Diabetic pregnancy impairs EDHF‐dependent uteroplacental vasodilation mediated by intermediate‐conductance Ca2+‐activated K+ channels

Abstract

Diabetes in pregnancy is associated with such adverse outcomes as hypertension, preeclampsia and stillbirth. Increased uteroplacental vascular resistance due to endothelial dysfunction may be an underlying mechanism. This study aimed to (1) Characterize the effect of diabetes on EDHF‐mediated uteroplacental vasodilation; (2) Explore the role of endothelial intermediate‐conductance (IKCa) K+ channels in impaired of EDHF responses. Diabetes was induced by injection of streptozotocin (STZ) on day 2 pregnant rats. Uteroplacental arteries from day 20 of pregnancy were cannulated, pressurized and loaded with fura 2. The vasodilator and smooth muscle cell (SMC) [Ca2+]i responses to ACh, EBIO or NS309 were studied in pre‐constricted arteries in the presence of L‐NNA and indomethacin. STZ injection produced sustained hyperglycemia in treated rats. ACh‐induced vasodilation and reduction in SMC [Ca2+]i were attenuated by diabetes. EDHF responses were not affected by iberiotoxin or apamin but abolished by charybdotoxin or TRAM‐34. EBIO‐ or NS309‐induced vasodilation was abolished by TRAM‐34 and was significantly impaired in hyperglycemic rats. Diabetes in pregnancy results in a marked impairment of EDHF‐mediated vasodilation most likely due to dysfunction of endothelial IKCa channels, which may serve as a target of future pharmacotherapy to improve uteroplacental blood flow.Supported by NIH HL088245