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.
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