tacrolimus and Fetal-Hypoxia

To assess the windows of therapeutic opportunity for drugs with various chemical actions on fetal growth retardation induced by transient intrauterine ischemia in rats.. At 17 days of gestation, ischemia was induced by 30 min of right uterine artery occlusion. The administration of either alpha-phenyl-N-tert-butyl-nitrone (PBN), FK 506, nifedipine, or MK-801 to pregnant rats was randomly started before occlusion, 1 hour, 3 hours, or 24 hours after recirculation. All of the pups were delivered by cesarean section at 21 days of gestation and were weighed to determine the degree of fetal growth retardation.. The vehicle-treated animals exposed to ischemia showed a significant decrease in fetal body weight compared with the normoxic control animals. The growth disturbances were prevented by nifedipine and MK-801 only when given just prior to ischemia. In contrast, PBN and FK 506 had a protective effect even when given 1 hour and 3 hours after the start of recirculation, respectively.. The present results indicate that treatment with PBN and FK 506 gives relatively wide windows of therapeutic opportunity in fetal growth retardation induced by transient intrauterine ischemia in rats and suggest the possibility of therapeutic intervention after the start of recirculation.

Topics: Animals; Cyclic N-Oxides; Dizocilpine Maleate; Female; Fetal Growth Retardation; Fetal Hypoxia; Ischemia; Neuroprotective Agents; Nifedipine; Nitrogen Oxides; Pregnancy; Random Allocation; Rats; Rats, Wistar; Tacrolimus

Mitochondrial respiratory activities and energy metabolism were measured in neonatal rat brains to evaluate the influence of transient intrauterine ischemia on the near-term fetus and to assess the effect of the immunosuppressant drug FK506 treatment. Transient intrauterine ischemia was induced by 30 min of right uterine artery occlusion at 17 days of gestation in Wistar rats. The vehicle or 1.0 mg/kg of FK506 was administered after 1 h of recirculation. All of the pups were delivered by cesarean section at 21 days of gestation and samples of cerebral cortical tissue were obtained from pups at 1 h after birth. The mitochondrial respiration was measured polarographically in homogenates. For the analysis of ATP, ADP, and AMP, neonatal brains were frozen in situ and fluorometric enzymatic techniques were used. In the neonatal cortical tissue exposed to ischemia, mitochondrial respiratory activities and ATP concentrations decreased significantly to approximately 59 and 67% of those in normoxic controls, respectively. The deterioration of both mitochondrial respiratory activities and high-energy phosphates was prevented by FK506, given 1 h after the start of recirculation. The present results indicate that transient intrauterine ischemia is accompanied by mitochondrial dysfunction and cellular bioenergetic failure in the neonatal rat brain and suggest that treatment with FK506 prevents the deterioration, even when administered after the ischemic periods.

Topics: Animals; Animals, Newborn; Brain; Brain Chemistry; Brain Ischemia; Cell Respiration; Energy Metabolism; Female; Fetal Hypoxia; Immunosuppressive Agents; Mitochondria; Oxygen Consumption; Pregnancy; Rats; Rats, Wistar; Tacrolimus