In Vitro Metabolism of (Nitrooxy)butyl Ester Nitric Oxide-Releasing Compounds: Comparison with Glyceryl Trinitrate

Govoni, Mirco; Casagrande, Simona; Maucci, Raffaella; Chiroli, Valerio; Tocchetti, Paola

doi:10.1124/jpet.105.097469

Cited by 36 publications

(41 citation statements)

References 29 publications

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“…Third, S-nitrosylation, an unambiguous marker of NO action, following exposure to NO-NSAIDs has been repeatedly identified [43]. Finally, Govoni et al using electron paramagnetic resonance demonstrated that NOflurbiprofen generated NO in erythrocytes, with hemoglobin mediating this biotransformation [44]. Their work and that of others suggests that the NO-releasing moiety (−ONO 2 ) undergoes 1 e − reduction to NO 2 − , which is then either converted to NO or oxidized to NO 3 − .…”

Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

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Section: No As the Mediator Of The Action Of No-nsaidsmentioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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“…Although much of nitroglycerin's pharmacology is known, the mechanisms through which nitroglycerin acts on the endothelium and the heart as well as the enzymatic pathways leading to its bioactivation are still controversial and under intense investigation. A number of hypotheses for nitroglycerin bioconversion in vivo have been formulated, implicating a multitude of enzymes such as GST (6,7), oxidoreductases (8), and mitochondrial aldehyde dehydrogenase (9,10) in the bioconversion of nitroglycerin to NO and/or other vasoactive compounds. For example, GST has been shown to catalyze the transnitration of lower thiols in the presence of nitroglycerin (6,7).…”

mentioning

confidence: 99%

“…A number of hypotheses for nitroglycerin bioconversion in vivo have been formulated, implicating a multitude of enzymes such as GST (6,7), oxidoreductases (8), and mitochondrial aldehyde dehydrogenase (9,10) in the bioconversion of nitroglycerin to NO and/or other vasoactive compounds. For example, GST has been shown to catalyze the transnitration of lower thiols in the presence of nitroglycerin (6,7). Xanthine oxidase and mitochondrial aldehyde dehydrogenase (which are closely related oxidoreductases) have been found to mediate nitroglycerin reduction to nitrite (11) and NO itself (8,10).…”

mentioning

confidence: 99%

Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation

Stadler¹,

Silva²,

Corbett³

et al. 2008

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

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The physiological effects of nitroglycerin as a potent vasodilator have long been documented. However, the molecular mechanisms by which nitroglycerin exerts its biological functions are still a matter of intense debate. Enzymatic pathways converting nitroglycerin to vasoactive compounds have been identified, but none of them seems to fully account for the reported clinical observations. Here, we demonstrate that nitroglycerin triggers constitutive nitric oxide synthase (NOS) activation, which is a major source of NO responsible for low-dose (1-10 nM) nitroglycerin-induced vasorelaxation. Our studies in cell cultures, isolated vessels, and whole animals identified endothelial NOS activation as a fundamental requirement for nitroglycerin action at pharmacologically relevant concentrations in WT animals.endothelial NOS ͉ neuronal NOS ͉ blood pressure I t has been Ͼ150 years since the effect of nitroglycerin as a potent vasodilator was first reported (1). Since then, intense research has led to extensive and well documented literature regarding nitroglycerin's physiological effects (2-4) and the identity of its derived metabolites in cells, tissues, laboratory animals, and humans (5, 6). Although much of nitroglycerin's pharmacology is known, the mechanisms through which nitroglycerin acts on the endothelium and the heart as well as the enzymatic pathways leading to its bioactivation are still controversial and under intense investigation. A number of hypotheses for nitroglycerin bioconversion in vivo have been formulated, implicating a multitude of enzymes such as GST (6, 7), oxidoreductases (8), and mitochondrial aldehyde dehydrogenase (9, 10) in the bioconversion of nitroglycerin to NO and/or other vasoactive compounds. For example, GST has been shown to catalyze the transnitration of lower thiols in the presence of nitroglycerin (6, 7). Xanthine oxidase and mitochondrial aldehyde dehydrogenase (which are closely related oxidoreductases) have been found to mediate nitroglycerin reduction to nitrite (11) and NO itself (8, 10). Several intermediate compounds, such as partially nitrated glycerin, nitrite (11), and nitrosothiols (6, 7), have been indicated as precursors of nitroglycerin-derived NO, which is ultimately responsible for the observed effects on the vasculature. Collectively, these studies contributed to establishing nitroglycerin as a metabolismdependent NO donor. Although some pathways have received more attention than others, none of the above-mentioned mechanisms seems to satisfactorily delineate nitroglycerin's peculiar kinetic and pharmacological behavior, which is distinct from that of other well characterized NO donors such as sodium nitroprusside (12). For instance, the nitrate groups of nitroglycerin are chemically resistant to rapid reduction because they are esters of nitrate. Also, minute doses of nitroglycerin [maximum plasma concentration Ϸ6 nM for 0.5 mg of nitroglycerin administered sublingually (13)], which are comparable to the basal levels of free NO [Ϸ5 nM as free NO (14)], result in...

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“…This mechanism, along with soluble guanylyl cyclase desensitization and activation of oxidative stress, has been described as mediating ISMN-induced tolerance (Minamiyama et al, 2004;Daiber and Munzel, 2015). However, this mechanism may not be as important for NCX1404 because similar NO-donating compounds were reported to rely on different bioactivation pathways compared with ISMN (Govoni et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Repeated Dosing with NCX1404, a Nitric Oxide-Donating Pregabalin, Re-establishes Normal Nociceptive Responses in Mice with Streptozotocin-Induced Painful Diabetic Neuropathy

Varani

Vincenzi

Targa

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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NCX1404 [(3S)-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy) carbonylamino) methyl)hexanoic acid] is a novel nitric oxide (NO)-donating pregabalin that is readily absorbed and processed in vivo to pregabalin and NO. We determined the antiallodynic response of NCX1404 after acute or after 7, 14, and 21 days of repeated daily oral dosing in mice with streptozotocin (STZ)-induced painful diabetic neuropathy (PDN). Pregabalin and its combination with the NO donor isosorbide mononitrate (ISMN) were used for comparison. The blood levels of pregabalin and nitrites, used as surrogate marker of NO release, after NCX1404 or pregabalin dosing were monitored in parallel experiments using liquid chromatography with tandem mass spectrometry (LC-MS/MS). NCX1404 and pregabalin resulted in similar pregabalin levels as it was their antiallodynic activity after acute dosing in STZ mice. However, NCX1404 resulted in disease-modifying properties when administered daily for 21 days, as indicated by the time-and dose-dependent reversal of STZ-induced mechanical allodynia (paw withdrawal threshold [PWT] Veh_21d 5 1.3 6 0.15 g for vehicle; PWT NCX1404_21d 5 1.4 6 0.5 g, 2.9 6 0.2 g* and 4.1 6 0.2 g*, respectively for 19, 63, and 190 mmol/kg, oral gavage [PO] of NCX1404; *P , 0.05 versus vehicle). This effect was not shared by pregabalin at equimolar doses (190 mmol/kg, PO, PWT Pregab_21d 5 1.4 6 0.1 g*, *P , 0.05 versus equimolar NCX1404). In addition, the NO donor ISMN (52.3 mmol/kg, PO) alone or combined with pregabalin (63 mmol/kg) was active at 7 days (PWT Veh_7d 5 1.7 6 0.16 g; PWT ISMN_7d 5 3.9 6 0.34 g*; PWT Pregab_7d 5 1.3 6 0.07 g; PWT ISMN1pregab_7d 5 3.8 6 0.29 g*; *P , 0.05) but not at later time points. The long-term effect of NCX1404 was independent of residual drug exposure and lasted for several days after the treatment was stopped. In summary, like pregabalin, NCX1404 is an effective antiallodynic agent. Differently from pregabalin, repeated dosing of NCX1404 re-established normal nociceptive responses in STZ-induced PDN in mice.

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In Vitro Metabolism of (Nitrooxy)butyl Ester Nitric Oxide-Releasing Compounds: Comparison with Glyceryl Trinitrate

Cited by 36 publications

References 29 publications

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation

Repeated Dosing with NCX1404, a Nitric Oxide-Donating Pregabalin, Re-establishes Normal Nociceptive Responses in Mice with Streptozotocin-Induced Painful Diabetic Neuropathy

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