PRENATAL POLYDRUG EXPOSURE & CARDIOVASCULAR DEVELOPMENT

怀孕期间胎儿长期接触多种药物的情况已经达到 一些城市中心的疫情比例。最常见的药物之一 组合是母亲使用可卡因和酒精，这一直是 与胎儿发育迟缓、神经行为后遗症和 先天结构缺陷。在细胞水平上，重复 宫内药物暴露已被证明可诱导突触前和 大鼠突触后单胺能受体通路的变化 中枢神经系统。关于它的影响，我们知之甚少。 孕期慢性药物暴露对周围自主神经功能的影响 尤其是心血管系统。然而，安装 新生儿心功能异常的证据与 妊娠期单独或与可卡因联合暴露 其他非法药物，已在临床上报告。 我们将使用一种慢性大鼠模型来测试母体 可卡因单独使用或与酒精一起使用(1)会改变 突触后心肌B肾上腺素能受体信号转导通路 通过胆碱能神经递质和自主神经改变其调节 神经肽、神经肽Y和血管活性肠肽； 增强突触前交感神经的发育和功能 (3)改善出生后心肌收缩功能和自主神经 新生大鼠心脏的反应性。 我们的具体目标是：(1)检查突触后心肌 Bataar通路及其M受体、NPY和VIP受体的调节 途径；以及建立由慢性产前药物引起的变化 暴露；(2)测定大鼠突触前肾上腺素能活动。 新生儿心脏和记录药物暴露对去甲肾上腺素的影响 合成、利用度、周转和再摄取；(3)阐明 接触药物对心率和收缩功能的影响；以及 外源性给药阳性引起的心肌收缩反应 和负性肌力药。此外，我们还将发展一种慢性 用妊娠大鼠血管收缩模型阐明原发胎儿 可卡因的影响来自于其对母亲的继发性影响。 从拟议的研究中获得的知识将提供更好的 对药物损伤机制及可能功能的认识 出生前接触可卡因引起的心脏改变 和/或酒精。

Chronic fetal exposure to polydrug use during pregnancy has reached epidemic proportions in some urban centers. One of the most common drug combinations is the maternal use of cocaine and alcohol, which has been linked to fetal growth retardation, neurobehavioral sequelae and congenital structural defects. At the cellular level, repeated intrauterine drug exposure has been shown to induce presynaptic and postsynaptic changes in the monoaminergic receptor pathways in the central nervous system. Much less is known regarding the effect of chronic prenatal drug exposure on peripheral autonomic function, specifically that of the cardiovascular system. However, mounting evidence of abnormal neonatal cardiac function associated with gestational exposure to cocaine, either alone or in combination with other illicit drugs, have been reported clinically. We will use a chronic rat model to test the hypotheses that maternal cocaine use alone or in combination with alcohol (1) changes the postsynaptic myocardial B adrenergic receptor signaling pathway and alters its modulation by cholinergic neurotransmitters and autonomic neuropeptides, neuropeptide Y and vasoactive intestinal peptide; (2) enhances the presynaptic sympathetic neural development and function and (3) modifies postnatal myocardial contractile function and autonomic responsiveness in the neonatal rat heart. Our specific aims will be (1) to examine the postsynaptic myocardial bataAR pathway and its modulation by the muscarinic, NPY and VIP receptor pathways; and to establish the changes due to chronic prenatal drug exposure; (2) to determine presynaptic adrenergic activity in the neonatal heart and document the effect of drug exposure on norepinephrine synthesis, availability, turnover and reuptake; (3) to elucidate the effect of drug exposure on cardiac rhythm and contractile function; and the myocardial contractile response to exogenously administered positive and negative inotropic agents. In addition, we will develop a chronic vasoconstrictor model in the pregnant rat to elucidate the primary fetal effects of cocaine from those secondary to its effects on the mother. Knowledge gained from the proposed research will provide a better understanding of the mechanism of drug injury and possible functional alterations in the heart resulting from prenatal exposure to cocaine and/or alcohol.