THE EFFECT OF VITAMIN C ON THE VASODILATOR RESPONSE TO NITROGLYCERIN IN THOSE WITH AND WITHOUT ALDEHYDE DEHYDROGENASE-2 POLYMORPHISM

Abstract

Nitroglycerin (GTN) is commonly used in the therapy of cardiovascular diseases for its vasodilating effects. Bioactivation, however, is necessary for the therapeutic effects of GTN, and aldehyde dehydrogenase 2 (ALDH-2), an enzyme that is highly polymorphic within the East Asian population, has attracted most recent attention as the major GTN bioactivating enzyme. However, human studies regarding the role of ALDH -2 as the primary mediator of GTN bioactivation have yielded conflicting results. We hypothesized that the lack of ALDH-2 activity leads to the accumulation of reactive cytotoxic aldehydes, which impair the activity of other GTN biotransformation pathways explaining the reported blunting of GTN responses in those with the ALDH-2 polymorphism. In the present study, tested the hypothesis that supplemental Vitamin C would increase vascular responses to GTN in humans with the ALDH-2 polymorphism via reduction of vascular ROS and reactive cytotoxic aldehyde levels. A Total of 24 East Asian subjects with and without the ALDH-2 polymorphism, denoted as wildtype group (n=12) and variant group (n=12) respectively, received 2, sequential intra-arterial infusions of GTN at 5, 11 and 22 nmol/min, separated by a 30-minute re-control. Both infusions were carried out in the presence and absence of vitamin C using a randomized crossover design. HR and arterial BP were measured at the end of each infusion. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN. Overall, there was no difference in HR and arterial BP between the 2 groups across all infusions. During the first GTN infusion, there was no difference in the blood flow response to GTN between subjects with and without functional ALDH-2. During the first infusion, vitamin C did not modify GTN responses in either group (Repeated Measure-ANOVA, P=NS). In subjects with the ALDH-2 polymorphism, the response to GTN was significantly blunted during the second GTN infusion while the response of the wildtype group was unchanged (Repeated Measure-ANOVA, effect of Genotype P=0.03). The co-administration of vitamin C restored blood flow responses in subjects with the ALDH-2 polymorphism to GTN during the second GTN infusion. There are likely alternative pathways underlying GTN bioactivation, particularly upon acute GTN administration. Subjects with the ALDH-2 polymorphism developed acute tolerance to GTN, possibly due to lack of ROS defense mechanisms, since the antioxidant vitamin C, prevented loss of GTN responses during the second exposure to GTN (P=NS, vs first infusion).