>Background: We have recently described a dose-dependent, endothelium-independent relaxation to progesterone in human placental arteries and veins. This receptor-operated, cAMP-mediated relaxation may be of value in maintaining adequate blood flow in the placental circulation.Objective: To investigate if gestational diabetes alters this relaxation to progesterone.Study design: Isolated human placental vessels from pregnancies complicated by gestational diabetes and well matched controls (uncomplicated term pregnancies), incubated in Krebs-bicarbonate buffer and submaximally precontracted with KCl, were exposed to cumulative doses of progesterone (0.01-30 µmol/liter), nitroglycerin (0.001-1 µmol/liter), arachidonic acid (0.01-10 µmol/liter), forskolin (0.01-10 µmol/liter) and 5-hydroxytryptamine (serotonin, 0.01-10 µmol/liter).Results: The relaxation to progesterone in vessels from patients with gestational diabetes was reduced by 50-100% in both arteries and veins compared with control (for example, relaxation to 10 µmol/liter progesterone was reduced from 52 +/- 7 to 18.8 +/- 5.4% in arteries and from 58 +/- 8 to 19 +/- 5.2% in veins, n = 7-13, P < 0.05), whereas responses to the other vasoactive agents were unchanged.Conclusion: Based on these results, gestational diabetes significantly reduces the relaxation to progesterone in human placental vessels. This alteration of the relaxation to progesterone may lead to an increase in placental vascular resistance and possibly to a reduction of placental blood flow.