Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy

Gokina NI, Kuzina OY, Vance AM. Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy. Am J Physiol Heart Circ Physiol 299: H1642-H1652, 2010. First published September 3, 2010; doi:10.1152/ajpheart.00227.2010.-A successful pregnancy outcome relies on extensive maternal cardiovascular adaptation, including enhanced uteroplacental vasodilator mechanisms. The objective of the present study was to determine the contribution of the endothelium-derived hyperpolarizing factor (EDHF) signaling in pregnancy-enhanced uterine vasodilation, to define the role of Ca2+-activated K+ channels in mediating EDHF effects, and to explore the impact of endothelial Ca2+ signaling in pregnancy-specific upregulation of EDHF. Fura 2-based measurements of smooth muscle cell (SMC) and endothelial cell cytosolic Ca2+ concentration ([Ca2+]i) were performed simultaneously with measurements of the diameter of uterine radial arteries from nonpregnant (NP) and late pregnant (LP) rats. Changes in SMC membrane potential of pressurized arteries from LP rats were assessed using glass microelectrodes. After blockade of nitric oxide and prostacyclin production, a cumulative application of ACh induced rapid and effective dilatation of uterine vessels from both NP and LP rats. This vasodilation was associated with SMC hyperpolarization and SMC [Ca2+]i reduction and was abolished by a high-K+ solution, demonstrating that N-G-nitro-L-arginine (L-NNA)- and indomethacin-resistant responses are attributable to EDHF. Pregnancy significantly potentiates EDHF-mediated vasodilation in part due to enhanced endothelial Ca2+ signaling. L-NNA- and indomethacin-resistant responses were insensitive to iberiotoxin but abolished by a combined treatment with apamin and charybdotoxin, supporting the key role of small- andand intermediate-conductance K+ channels in mediating EDHF signaling in the maternal uterine resistance vasculature.