Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Division of Cardiology, Department of Medicine, Sinai Health System and the Peter Munk Cardiac Centre, University Health Network, Toronto, Canada.
Br J Clin Pharmacol. 2023 Sep;89(9):2767-2774. doi: 10.1111/bcp.15755. Epub 2023 May 21.
To mediate its pharmacodynamic effects, glyceryl trinitrate (GTN) requires bioactivation, by which it releases nitric oxide or a nitric oxide moiety. The exact mechanism of GTN bioactivation remains uncertain. Mitochondrial aldehyde dehydrogenase (ALDH-2) has been proposed as the primary enzyme responsible for this bioactivation process. Evidence for the importance of ALDH-2 in GTN bioactivation has been inconsistent, particularly in human models. An alternative hypothesis suggests that decreased ALDH-2 activity leads to accumulation of reactive cytotoxic aldehydes, which either inhibit the vasoactive product(s) of GTN or impair other enzymatic pathways involved in the bioactivation of GTN. We investigated the effect of supplemental vitamin C on vascular responses to GTN in healthy volunteers of East Asian descent, of whom 12 with and 12 without the ALDH-2 polymorphism participated.
Subjects underwent 2 sequential brachial artery infusions of GTN at rates of 5, 11 and 22 nmol/min, separated by a 30-min washout period. The GTN infusions were carried out in the presence and absence of vitamin C using a randomized, crossover design. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN.
Compared to subjects with functional ALDH-2, the variant group exhibited blunted hemodynamic responses to intra-arterial GTN infusions, although this reduction in response was not statically significant. Contrary to our hypothesis, vitamin C had an inhibitory effect on GTN mediated vasodilation as compared to GTN during saline in both groups.
We conclude that vitamin C did not augment the acute vascular response to GTN in those with the ALDH-2 polymorphism.
甘油三硝酸酯（GTN）需要生物活化才能发挥药效，在此过程中释放出一氧化氮或含一氧化氮的部分。GTN 的生物活化的确切机制仍不确定。线粒体乙醛脱氢酶（ALDH-2）已被提议为负责此生物活化过程的主要酶。ALDH-2 在 GTN 生物活化中的重要性的证据并不一致，特别是在人体模型中。另一种假设表明，ALDH-2 活性降低会导致反应性细胞毒性醛的积累，这些醛要么抑制 GTN 的血管活性产物，要么损害 GTN 生物活化过程中涉及的其他酶途径。我们研究了补充维生素 C 对东亚裔健康志愿者对 GTN 血管反应的影响，其中 12 名志愿者携带 ALDH-2 多态性，12 名志愿者不携带 ALDH-2 多态性。
受试者接受了 2 次 GTN 肱动脉输注，输注速度分别为 5、11 和 22 nmol/min，两次输注之间有 30 分钟的洗脱期。GTN 输注采用随机交叉设计，在存在和不存在维生素 C 的情况下进行。静脉闭塞体积描记法用于测量前臂血流对 GTN 的反应。
与具有功能性 ALDH-2 的受试者相比，变异组对动脉内 GTN 输注的血流动力学反应减弱，尽管这种反应的减少没有统计学意义。与我们的假设相反，与 GTN 在盐水期间相比，维生素 C 对 GTN 介导的血管扩张具有抑制作用。
我们的结论是，维生素 C 并没有增强携带 ALDH-2 多态性的个体对 GTN 的急性血管反应。
