ABSTRACT. This study was carried out to determine the proliferation profile of the smooth muscle cells (SMC) in the media of the ductus arteriosus (DA) and the descending aorta (Ao), and to examine the effects of the angiotensin-converting enzyme inhibitor enalapril on the proliferation of these cells in perinatal rats. The proliferating cell nuclear antigen (PCNA) index of the DA peaked in 19-day-old fetuses at 75%, and the index significantly declined in 20-day-old fetuses. The PCNA index of the Ao showed a similar profile until pups reached 1 day of age; however, the index of the Ao then increased in 3-day-old pups. The PCNA indices of the DA and Ao decreased significantly after maternal oral treatment with enalapril (10 mg/kg for 7 days), with a more marked decline in the DA than in the Ao. The PCNA indices of these vessels in 20-day-old fetuses were not altered by maternal treatment with enalapril. These results indicate that the SMC proliferation rate in the DA was similar to that in the Ao until pups reached the age of 1 day, and that the inhibitory effect of enalapril on the SMC proliferation was age-dependent and more prominent in the DA than in the Ao.-KEY WORDS: ductus arteriosus, enalapril, PCNA, proliferation, SMC.J. Vet. Med. Sci. 61(11): 1215-1218, 1999 investigated the PCNA labeling index to monitor the proliferating activity of the SMC, and we compared the effects of enalapril on SMC proliferation in the DA and the descending aorta (Ao). MATERIALS AND METHODSFemale Crj: Wistar rats, 10-12 weeks old at the time of mating, were used. They were maintained with commercial rat chow (CE-2, Clea Japan, Tokyo) and tap water ad libitum, and kept in a room at a temperature of 22 ± 3°C with a relative humidity of 55 ± 10%. Three females were placed with a male overnight, and were examined the next morning for the presence of sperm in a vaginal smear. The day when sperm was found was designated as day 0 of gestation, and the females were caged individually thereafter.To examine the age-related changes of the PCNA labeling indices of the DA and the Ao, fetuses were quickly removed from the uteri of mother rats from day 18 to day 21 of gestation, and 1 or 3 day-old newborn pups were obtained from witnessed deliveries. To examine the effect of enalapril on the PCNA labeling indices of these vessels, fetuses were obtained on day 19 or 20 of gestation from pregnant rats and were transplacentally administered enalapril (10 mg/kg) from day 12 or 13 for 7 consecutive days.Fetuses and newborn pups were decapitated, and then the thoracic cavity was opened and immersed in fresh fixative fluid. Fixation was performed in 100% ethanol for 24 hr, and the fixed materials were then freed of alcohol by treatment with xylene, embedded in Paraplast (Sherwood Closure of the ductus arteriosus (DA) is one of the most critical events for adaptation of mammals to extrauterine life. The ductal closure after birth occurs in two stages, i.e., initial closure and anatomical closure. Initial closure is brought about by contraction of th...

ABSTRACT. This work was conducted to determine whether aspirin and ibuprofen, when administered prenatally may potentiate a reopening of the neonatal ductus arteriosus (DA) induced by PGE 2 after postnatal closure. In the first experiment, a subcutaneous injection of PGE 2 (4 µg) was administered to newborn rats 3 hr after a Cesarean delivery from pregnant females which had been orally given 100 or 300 mg/kg/day of aspirin and 10 or 30 mg/kg/day of ibuprofen on days 18, 19 and 20 of gestation. The ratio of the DA to the pulmonary artery (PA) was determined at intervals after the injection. The DA/PA ratio was significantly higher in newborn rats from mothers who were transplacentally administered these agents than the control. We also examined the hypothesis that maternal treatment with nonsteroidal anti-inflammatory drugs (NSAID), such as aspirin and ibuprofen, inhibits the catabolism of PGE 2 and that the increased reopening of the DA was partly due to this inhibition. 15-hydroxy prostaglandin dehydrogenase (15-PGDH) in neonatal lungs, the key enzyme involved in catalyzing PGE 2 to convert it to its inactive metabolite 15-keto-PGE 2 , was not affected by maternal treatment with aspirin and ibuprofen. These results suggest that the increased ductal responsiveness to PGE 2 in newborn rats was a common response after maternal NSAID treatment, but the catabolism of PGE 2 in the lungs did not always contribute to this response. -KEY WORDS: neonatal lung, PGE 2 catabolism, re-opening.J. Vet. Med. Sci. 60(3): 377-379, 1998 females were caged individually thereafter.In the first experiment, the effect of prenatal aspirin and ibuprofen treatment on the re-opening of the DA induced by PGE 2 was examined. Aspirin (100, 300 mg/kg/day) and ibuprofen (10, 30 mg/kg/day) administration was carried out on days 18, 19 and 20 of gestation. Pregnant females given only saline served as the controls. Females were killed by decapitation at 1 p.m. on day 21 of gestation at least 24 hr after the last drug administration, and the newborn pups were immediately obtained by Cesarean delivery. Only male pups were used in this study. The pups were placed in a humid chamber at 37°C and maintained for 3 hr after the Cesarean delivery, at which time the DA would have been completely closed under normal conditions [5]. Then, each pup was given a subcutaneous injection of 4 µg of PGE 2 (Sigma Chemical Co., St. Louis) dissolved in 50 µl of physiological saline. The pups were returned to the same chamber until their DAs and pulmonary arteries (PAs) were measured. The calibrations were made 0, 15, 30, 60, 90 and 180 min after the injection.Each pup was rapidly frozen in an acetone-dry ice mixture at the time of death. The frozen pups were weighed and then 4 or 5 pups of similar weight were selected from each litter and stored for a couple of days at 20°C until the DA and PA were measured. Measurements were obtained by the whole-body freezing and shaving method described elsewhere [2], and the DA/PA ratio was obtained by previously described meth...

ABSTRACT. This work was conducted to determine whether the angiotensin-converting enzyme inhibitors (ACEIs) (enalapril and captopril) administered to mother rats prenatally can potentiate a re-opening of the neonatal ductus arteriosus (DA) induced by prostaglandin E 2 (PGE 2 ) after postnatal closure. A subcutaneous injection of PGE 2 (4 µg) was administered to newborn rats 3 hr after a Cesarean delivery from females which had been orally given 0.1, 1 or 10 mg/kg/day of enalapril or 15 or 150 mg/kg/day of captopril from day 14 to day 20 of gestation. The ratio of the DA to the pulmonary artery (PA) was determined at intervals after the injection. The DA/PA ratio was significantly higher in the newborn rats of mothers who were transplacentally administered these agents compared to the controls, except at the low dose (0.1 mg/kg) group of enalapril. We found that the level in the neonatal lungs of 15-hydroxy prostaglandin dehydrogenase, a key enzyme that catalyzes PGE 2 to convert it to its inactive metabolite 15-keto-PGE 2 , was not affected after maternal treatment with enalapril or captopril. These results indicate that the increased ductal responsiveness to PGE 2 in newborn rats was a common response after maternal ACEI treatment, but the catabolism of PGE 2 in the lungs did not contribute to this response. -KEY WORDS: ductus arteriosus, PGE 2 catabolism, re-opening.J. Vet. Med. Sci. 60(8): 989-991, 1998 that the maternal administration of ACEIs such as enalapril and captopril can potentiate the neonatal ductal responsiveness to PGE 2 after the postnatal closure of the DA and can inhibit the catabolism of PGE 2 in the lungs. We investigated the effects of enalapril and captopril on the re-opening of the DA as well as the effect of these agents on the activity in the lungs of 15-hydroxy prostaglandin dehydrogenase (15-PGDH), a key enzyme which catalyzes the initial reactions converting the biologically active PGE 2 to its inactive metabolite, 15-keto-PGE 2 .Female Crj: Wistar rats, 10-12 weeks old at the time of mating, were used. They were maintained on a commercial diet (CE-2, Clea Japan, Tokyo) and tap water ad libitum, and kept in a room at a temperature of 22 ± 3°C with a relative humidity of 55 ± 10%. Three females were placed with a male overnight and examined the next morning for the presence of sperm in the vaginal smear. The day on which sperm was found was designated as day 0 of gestation, and the females were caged individually thereafter.In the first experiment, the effects of prenatal enalapril and captopril treatments on the re-opening of the DA induced by PGE 2 was examined. Enalapril (0.1, 1, 10 mg/ kg/day) or captopril (15, 150 mg/kg/day) administration was carried out from day 14 to day 20 of gestation. Pregnant females given only saline served as the controls. The rats were killed by decapitation at 1 p.m. on day 21 of gestation at least 24 hr after the last drug administration, and the newborn pups were immediately obtained by Cesarean delivery. Only male pups were used in this study. Th...