Allicin and NO Modulation of Pulmonary Vasoactivity

大蒜素和 NO 对肺血管活性的调节

• 批准号: 6891599
• 负责人: DAVID D KU
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891599
• 关键词: angiosperms; biotherapeutic agent; blood circulation; high performance liquid chromatography; laboratory rat; muscle contraction; muscle relaxation; nitric oxide; nitric oxide synthase; plant extracts; pulmonary hypertension; respiratory circulation; vascular smooth muscle; vasoconstrictors

DESCRIPTION (provided by applicant): Allicin (diallyl thiosulfinate) has been shown to elicit a marked pulmonary vasodepressor response and is widely regarded as one of the most important biologically active compounds produced by garlic (Allium sativum). We reported that long-term oral garlic feeding in rats was effective in preventing the development of hypoxic pulmonary hypertension. However, inability to accurately detect allicin in plasma following garlic ingestion and a lack of understanding of its pulmonary vasodepressor actions have slowed its development as a complementary therapeutic agent. Recently, we developed a simple HPLC method coupled to mass spectrometry (MS-MRM) to precisely identify and quantify allicin content in both aqueous and plasma samples. We found that allicin content, from either pure allicin, freshly crushed garlic or freeze-dried preparations, correlated directly with a vasorelaxation responses, which in part mediated via an increase in nitric oxide (NO) production. The goal of this proposal is to investigate the cellular and molecular mechanisms of garlic/allicin modulation of pulmonary vasoactivity and function. Our hypothesis is that garlic and its active metabolite, allicin, act either singularly via an activation of endothelial nitric oxide synthase (NOS) and an increase in NO production or in concert with a direct inhibition of vascular smooth muscle contraction to modulate pulmonary vascular tone and reactivity. Five Specific Aims are proposed. We will investigate: First, whether precursors of allicin and/or its degradative products may contribute to the relaxation. Second, the mechanisms of allicin-induced NO-dependent relaxation. Third, the mechanisms of allicin induced direct vascular smooth muscle relaxation. Fourth, the chemical/biological fate of allicin following its entry into the blood circulation, which may explain the transient vasodepressor responses in intact animals. And Fifth, if oral administration of garlic with different allicin yields produces a graded protection against hypoxia and monocrotaline-induced pulmonary hypertension. We believe that our novel HPLC/MS-MRM method of detection/quantitation of allicin coupled with a comprehensive approach to studying its biological activities both in vitro and in vivo will provide important new insights into the role of garlic/allicin modulation of pulmonary vasoactivity and function. Our long-term objective is to identify novel therapeutic agents to improve the clinical management of pulmonary vascular disorders.

描述（由申请人提供）： 大蒜素（二烯丙基硫代亚磺酸盐）已被证明可引起显着的肺血管减压反应，并被广泛认为是大蒜（Allium sativum）产生的最重要的生物活性化合物之一。我们报道，长期口服大蒜喂养大鼠可有效预防缺氧性肺动脉高压的发生。然而，由于无法准确检测摄入大蒜后血浆中的大蒜素，并且对其肺血管抑制作用缺乏了解，因此减缓了其作为补充治疗剂的发展。最近，我们开发了一种简单的 HPLC 方法与质谱法 (MS-MRM) 相结合，以精确识别和定量水样和血浆样品中的大蒜素含量。我们发现，无论是纯大蒜素、新鲜压碎的大蒜还是冻干制剂中的大蒜素含量，都与血管舒张反应直接相关，而血管舒张反应在一定程度上是通过一氧化氮 (NO) 产生的增加来介导的。该提案的目的是研究大蒜/大蒜素调节肺血管活性和功能的细胞和分子机制。我们的假设是，大蒜及其活性代谢物大蒜素要么通过激活内皮一氧化氮合酶（NOS）并增加一氧化氮的产生而单独发挥作用，要么与直接抑制血管平滑肌收缩一起发挥作用，从而调节肺血管张力和呼吸功能。反应性。提出了五个具体目标。我们将调查：首先，大蒜素和/或其降解产物的前体是否可能有助于松弛。其次，大蒜素诱导NO依赖性松弛的机制。第三，大蒜素诱导血管平滑肌直接松弛的机制。第四，大蒜素进入血液循环后的化学/生物命运，这可以解释完整动物中短暂的血管抑制反应。第五，口服不同大蒜素含量的大蒜是否能对缺氧和野百合碱引起的肺动脉高压产生分级保护作用。我们相信，我们的新型 HPLC/MS-MRM 检测/定量大蒜素的方法，加上研究其体外和体内生物活性的综合方法，将为大蒜/大蒜素调节肺血管活性和作用提供重要的新见解。功能。我们的长期目标是寻找新的治疗药物来改善肺血管疾病的临床治疗。