Endogenous carbon monoxide production by menadione

Introduction: Smokers have a significantly decreased risk of pre-eclampsia (PE), possibly attributed to an increase in blood carbon monoxide (CO) concentrations. At physiological concentrations, CO has been demonstrated to have placental vasodilatory and anti-inflammatory properties. Increasing endogenous CO production may have therapeutic potential to either prevent or treat PE. Menadione (MD), synthetic vitamin K3, increases CO in rat microsomes. Our objective was to investigate MD's ability to increase endogenous CO concentrations in pregnancy.

Methods: Three experiments were completed. First, in vitro CO production was measured using isolated GD15 placentas. Second, non-pregnant normotensive mice received no, 1.5, 4.0 or 6.5 g/L MD for 7 days. Lastly, pregnant normotensive mice received either no or 6.5 g/L MD in water from GD10.5 to GD17.5. Consumption was measured as average daily water intake per gram of body weight. Maternal and fetal CO levels in the blood and tissue were quantified using headspace gas chromatography.

Results: MD significantly increased CO production in isolated GD15 placentas. In both pregnant and non-pregnant experiments, splenic CO, hepatic CO, and splenic mass were higher in treated mice compared to controls (all p < 0.05). Maternal %COHb and Hb in treated dams were not significantly different compared to controls. The fetal:placental mass ratio was significantly lower in the treatment group (p = 0.002).

Discussion: Placental CO production was observed in GD15 placentas after co-incubation with MD. MD administration increased CO in the liver and spleens of pregnant mice. Further investigation into different doses of MD is required to identify one without demonstrable fetal/placental effects.