Impairment of IKCa channels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy

Am J Physiol Heart Circ Physiol. 2015 Aug 15;309(4):H592-604. doi: 10.1152/ajpheart.00901.2014. Epub 2015 Jun 19.

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.

Keywords: Ca2+-activated K+ channels; fura-2; membrane potential; patch clamp; pressurized arteries.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Animals
  • Calcium / pharmacology
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / physiopathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelial Cells / physiology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Female
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / physiology
  • Placental Circulation*
  • Potassium Channel Blockers / pharmacology
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Vasodilation

Substances

  • Potassium Channel Blockers
  • Small-Conductance Calcium-Activated Potassium Channels
  • Calcium