title: Impairment of IKCa channels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy.
abstract: Diabetes in rat pregnancy is associated with impaired vasodilation of the maternal uteroplacental vasculature. In the present study, we explored the role of endothelial cell (EC) Ca(2+)-activated K(+) channels of small conductance (SKCa channels) and intermediate conductance (IKCa channels) in diabetes-induced uterine vascular dysfunction. Diabetes was induced by injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with citrate buffer. Changes in smooth muscle cell intracellular Ca(2+) concentration, membrane potential, and vasodilation induced by SKCa/IKCa channel activators were studied in uteroplacental arteries of control and diabetic rats. The impact of diabetes on SKCa- and IKCa-mediated currents was explored in freshly dissociated ECs. NS309 evoked a potent vasodilation that was effectively inhibited by TRAM-34 but not by apamin. NS309-induced smooth muscle cell intracellular Ca(2+) concentration, membrane potential, and dilator responses were significantly diminished by diabetes; N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA)-evoked responses were not affected. Ca(2+)-activated ion currents in ECs were insensitive to paxilline, markedly inhibited by charybdotoxin (ChTX), and diminished by apamin. NS309-induced EC currents were generated mostly due to activation of ChTX-sensitive channels. Maternal diabetes resulted in a significant reduction in ChTX-sensitive currents with no effect on apamin-sensitive or CyPPA-induced currents. We concluded that IKCa channels play a prevalent role over SKCa channels in the generation of endothelial K(+) currents and vasodilation of uteroplacental arteries. Impaired function of IKCa channels importantly contributes to diabetes-induced uterine endothelial dysfunction. Therapeutic restoration of IKCa channel function may be a novel strategy for improvement of maternal uteroplacental blood flow in pregnancies complicated by diabetes.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and Natalia.Gokina@uvm.edu.
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Gokina
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Bonev
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Julie
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Gokin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Veilleux
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Karen
authors.initials: K
authors.lastname: Oppenheimer
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Vermont, Burlington, Vermont; and.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Goloman
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D021041:Placental Circulation; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D002118:Calcium
keywords: Ca2+-activated K+ channels; fura-2; membrane potential; patch clamp; pressurized arteries