Effects of Nitroglycerin on Soluble Guanylate Cyclase

Artz, J.D.; Schmidt, Bryan; McCracken, John; Marletta, Michael A.

doi:10.1074/jbc.c200170200

Cited by 39 publications

(30 citation statements)

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“…Specific sGC activity was decreased by approximately 50% upon exposure of the cells to GTN, and the effect of the organic nitrate was prevented by coincubation of the cells with GTN and sepiapterin. Activation of sGC by protoporphyrin IX, which acts through binding to heme-free sGC, was not affected by pretreating the cells with GTN, indicating that the effect of the organic nitrate is due to oxidation of ferrous sGC and subsequent loss of the ferric heme, as suggested previously (Schröder et al, 1988;Schrammel et al, 1996;Artz et al, 2002;Gorren et al, 2005;Schmidt et al, 2010). Thus, the present data suggest that BH4 protects sGC-bound heme against oxidation.…”

Section: Resultssupporting

confidence: 68%

“…Both functional and spectroscopic data published previously clearly indicate that GTN and ODQ oxidize the ferrous heme iron of sGC, resulting in loss of NO sensitivity of the enzyme (Schröder et al, 1988;Schrammel et al, 1996;Artz et al, 2002;Gorren et al, 2005;Schmidt et al, 2010). Early studies by Ignarro et al (1982) showed that the heme-free enzyme is activated by protoporphyrin IX, and the new sGC activators, including BAY 60-2770 (Knorr et al, 2008) seem to act as highly potent protoporphyrin IX mimetics that activate heme-free sGC formed subsequent to oxidation by ODQ (Roy et al, 2008;Hoffmann et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation

et al. 2012

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Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Therefore, administration of BH4 is considered a promising therapy for cardiovascular diseases associated with endothelial dysfunction and oxidative stress. Here we report on a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. . Whereas scavenging of superoxide and/or peroxynitrite with superoxide dismutase, tiron, Mn(III)tetrakis(4-benzoic acid)porphyrin, and urate had no protective effects, supplementation of the cells with BH4, either by application of BH4 directly or of its precursors dihydrobiopterin or sepiapterin, completely prevented the inhibition of NO-induced cGMP accumulation by GTN and ODQ. Tetrahydroneopterin had the same effect, and virtually identical results were obtained with RFL-6 fibroblasts, suggesting that our observation reflects a general feature of tetrahydropteridines that is unrelated to NO synthase function and not limited to endothelial cells. Protection of sGC against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.

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Section: Resultssupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation

et al. 2012

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“…Thus, it appears that the decrease in sGC expression elicited by high blood pressure is not exclusively 77 These authors…”

Section: Effects Of Oxidativementioning

confidence: 99%

“…77 The availability of specific activators of heme-oxidized sGC 78 should help to clarify whether or not nitrate tolerance is mediated in part on oxidation of the sGC heme-iron in intact cells.…”

Section: Effects Of Oxidativementioning

confidence: 99%

Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase

Münzel¹,

Daiber²,

Ullrich³

et al. 2005

ATVB

345

251

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Abstract-Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxideproducing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases. Key Words: endothelium Ⅲ vasodilation Ⅲ nitric oxide Ⅲ endothelial NO-synthase Ⅲ oxidative stress T raditionally, the role of the endothelium was thought primarily to be that of a selective barrier to the diffusion of macromolecules from the vessel lumen to the interstitial space. During the past 20 years, numerous additional roles for the endothelium have been defined such as regulation of vascular tone, modulation of inflammation, promotion, and inhibition of vascular growth and modulation of platelet aggregation and coagulation. Endothelial dysfunction is a characteristic feature of patients with coronary atherosclerosis and more recent studies indicate that it may predict long-term atherosclerotic disease progression as well as cardiovascular event rate. 1 Although the mechanisms underlying endothelial dysfunction may be multifactorial, there is a growing body of evidence that increased production of reactive oxygen species (ROS) may contribute considerably to this phenomenon. ROS production has been demonstrated to occur in the endothelial cell layer, but also within the media and adventitia, all of which may impair nitric oxide (NO) signaling within vascular tissue to endotheliumdependent, but also endothelium-independent, vasodilators. More recent...

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“…10 -13 The medical use of GTN is limited by the development of tolerance, which occurs following prolonged administration or the application of high doses. This phenomenon has been related to various mechanisms, in particular, desensitization of sGC, 14 and, mainly, impairment of GTN biotransformation by inhibition of ALDH-2. 10 -12 These actions, like others associated with GTN, have been linked to an increase in the production of reactive oxygen species (ROS), 15 as well as mitochondrial dysfunction.…”

mentioning

confidence: 99%

Complex I Dysfunction and Tolerance to Nitroglycerin

Esplugues

Rocha

Núñez

et al. 2006

Circulation Research

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Abstract-Nitroglycerin (GTN) tolerance was induced in vivo (rats) and in vitro (rat and human vessels). Electrochemical detection revealed that the incubation dose of GTN (5ϫ10 Ϫ6 mol/L) did not release NO or modify O 2 consumption when administered acutely. However, development of tolerance produced a decrease in both mitochondrial O 2 consumption and the K m for O 2 in animal and human vessels and endothelial cells in a noncompetitive action. GTN tolerance has been associated with impairment of GTN biotransformation through inhibition of aldehyde dehydrogenase (ALDH)-2, and with uncoupling of mitochondrial respiration. Feeding rats with mitochondrial-targeted antioxidants (mitoquinone [MQ]) and in vitro coincubation with MQ (10 Ϫ6 mol/L) or glutathione (GSH) ester (10 Ϫ4 mol/L) prevented tolerance and the effects of GTN on mitochondrial respiration and ALDH-2 activity. Biotransformation of GTN requires functionally active mitochondria and induces reactive oxygen species production and oxidative stress within this organelle, as it is inhibited by mitochondrial-targeted antioxidants and is absent in HUVEC 0 cells. Experiments analyzing complex I-dependent respiration demonstrate that its inhibition by GTN is prevented by mitochondrial-targeted antioxidants. Furthermore, in presence of succinate (10ϫ10 Ϫ3 mol/L), a complex II electron donor added to bypass complex I-dependent respiration, GTN-treated cells exhibited O 2 consumption rates similar to those of controls, thus suggesting that complex I was affected by GTN. We propose that, following prolonged treatment with GTN in addition to ALDH-2, complex I is a target for mitochondrially generated reactive oxygen species. Our data also suggest a role for mitochondrial-targeted antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use. ) have generally been attributed to its bioconversion into the relaxant agent nitric oxide (NO), which acts on the enzyme soluble guanylate cyclase (sGC). [1][2][3] However, most studies that support the existence of such a pathway have demonstrated increases of NO only when GTN concentrations considerably exceeded the plasma levels reached during clinical dosing. 4 Moreover, the involvement of other NO-related species in the actions of GTN when used at clinically relevant concentrations is also under debate. 5,6 Different enzymes have been implicated in the bioconversion of GTN, in particular, glutathione S-transferases, 7 the cytochrome p450 system, 8 and xanthine oxidoreductase, 9 although the most recent evidence suggests a central role for mitochondrial aldehyde dehydrogenase (ALDH)-2. 10 -13 The medical use of GTN is limited by the development of tolerance, which occurs following prolonged administration or the application of high doses. This phenomenon has been related to various mechanisms, in particular, desensitization of sGC, 14 and, mainly, impairment of GTN biotransformation by inhibition of ALDH-2. 10 -12 These actions, like others associated with GTN, have been linked to a...

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Effects of Nitroglycerin on Soluble Guanylate Cyclase

Cited by 39 publications

References 35 publications

Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation

Tetrahydrobiopterin Protects Soluble Guanylate Cyclase against Oxidative Inactivation

Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase

Complex I Dysfunction and Tolerance to Nitroglycerin

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