Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans

Abstract

The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.

Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Induced Vasodilation of Coronary and Systemic Vessels

“…8 -12 Furthermore, continued use of GTN is associated with endothelial dysfunction, a predictor of adverse cardiac events. 11,13,14 Thus, the molecular basis of neither GTN bioactivation nor tolerance is well understood.…”

Effect of Pioglitazone on Nitroglycerin-Induced Impairment of Nitric Oxide Bioavailability by a Catheter-Type Nitric Oxide Sensor

“…4 In addition, Gori et al have shown that continuous NTG treatment induces significant changes in the function of the endothelium in humans. 18 However, in this study, we could not evaluate the extent to which exogenous NO, such as ambient environment, food, and water, affected our results. Further studies will be needed on this subject.…”

“…Increased vascular peroxynitrite formation might affect the proper function of eNOS and thus induce the impairment of bioavailability of NO. As pointed out by Gori et al, 2 peroxynitrite is a strong stimulus for the oxidation of the eNOS cofactor BH4 to dihydrobiopterin. The resulting intracellular BH4 deficiency might switch eNOS from a NO to a superoxide-producing enzyme, which may further increase oxidative stress in vascular tissue in a positive feedback fashion.…”

“…[1][2][3] This cross-tolerance to endogenous NO would imply that nitrate therapy might be potentially harmful to longterm clinical outcomes. In the present study, we have shown for the first time that NTG-induced impairment of NO bioavailability could be improved by co-treatment with a PPAR agonist, pioglitazone.…”

“…[1][2][3] However, the limitation of these data is that the release of nitric oxide (NO) from the endothelium was estimated on the basis of the comparison of vessel relaxation. We have very recently shown that longterm treatment of New Zealand White rabbits with NTG decreases basal, as well as acetylcholine (ACh)-induced plasma NO concentrations by using a catheter-type NO sensor, accompanied with augmentation of nitrosative stress.…”