Abstract
Normal pregnancy is associated with enhanced uterine vasodilation secondary to up-regulation of endothelial NO signaling. Continuous exposure of uteroplacental vessels to high levels of NO might result in induction of nitrate tolerance. The objectives of this study were to: (1) characterize vasodilator effects of sodium nitroprusside, (SNP) in uterine arteries of non-pregnant (NP) and late pregnant (LP) rats; (2) define the role of smooth muscle cell (SMC) Ca2+ signaling in mediating the effects of SNP; (3) explore the role of SMC calcium-activated potassium (BK) channels in development of nitrate tolerance. Uterine radial arteries were pressurized to 50 mmHg and pre-constricted with phenylephrine. Changes in arterial diameter and SMC [Ca2+]i in response to SNP (0.001–10 μM) were studied using arteries loaded with fura 2. BK currents and single channel activity were characterized in myocytes using the whole-cell patch clamp technique. Maximal vasodilation and sensitivity to SNP were both significantly decreased in LP vs. NP arteries. SNP-induced vasodilation was associated with a reduction in SMC [Ca2+]i that was significantly attenuated during gestation. BK currents and single channel activity were both significantly reduced in late pregnancy. In summary: (1) Late pregnancy is associated with a marked reduction in uterine vasodilation to SNP linked to SMC Ca2+ signaling, (2) Inhibition of BK channel function and/or expression in part contributes to the development of nitrate tolerance in the maternal uteroplacental circulation. Supported by NIH HL067250 and HL073895
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