Oxygen-Sensitive K(+) Channels Modulate Human Chorionic Gonadotropin Secretion from Human Placental Trophoblast

Human chorionic gonadotropin (hCG) is a key autocrine/paracrine regulator of placental syncytiotrophoblast, the transport epithelium of the human placenta. Syncytiotrophoblast hCG secretion is modulated by the partial pressure of oxygen (pO(2)), reactive oxygen species (ROS) and potassium (K(+)) channels. Here we test the hypothesis that K(+) channels mediate the effects of pO(2) and ROS on hCG secretion. Placental villous explants from normal term pregnancies were cultured for 6 days at 6% (normoxia), 21% (hyperoxia) or 1% (hypoxia) pO(2). On days 3–5, explants were treated with 5mM 4-aminopyridine (4-AP) or tetraethylammonium (TEA), blockers of pO(2)-sensitive voltage-gated K(+) (K(V)) channels, or ROS (10–1000μM H(2)O(2)). hCG secretion and lactate dehydrogenase (LDH) release, a marker of necrosis, were determined daily. At day 6, hCG and LDH were measured in tissue lysate and (86)Rb (K(+)) efflux assessed to estimate syncytiotrophoblast K(+) permeability. hCG secretion and (86)Rb efflux were significantly greater in explants maintained in 21% pO(2) than normoxia. 4-AP/TEA inhibited hCG secretion to a greater extent at 21% than 6% and 1% pO(2), and reduced (86)Rb efflux at 21% but not 6% pO(2). LDH release and tissue LDH/hCG were similar in 6%, 21% and 1% pO(2) and unaffected by 4-AP/TEA. H(2)O(2) stimulated (86)Rb efflux and hCG secretion at normoxia but decreased (86)Rb efflux, without affecting hCG secretion, at 21% pO(2). 4-AP/TEA-sensitive K(+) channels participate in pO(2)-sensitive hCG secretion from syncytiotrophoblast. ROS effects on both hCG secretion and (86)Rb efflux are pO(2)-dependent but causal links between the two remain to be established.