Nitric Oxide Facilitates Nicotine Absorption During Cigarette Smoking

 描述（由申请人提供）：吸烟是美国可预防死亡的主要原因。2009年，国会通过了《烟草控制法》，授权FDA对卷烟成分进行监管，以减少其对公众的危害。因此，迫切需要了解导致吸烟成瘾性的因素。该项目的目的是检验香烟烟雾中的一氧化氮（NO）通过促进尼古丁的吸入和吸收而增强吸烟成瘾性的假设。NO是一种内源性信号气体，是气道和肺血管的强有力扩张剂，对正常肺功能非常重要。长期吸烟减少NO的产生，诱导肺部系统的炎症过程，增加气道和肺血管的阻力，并可能最终导致慢性阻塞性肺病（COPD）和肺动脉高压。吸入的香烟烟雾中含有高水平的NO，这可能会通过扩张气道和肺血管并降低其阻力来增加吸入量和肺灌注以及空气交换，从而促进尼古丁的吸入和吸收，特别是在肺功能受损的慢性吸烟者中。与NO的这种潜在作用有关，卷烟制造商通过增加卷烟中的硝酸盐（NO的主要前体）来增加烟雾中的NO，尽管他们在20世纪50年代至90年代的同一时期减少了尼古丁和焦油。增加的NO可能有助于所谓的吸烟补偿;即，烟草依赖的吸烟者在吸尼古丁减少的香烟时比吸普通香烟时吸气更深。为了测试NO是否有助于尼古丁的吸收，我们将要求烟草依赖的吸烟者在过夜戒烟后的两个不同的日子参加两次吸烟会议。吸烟者将在每次研究期间通过过滤嘴吸烟。过滤器将在一个会话期间从主流烟气中去除NO（即，真实的过滤会话（RFS））但在另一会话期间将不移除NO（即，虚拟过滤会话（DFS））。在每次治疗期间，将在吸烟前后采集用于评估血浆尼古丁水平的血样。与RFS相比，DFS中吸烟后血浆尼古丁水平相对于吸烟前显著增加，这将支持我们的假设，即吸烟期间NO促进尼古丁吸收。我们将在每一次会议期间获得渴望，负面影响和吸烟影响的测量结果，以比较两次会议期间吸烟的主观影响。这项研究的积极结果将为后续研究提供基础，更充分地评估NO在烟草使用障碍中的作用。这些研究的目标是为FDA提供数据，以决定是否以及如何调节NO和/或其前体（例如，硝酸盐），以促进公众健康，减少吸烟上瘾的特性。

 DESCRIPTION (provided by applicant): Cigarette smoking is the leading cause of preventable death in the USA. In 2009, Congress passed the Tobacco Control Act and authorized the FDA to regulate cigarette ingredients to reduce their harm to the public. Therefore, knowledge of factors contributing to the addictive properties of cigarette smoking is urgently needed. The aim of the proposed project is to test the hypothesis that nitric oxide (NO) in cigarette smoke enhances the addictive properties of cigarette smoking by facilitating nicotine inhalation and absorption. NO is an endogenous signaling gas and a powerful dilator of airways and pulmonary vessels, and important for normal pulmonary function. Chronic smoking reduces NO production, induces an inflammation process in the pulmonary system, increases resistance of airways and pulmonary vessels, and may finally result in chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. Inhaled cigarette smoke contains a high level of NO which may increase inhalation volume and pulmonary perfusion and air exchange by dilating airways and pulmonary vessels and reducing their resistance, thus facilitating nicotine inhalation and absorption, especially in chronic smokers with impaired pulmonary function. Relevant to this potential role of NO, cigarette manufacturers increased the NO in smoke by increasing nitrate, a main precursor of NO, in cigarettes, even though they reduced nicotine and tar during the same period from the 1950s-1990s. The increased NO may contribute to the so-called smoking compensation; i.e., tobacco-dependent smokers inhale deeper when smoking nicotine-reduced cigarettes relative to regular cigarettes. To test whether NO facilitates nicotine absorption, we will ask tobacco-dependent smokers to participate in two smoking sessions on two different days after overnight abstinence. Smokers will smoke a regular cigarette through a filter during each study session. The filter will remove NO from mainstream smoke during one session (i.e., real filter session (RFS)) but will not remove NO during the other session (i.e., dummy filter session (DFS)). Blood samples for assessing plasma nicotine levels will be acquired both before and after smoking during each session. Compared with the RFS, a significantly greater increase in plasma nicotine levels after smoking relative to before smoking in the DFS will support our hypothesis that NO facilitates nicotine absorption during cigarette smoking. We will acquire measures on craving, negative affect, and smoking effects during each session for comparing subjective effects of smoking during the two sessions. Positive findings from the proposed study will provide a foundation for subsequent studies assessing more fully a role for NO in tobacco-use disorder. The goal of these studies is to generate data for the FDA to decide whether and how to regulate NO and/or its precursors (e.g., nitrate) in cigarettes to promote public health by reducing the addictive properties of cigarette smoking.