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Baseline function of placental vascular KATP‐channels in healthy and in diabetic women

During pregnancy an optimal vascular function in the placenta is essential for normal fetal development and growth. Endothelial dysfunction in the fetal placental vascular bed in diabetes type 1 (DM) may contribute to the elevated perinatal morbidity and mortality in DM. The placental vascular bed is unique because it lacks autonomic innervation. Regulation of the placental circulation depends completely on locally produced vasoactive mediators. 
 
DM has been associated with endothelial dysfunction, in particular concerning the release of endothelium derived relaxing factors. One such factor is endothelium-derived hyperpolarising factor (EDHF) of which the identity remains unknown. EDHF relaxes smooth muscle cells at least partly by opening of ATP-dependent K+-channels (KATP-channels). We investigated whether the potassium efflux through KATP-channels contributes to the baseline vascular tone in the fetal placental vascular bed in diabetic patients as compared with healthy controls. 
 
We collected 11 placentas: four from diabetic patients and seven from healthy controls. Within 20 min of delivery a suitable cotyledon was selected for ex vivo dual perfusion. Fetal and maternal inflow were kept constant, perfusion fluid was oxygenated with 95% O2/5% CO2, temperature was 37° C and pH 7.4. A continuous measurement of fetal arterial blood pressure was performed. Because the perfusion flow was set at a constant level, the pressure in the circulation was considered to be a measure of the vascular resistance. By adding increasing concentrations of the KATP-channel blocker glibenclamide the KATP-channel dependent component of the baseline vascular tone in the fetal placental circulation was quantified. Concentration-response curves to glibenclamide were fitted by the sigmoid Emax model (GraphPad Prism), and the calculated Emax and EC50 were compared by two-tailed unpaired Student's t-tests (SPSS). 
 
The results as mean±s.e. mean. Baseline fetal arterial pressure was comparable in DM and controls (22.8 ± 2.8 vs 19.8 ± 0.4 mmHg). In controls, glibenclamide increased fetal arterial pressure concentration-dependently up to 56.3 ± 5.7 mmHg. In diabetes, a maximum pressure of 37.6 ± 4.2 mmHg was reached. The net glibenclamide-induced increase in pressure was attenuated in diabetes as compared with controls (14.7 ± 5.6 vs 36.5 ± 5.8 mmHg, P = 0.03) (Figure 1). The log EC50 did not differ between groups. 
 
 
 
Figure 1 
 
The net glibenclamide-induced fetal arterial pressure in DM (n = 4, □) vs controls (n = 7, ▪). 
 
 
 
Glibenclamide induces vasoconstriction, pointing towards a functional role of KATP-channels in the regulation of baseline vascular tone in the placenta. In diabetes, this vasodilator mechanism appears to be impaired.