THE EFFECTS OF COCAINE ON FETAL OXYGENATION

可卡因对胎儿氧合的影响

• 批准号: 3210020
• 负责人: JAMES R WOODS
• 金额: $ 17.53万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3210020
• 关键词: cardiotoxin; cardiovascular pharmacology; catecholamines; catheterization; cocaine; detoxification; developmental neurobiology; dosage; drug administration routes; embryo /fetus; embryo /fetus drug adverse effect; embryo /fetus toxicology; evoked potentials; gestational age; heart metabolism; infant animal; neuropharmacology; neurotoxins; neurotransmitters; oxygen consumption; placenta; postpartum; pregnancy; pregnancy circulation; progesterone; sheep; toxin metabolism; vascular resistance

Cocaine produces increases in blood pressure and heart rate by interfering with the uptake and degradation of norepinephrine at adrenergic nerve terminals. Animal studies in our laboratory suggest that intravenous cocaine produces greater systemic responses in the pregnant than nonpregnant sheep which are accompanied by reduced uterine blood flow and fetal oxygen levels. Our study is based on the hypotheses that: 1) the systemic cardiovascular response to intravenous cocaine is greater during pregnancy than observed in the non-pregnant state. 2) The pregnant uterus, when compared with a parallel vascular bed (hind limb) is a primary target organ for cocaine action. 3) The response of the pregnant uterus to cocaine is mediated by norepinephrine and serotonin receptors. 4) Fetal oxygen utilization is directly affected by cocaine-induced reductions in uterine blood flow. Phase I (maternal) studies will be conducted in the pregnant ewe and repeated two weeks postpartum to contrast the pregnant and nonpregnant response to cocaine. At 100 days of gestation pregnant sheep will undergo arterial and venous catheterization and thoracotomy for placement of a pulmonary artery flow probe for measurement of maternal heart rate, blood pressure, cardiac output and calculation of systemic vascular resistance. In a second surgery ten days later, flow probes will be secured for maternal femoral and uterine blood flow measurements and fetal arterial and venous catheters will be placed for fetal blood pressure, heart rate, and blood gas (p02, 02 content, pC02, pH) levels. Cocaine in graded doses will be randomized and given intravenously or locally into the uterine artery to determine cocaine effects on maternal systemic vascular resistance, uterine and femoral blood flow and vascular resistance. Analysis for maternal and fetal plasma cocaine levels will define distribution and half life in the fetal and maternal compartments. Cocaine administration following complete alpha adrenergic blockade with phenoxybenzamine and serotonergic blockade with Katanserin will help define the mechanism of cocaine induced vasoconstriction in the uterus. Two weeks postpartum the ewes will be retested with cocaine to determine systemic and peripheral vascular response in the non-pregnant state. In Phase II (fetal) studies surgical instrumentation at 110 days will consist of catheters in the maternal femoral artery and vein, fetal umbilical vein and fetal aorta and placement of an electromagnetic flow probe on the fetal common internal iliac artery for umbilical blood flow determinations. From these measurements, fetal-placental cardiovascular function, cocaine accumulation, oxygen delivery to the fetus and fetal oxygen extraction and consumption will be evaluated during single and repetitive maternal or direct fetal cocaine administration. The composite data from this comprehensive study will provide new information on the risks of cocaine use during pregnancy.

可卡因通过干扰血压和心率而增加血压和心率， 随着肾上腺素能神经对去甲肾上腺素的摄取和降解 terminals. 我们实验室的动物研究表明， 可卡因在孕妇中产生的全身反应比 非妊娠绵羊，伴有子宫血流减少， 胎儿血氧水平 我们的研究基于以下假设：1） 静脉注射可卡因的全身性心血管反应在 怀孕比在非怀孕状态下观察到的。 2)怀孕的子宫， 与平行血管床（后肢）相比， 可卡因作用的器官。 3)妊娠子宫对 可卡因由去甲肾上腺素和5-羟色胺受体介导。 4)胎儿 氧气利用率直接受到可卡因引起的 子宫血流 I期（母体）研究将在 妊娠母羊和产后两周重复，以对比妊娠母羊和 对可卡因的非妊娠反应 怀孕100天的绵羊 将接受动脉和静脉导管插入术和胸廓切开术， 放置肺动脉血流探头测量产妇 心率、血压、心输出量和计算全身 血管阻力 在10天后的第二次手术中，流量探头将 用于测量母体股动脉和子宫血流， 将放置胎儿动脉和静脉导管以采集胎儿血液 血压、心率和血气（p02、02含量、pC 02、pH）水平。 分级剂量的可卡因将被随机分配并静脉注射，或 局部进入子宫动脉，以确定可卡因对母体 全身血管阻力、子宫和股动脉血流以及血管阻力 阻力 分析母体和胎儿血浆可卡因水平将 定义在胎儿和母体隔室中的分布和半衰期。 完全α-肾上腺素能阻滞后给予皮质醇， 酚苄明和卡坦色林的肾上腺素能阻滞将有助于确定 可卡因引起子宫血管收缩的机制 两周 产后，母羊将用可卡因重新测试，以确定全身和 非妊娠状态下的外周血管反应。 在第二阶段 （胎儿）研究110天时的手术器械将包括 母体股动脉和静脉、胎儿脐静脉和 胎儿主动脉和电磁流量探头在胎儿上的放置 髂内总动脉用于测定脐血流。 从 这些测量，胎儿-胎盘心血管功能，可卡因 积累，氧气输送到胎儿和胎儿氧提取， 将在单次和重复性孕产妇或 直接给胎儿注射可卡因 从这个合成数据 一项全面的研究将提供有关可卡因风险的新信息 怀孕期间使用。