This study was performed to determine the action mode of oxytocin antagonist. In Study 1, the duration of in vivo action of oxytocin antagonist I (AI) was examined. After infusing AI, oxytocin was given and repeated every hour for 5 hr. Uterine activities were monitored with a polygraph. Study 2 determined the effect of AI on uterine oxytocin receptor number (Rn) and binding affinity (Kd). AI treated rats were sacrificed at 0.5 and 4 hr later for receptor assay. In Study 1, the uterine contractile response to oxytocin was significantly inhibited (p>0.05) compared to controls at five min, 1 and 2 hr after injection of AI. No differences in response were detected compared to controls (p>0.05) at later hours. In Study 2, no differences (p>0.05) between the AI and control animals in either oxytocin receptor number or binding affinity was found. These data suggest that the major mode of AI action is via competitive inhibition at the uterine oxytocin receptor and not by altering receptor number or binding affinity. AI is suggested to have the potential of being a potent and specific tocolytic agent for prevention of preterm labor in human.
Animal ; Female ; Oxytocin/pharmacology ; Oxytocin/metabolism ; Oxytocin/antagonists & inhibitors* ; Rats ; Receptors, Oxytocin/metabolism ; Uterus/physiology ; Uterus/drug effects*

This study was performed to determine the action mode of oxytocin antagonist. In Study 1, the duration of in vivo action of oxytocin antagonist I (AI) was examined. After infusing AI, oxytocin was given and repeated every hour for 5 hr. Uterine activities were monitored with a polygraph. Study 2 determined the effect of AI on uterine oxytocin receptor number (Rn) and binding affinity (Kd). AI treated rats were sacrificed at 0.5 and 4 hr later for receptor assay. In Study 1, the uterine contractile response to oxytocin was significantly inhibited (p>0.05) compared to controls at five min, 1 and 2 hr after injection of AI. No differences in response were detected compared to controls (p>0.05) at later hours. In Study 2, no differences (p>0.05) between the AI and control animals in either oxytocin receptor number or binding affinity was found. These data suggest that the major mode of AI action is via competitive inhibition at the uterine oxytocin receptor and not by altering receptor number or binding affinity. AI is suggested to have the potential of being a potent and specific tocolytic agent for prevention of preterm labor in human.
Animal ; Female ; Oxytocin/pharmacology ; Oxytocin/metabolism ; Oxytocin/antagonists & inhibitors* ; Rats ; Receptors, Oxytocin/metabolism ; Uterus/physiology ; Uterus/drug effects*

BACKGROUND: The extrauterine fetal incubation system must meet stable blood gas exchange and sufficient oxygen supply to provide the physiologic oxygen consumption of the fetus. In the fetus, blood gas exchange is totally sustained by the placental circulation. The placenta can be regarded as an extracorporeal organ, and the basic structure of placental circulation comprises arteriovenous (AV) bypass. To mimic this mode of circulation, we used AV ECMO (extracorporeal membrane oxygenation) in the goat fetus, and attempted to achieve stable blood gas exchange and oxygen supply to the fetus. METHODS: Pregnant goats, weighting 30 - 35 kg, were anesthetized with N2O-O2-enflurane. We performed a cesarean section with a midline incision, and cannulated via the umbilical vessels after a hysterotomy, and connected the fetuses to an ECMO circuit. The fetus was transferred to an incubator containing normal saline mixed with antibiotics. Blood samples were obtained every 4 to 6 hours from the circuit for electrolytes, hemoglobin and blood gas analysis and arterial blood pressure and heart rate were monitored through the umbilical artery. Oxygen delivery and consumption were calculated from the measured parameters. Microscopic examinations of the liver, kidney and lung were performed 24 hours after ECMO to know the effect of AV ECMO on the circulation of the organ. RESULTS: AV ECMO was done for 24 hours in the six goat fetuses and the main cause of death was circulatory failure. Heart rates and blood pressure were stable during ECMO. Sodium bicarbonate was injected when mild acidosis occurred and blood gas exchange was maintained stable. Mean pump flow rate was 156 +/- 62 ml/min/kg and oxygen extraction ratio was 30.4%. The liver function tests were sustained within normal limits both before and 24 hours after ECMO, but BUN and creatininincreased beyond upper normal limits 24 hours after ECMO. Microscopic features of the liver and kidney showed congestion 24 hours after ECMO. The fetal lung after 24 hours of ECMO especially showed an increase of mature capillaries in the septum and wall of alveoli compared with the twin fetal lung. CONCLUSIONS: These results indicate that the extrauterine fetal incubation model used for this study was suitable to blood gas exchange and utility of oxygen for goat fetuses.
Acidosis ; Anti-Bacterial Agents ; Arterial Pressure ; Blood Gas Analysis ; Blood Pressure ; Capillaries ; Cause of Death ; Cesarean Section ; Electrolytes ; Estrogens, Conjugated (USP) ; Extracorporeal Membrane Oxygenation ; Female ; Fetus* ; Goats* ; Heart Rate ; Hemodynamics ; Humans ; Hysterotomy ; Incubators ; Kidney ; Liver ; Liver Function Tests ; Lung ; Membranes ; Oxygen ; Oxygen Consumption ; Placenta ; Placental Circulation ; Pregnancy ; Shock ; Sodium Bicarbonate ; Twins ; Umbilical Arteries

Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the α-synuclein (α-syn) gene. Mutant α-syn expression increases the vulnerability of neurons to exogenous insults. In this study, we developed a new PD model in the transgenic mice expressing mutant hemizygous (hemi) or homozygous (homo) A53T α-synuclein (α-syn Tg) and their wildtype (WT) littermates by treatment with sub-toxic (10 mg/kg, i.p., daily for 5 days) or toxic (30 mg/kg, i.p., daily for 5 days) dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase and Bcl-2 levels were reduced in the α-syn Tg but not WT mice by sub-toxic MPTP injection. In the adhesive removal test, time to remove paper was significantly increased only in the homo α-syn Tg mice. In the challenging beam test, the hemi and homo α-syn Tg mice spent significantly longer time to traverse as compared to that of WT group. In order to find out responsible proteins related with vulnerability of mutant α-syn expressed neurons, DJ-1 and ubiquitin enzyme expressions were examined. In the SN, DJ-1 and ubiquitin conjugating enzyme, UBE2N, levels were significantly decreased in the α-syn Tg mice. Moreover, A53T α-syn overexpression decreased DJ-1 expression in SH-SY5Y cells. These findings suggest that the vulnerability to oxidative injury such as MPTP of A53T α-syn mice can be explained by downregulation of DJ-1.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Adhesives ; Animals ; Apoptosis ; Dopamine* ; Dopaminergic Neurons* ; Down-Regulation* ; Hominidae ; Humans ; Mice* ; Mice, Transgenic ; Neurons ; Parkinson Disease ; Point Mutation ; Synucleins ; Tyrosine 3-Monooxygenase ; Ubiquitin