In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide

Laursen, Jørn Bech; Mülsch, Alexander; Boesgaard, S.; Mordvintcev, Peter I.; Trautner, Simon; Gruhn, Nicolai; Nielsen‐Kudsk, Jens Erik; Busse, Rudi; Aldershvile, Jan

doi:10.1161/01.cir.94.9.2241

Cited by 66 publications

(30 citation statements)

References 18 publications

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“…We have demonstrated in this study that capacity of GTNtolerant aortas to produce NO from 100 mol/L GTN was not different from control aortas. These results are consistent with a previous study 66 and argue against the idea of decreased bioconversion of GTN into NO in GTN-tolerant vessels. These results also do not support a role for NO in GTNinduced vasodilatation.…”

Section: Gtn/no In Blood Vesselssupporting

confidence: 92%

Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?

Kleschyov

Oelze

Daiber

et al. 2003

Circulation Research

153

134

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Abstract-Nitroglycerin (glyceryl trinitrate, GTN) relaxes blood vessels primarily via activation of the soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK-I) pathway. Although the precise mechanism of sGC activation by GTN in the vascular wall is unknown, the mediatory role of nitric oxide (NO) has been postulated. We tested the GTN/NO hypothesis in different types of isolated rat and rabbit blood vessels using two novel approaches:(1) EPR spin trapping using colloid Fe(DETC) 2 and (2) analysis of cGK-I-dependent phosphorylation of the vasodilator-stimulated phosphoprotein at Ser239 (P-VASP). For comparison, another organic nitrate, isosorbide dinitrate (ISDN), and endothelium-dependent vasodilator, calcium ionophore A23187, were tested. We found a marked discrepancy between GTN's strong vasoactivity (vasodilation and augmentation of P-VASP) and its poor NO donor properties. In aortas precontracted with phenylephrine, GTN, ISDN, and A23187 induced nearly full relaxations (Ͼ80%) and doubling of vascular P-VASP content at concentrations of 100 nmol/L, 100 mol/L, and 1 mol/L, respectively. GTN applied in vasorelaxant concentrations (10 to 1000 nmol/L) did not significantly increase the basal vascular NO production, in contrast to ISDN and A23187. The absence of GTN-derived NO was confirmed in rabbit vena cava and renal artery. A significant increase in vascular NO formation was observed only at suprapharmacological GTN concentrations (Ͼ10 mol/L). The concentration dependency of NO formation from GTN was comparable to that of ISDN, although the latter exhibits 100-folds lower vasorelaxant potency. We conclude that GTN activates the sGC/cGMP/cGK-I pathway and induces vasorelaxation without intermediacy of the free radical NO. 2 It is believed that the beneficial therapeutic effect of GTN is due to selective vasodilation of coronary arteries and venous capacitance vessels with minimal effect on arteriolar tone. 3 Several evidences indicate that the principal mechanism of GTN-induced smooth muscle relaxation is the activation of the intracellular enzyme, soluble guanylyl cyclase (sGC), and subsequent elevation of the cyclic guanosine-3Ј,-5Ј-monophosphate (cGMP) levels 4 -12 (see reviews 13,14 ). Among other effects, the elevated cGMP level leads to activation of cGMP-dependent protein kinase (cGK-I), which in turn mediates vasorelaxation via phosphorylation of several proteins regulating intracellular Ca 2ϩ mobilization. 15 However, the precise mechanism by which GTN activates vascular sGC is still controversially discussed. 16 -19 According to the hypothesis presently favored, GTN undergoes intracellular bioconversion into the putative metabolite nitric oxide (NO), which is known as a direct activator of sGC and as a smooth muscle relaxant. 5,8,20 -23 After the discovery of endothelium-derived NO, 24 -26 the idea of NO being the active principle of GTN has been widely accepted by the scientific community, and it has been often speculated that GTN can replace the compromised endothelial NO produ...

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Section: Gtn/no In Blood Vesselssupporting

confidence: 92%

Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?

Kleschyov

Oelze

Daiber

et al. 2003

Circulation Research

153

134

View full text Add to dashboard Cite

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“…However, it has been shown that even during nitrate tolerance caused by long-term GTN administration, the bioconversion of GTN to NO may remain unaltered. 20 Given the subtle nature of the impairment in NMD observed in the present study, it is unlikely that this defect would significantly influence the measurement of FMD. Our present results demonstrate a close relationship between NMD and FMD, but causality of this association cannot be proven in this cross-sectional study setting, and it is possible that the correlation is merely a result of colinearity attributable to similar risk factor influences on these measures of arterial function.…”

mentioning

confidence: 71%

Determinants of Arterial Nitrate-Mediated Dilatation in Children

2004

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Background-Impaired arterial dilatation response to nitroglycerin has been observed in adults with risk factors for atherosclerosis and in patients with established atherosclerotic disease. This defect parallels changes in vascular endothelial function and may be attributed to increased oxidative stress. Because atherosclerosis begins in childhood, we examined the correlates of nitrate-mediated dilatation (NMD) in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). Methods and Results-Brachial artery flow-mediated endothelium-dependent dilatation (FMD) Key Words: arteries Ⅲ diabetes mellitus Ⅲ endothelium Ⅲ nitroglycerin Ⅲ pediatrics E ndothelial dysfunction is currently considered a key early event in the atherosclerotic process already evident in children with cardiovascular risk factors, such as hypercholesterolemia 1 and diabetes. 2 The brachial artery ultrasound test for flow-mediated endothelial-dependent vasodilatory function (FMD), described by Celermajer et al, 1 includes administration of sublingual nitrates to examine the vasodilating effect of an exogenous source of nitric oxide (NO). NO acts directly at the level of the arterial smooth muscle cells and produces an endothelium-independent dilatation response. Nitrate-mediated dilatation (NMD) has therefore been used as a control test for the FMD measurement to ensure that a decreased FMD capacity observed is truly a consequence of endothelial dysfunction and not a reflection of underlying smooth muscle dysfunction.Recent evidence indicates that in addition to influencing endothelial function, atherosclerosis may also induce changes in arterial dilatation responses to exogenous NO. 3,4 Adult patients with coronary artery disease show impaired brachial NMD compared with healthy control subjects. 4 Attenuated NMD is associated with serum cholesterol concentration independently of endothelial function in apparently healthy adults. 3 In most previous studies in children, the NMD responses have actually been mildly reduced in high-risk individuals, although the difference has not reached statistical significance, possibly because of limited sample size. 1,2,5 Increased oxidative stress and oxidized LDL have been implicated as risk factors for atherosclerosis 6 and shown to potently quench NO 7 and decrease its production 8 in experimental studies. Recent studies have associated oxidative stress with nitrate tolerance. 9 Because the atherosclerotic process begins in childhood, 10 we examined the correlates of NMD in children, including brachial artery endothelial function, oxidized LDL, and carotid artery intima-media thickness (IMT). Methods SubjectsWe studied 142 children (83 boys; mean age, 11 years; range, 8 to 17 years), including 41 children with diabetes and 14 children with familial hypercholesterolemia (FH). All subjects were nonsmokers.Received December 8, 2003; revision received February 27, 2004; accepted March 4, 2004. Children with diabetes were consecutively recruited fro...

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“…1 A-D) is compatible with reports that rabbit (34)(35)(36) and rat (37) organs differ in their capacity to generate NO from GTN. These spin-trapping studies indicate that NO formation during acute GTN infusion (34,35,37) or more prolonged transdermal administration (36) is greatest in kidney, liver, and lung, less in heart and vena cava, and marginal in aorta and RBCs. Our data show that, during GTN biotransformation, heart and liver also are major nitros(yl)ation sites, especially compared with vascular tissue.…”

Section: Discussionmentioning

confidence: 92%

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

Janero

Bryan

Saijo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Nitric oxide (NO)-derived products may modify tissue constituents, forming S-and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed ''NObonomics'') for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg͞kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S-and N-nitrosation, and RBC S-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitrite͞nitrate as an index of NO͞NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation (''metabolic shunting'') from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the NObonomic analysis of NO-donor metabolism and signaling.nitric oxide ͉ nitrosylheme ͉ nitrosothiols ͉ metabonomics N itric oxide (NO) regulates diverse aspects of mammalian physiology by enhancing cGMP production through soluble guanylyl cyclase activation (1). This classic signal transduction mechanism notwithstanding, NO's highly reactive, diffusible nature fosters an extensive chemical biology in vivo that influences gene expression, mitochondrial respiration, and drug metabolism; induces posttranslational protein modification; and generates numerous NO-derived metabolites (2, 3) (collectively referred to herein as the NO metabonome or ''NObonome'').¶ Some of these metabolites have been implicated in NO's beneficial and pathological effects (2, 3). Recent demonstration that constitutive thiol, amine, and heme nitros(yl)ation in mammalian tissues generates, respectively, S-nitrosothiols (RSNOs), N-nitroso compounds (RNNOs), and nitrosylheme (NO-heme) species suggests new signaling pathways through which nitrogen oxides might influence cell physiology by covalently modifying tissue biomolecules (3,5). Given the mounting evidence that thiol nitrosation modulates cell function (6), it is a matter of great interest to identify the biological targets of NO-dependent modification, the mechanism(s) responsible, and the dis...

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In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide

Cited by 66 publications

References 18 publications

Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?

Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?

Determinants of Arterial Nitrate-Mediated Dilatation in Children

Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo

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