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）香烟烟雾中含有多种有毒物质 物质，看来尼古丁可能是造成不良影响的原因 烟草制品对心血管系统的影响。最近的研究表明 尼古丁会损害一氧化氮合酶依赖性，但不是独立的， 外周小动脉扩张。虽然有证据表明 认为吸烟是脑血管病发病的危险因素 疾病，包括中风，机制，有助于发展 脑血管疾病仍不确定。因此，中心假设 该应用是尼古丁有助于发病机制 通过细胞过程的改变导致脑血管异常， 控制脑小动脉的反应性。 我们提出两个具体目标。在目标#1中，我们将确定以下效果： 尼古丁对一氧化氮合酶依赖性和非依赖性反应的影响 脑小动脉阻力。此外，我们建议审查几项 急性和慢性接触尼古丁的潜在机制 影响脑小动脉的一氧化氮合酶依赖性反应性。 我们的假设是尼古丁通过以下方式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 刺激氧衍生的自由基。在目标#2中，我们将确定 尼古丁对脑小动脉激活反应的影响 钾通道。钾通道的激活在 调节脑血管张力以响应各种刺激。我们 提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机制， 有助于改变大脑小动脉在激活过程中的反应 钾通道。我们的假设是尼古丁会改变 脑小动脉对钾通道的激活作出反应。 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途径的影响， 控制脑小动脉的反应性。我们的研究将提供 关于尼古丁可能促进大脑功能的机制的宝贵见解 在吸烟者中观察到的微血管功能障碍，包括中风 烟草制品的使用者。此外，这些研究的结果可能会提供 关于治疗该病的可能治疗方法的见解 尼古丁引起的血管功能障碍。