthase