NICOTINE INDUCED CEREBROVASCULAR DYSFUNCTION

尼古丁引起的脑血管功能障碍

• 批准号: 6355434
• 负责人: WILLIAM G MAYHAN
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355434
• 关键词: arginine; arterioles; brain circulation; cardiovascular pharmacology; enzyme activity; laboratory rat; nicotine; nitric oxide synthase; potassium channel; smoking; stroke; tobacco abuse

DESCRIPTION: (provided by applicant) While cigarette smoke contains many toxic substances, it appears that nicotine may be responsible for the adverse effects of tobacco products on the cardiovascular system. Recent studies suggest that nicotine impairs nitric oxide synthase-dependent, but not -independent, dilatation of peripheral arterioles. While there is evidence, which suggests that smoking is a risk factor for the pathogenesis of cerebrovascular disorders, including stroke, mechanisms, which contribute to the development of cerebrovascular disorders remain uncertain. Thus, the central hypothesis of this application is that nicotine contributes to the pathogenesis of cerebrovascular abnormalities via alterations in cellularprocesses, which govern reactivity of cerebral arterioles. We propose two specific aims. In aim #1, we will determine the effects of nicotine on nitric oxide synthase-dependent and -independent responses of cerebral resistance arterioles. In addition, we propose to examine several potential mechanisms by which acute and chronic exposure to nicotine might influence nitric oxide synthase-dependent reactivity of cerebral arterioles. Our hypothesis is that nicotine impairs dilatation of cerebral arterioles via impairment in the arginine/nitric oxide syntheses biosynthetic pathway, and/or stimulation of oxygen derived free radicals. In aim #2, we will determine the effects of nicotine on reactivity of cerebral arterioles to activation of potassium channels. Activation of potassium channels plays an important role in the regulation of cerebrovascular tone in response to a variety of stimuli. We propose to examine the effects of nicotine on reactivity of cerebral arterioles to activation of potassium channels and examine potential mechanisms, which contribute to altered responses of cerebral arterioles during activation of potassium channels. Our hypothesis is that nicotine alters dilatation of cerebral arterioles in response to activation of potassium channels. In summary, studies proposed in this application will be the first comprehensive attempt to examine the effects of nicotine on cellular pathways, which govern reactivity of cerebral arterioles. Our studies will provide valuable insights into mechanisms by which nicotine may contribute to cerebral microvascular dysfunction, including stroke, observed in cigarette smokers and users of tobacco products. In addition, results of these studies may provide insights regarding possible therapeutic approaches for the treatment of nicotine-induced vascular dysfunction.

描述：（由申请人提供）虽然香烟烟雾含有许多有毒物质， 物质，尼古丁似乎可能是负责任的不利影响 烟草制品对心血管系统的影响最近的研究表明， 尼古丁损害一氧化氮合酶依赖性，但不是非依赖性， 周围小动脉扩张。虽然有证据表明， 吸烟是脑血管病发病的危险因素 疾病，包括中风，机制，这有助于发展 脑血管疾病仍不确定。因此， 这种应用是尼古丁有助于 脑血管异常通过细胞过程的改变， 控制着大脑小动脉的反应性 我们提出两个具体目标。在目标#1中，我们将确定 尼古丁对一氧化氮合酶依赖性和非依赖性反应的影响 脑阻力小动脉此外，我们建议审查几个 急性和慢性暴露于尼古丁可能 影响脑小动脉一氧化氮合酶依赖性反应性。 我们的假设是，尼古丁损害脑小动脉的扩张， 精氨酸/一氧化氮合成生物合成途径受损，和/或 氧衍生自由基的刺激。在目标#2中，我们将确定 尼古丁对脑小动脉对兴奋性神经递质反应性的影响 钾离子通道钾离子通道的激活在 对各种刺激做出反应的脑血管张力调节。我们 建议检查尼古丁对脑小动脉反应性的影响 激活钾通道并检查潜在的机制， 有助于改变脑小动脉的反应过程中激活 钾离子通道我们的假设是尼古丁改变了 脑小动脉对钾通道激活的反应。 总之，本申请中提出的研究将是第一个 全面尝试检查尼古丁对细胞通路的影响， 控制着大脑小动脉的反应性我们的研究将提供 尼古丁可能有助于大脑的机制的宝贵见解 在吸烟者中观察到的微血管功能障碍，包括中风， 烟草产品的使用者。此外，这些研究的结果可以提供 关于可能的治疗方法的见解， 尼古丁引起的血管功能障碍。