Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition.
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.
Hampl
Václav
V
Department of Physiology, Charles University Second Medical School, 15000 Prague 5, Czech Republic. vaclav.hampl@lfmotol.cuni.cz
Bíbová
Jana
J
Stranák
Zbynek
Z
Wu
Xichen
X
Michelakis
Evangelos D
ED
Hashimoto
Kyoko
K
Archer
Stephen L
SL
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
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine; D019001:Nitric Oxide Synthase