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Thomas Münzel - One of the best experts on this subject based on the ideXlab platform.
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inOrganic nitrite and Nitrate in cardiovascular therapy a better alternative to Organic Nitrates as nitric oxide donors
Vascular Pharmacology, 2017Co-Authors: Thomas Münzel, Andreas DaiberAbstract:In 1867 the Organic nitrite, amyl nitrite, was introduced as a therapeutic agent in the treatment of angina pectoris and was later substituted by the Organic Nitrate nitroglycerin (NTG). Despite having a highly potent vasodilator capacity in veins>coronary arteries>arterioles, the vasodilator effects NTG are rapidly attenuated by the development of Nitrate tolerance. We and others established that NTG treatment stimulates the production of reactive oxygen species such as superoxide and peroxynitrite with subsequent marked attenuation of the NTG vasodilator potency. The nitrite anion (NO2-) has more recently been characterized to possess novel pharmacotherapeutic actions such as modulation of vasodilation under hypoxic conditions, thereby providing protection in ischemia-reperfusion injury. Administration of NO2-/NO3- has also been shown to improve myocardial function in heart failure and to lower blood pressure. Despite these positive aspects there is still a great need to study inOrganic Nitrate and nitrite therapy in various cardiovascular diseases in prospective outcome directed studies. In case being successful, this kind of therapy would indeed represent a cheap, therefore affordable, effective cardiovascular therapy without major side effects as observed in response to therapy with Organic Nitrates.
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Organic Nitrate therapy Nitrate tolerance and Nitrate induced endothelial dysfunction emphasis on redox biology and oxidative stress
Antioxidants & Redox Signaling, 2015Co-Authors: Andreas Daiber, Thomas MünzelAbstract:Abstract Organic Nitrates, such as nitroglycerin (GTN), isosorbide-5-monoNitrate and isosorbide diNitrate, and pentaerithrityl tetraNitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of Organic Nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial ...
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efficacy of the long acting nitro vasodilator pentaerithrityl tetraNitrate in patients with chronic stable angina pectoris receiving anti anginal background therapy with beta blockers a 12 week randomized double blind placebo controlled trial
European Heart Journal, 2014Co-Authors: Thomas Münzel, Tommaso Gori, Thomas Meinertz, U Tebbe, Heinrich Theodor Schneider, Dirk Stalleicken, Manfred Wargenau, Ingrid KlingmannAbstract:Background The Organic Nitrate pentaerithrityl tetraNitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study (‘CLEOPATRA’ study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris. Methods and results A total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo ( n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline ≤9 min, n = 257), PETN appeared more effective than placebo treatment ( P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels ( n = 120; P = 0.017). Pentaerithrityl tetraNitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo. Conclusion Although providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity.
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Nitrate reductase activity of mitochondrial aldehyde dehydrogenase aldh 2 as a redox sensor for cardiovascular oxidative stress
Methods of Molecular Biology, 2010Co-Authors: Andreas Daiber, Thomas MünzelAbstract:In 2002, mitochondrial aldehyde dehydrogenase (ALDH-2) was identified as an Organic Nitrate bioactivating enzyme. This so-called Nitrate reductase activity deNitrates nitroglycerin (glycerol triNitrate) to its 1,2-glycerol diNitrate metabolite and nitrite. This reaction relies on reduced thiols at the active site of the enzyme and on the presence of reduced dithiols as the electron source. During bioconversion of nitroglycerin, and also in the presence of reactive oxygen and nitrogen species, the active site thiols of ALDH-2 are oxidized and the enzyme looses its activity. We, therefore, speculated that ALDH-2 activity could be a useful marker for cardiovascular oxidative stress. Indeed, this hypothesis was supported by a number of studies, indicating that ALDH-2 activity is impaired in experimental animal models of increased oxidative stress and may be used for detection of an imbalance of mitochondrial and cellular redox state.
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New insights into bioactivation of Organic Nitrates, Nitrate tolerance and cross-tolerance
Clinical Research in Cardiology, 2008Co-Authors: Andreas Daiber, Philip Wenzel, Matthias Oelze, Thomas MünzelAbstract:Organic Nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with Organic Nitrates, however, results in a rapid development of Nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of Nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of Nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for Organic Nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various Organic Nitrates. Finally, we would like to draw the reader’s attention to the protective properties of the Organic Nitrate pentaerithrityl tetraNitrate (PETN), which, in contrast to all other Organic Nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
Andreas Daiber - One of the best experts on this subject based on the ideXlab platform.
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inOrganic nitrite and Nitrate in cardiovascular therapy a better alternative to Organic Nitrates as nitric oxide donors
Vascular Pharmacology, 2017Co-Authors: Thomas Münzel, Andreas DaiberAbstract:In 1867 the Organic nitrite, amyl nitrite, was introduced as a therapeutic agent in the treatment of angina pectoris and was later substituted by the Organic Nitrate nitroglycerin (NTG). Despite having a highly potent vasodilator capacity in veins>coronary arteries>arterioles, the vasodilator effects NTG are rapidly attenuated by the development of Nitrate tolerance. We and others established that NTG treatment stimulates the production of reactive oxygen species such as superoxide and peroxynitrite with subsequent marked attenuation of the NTG vasodilator potency. The nitrite anion (NO2-) has more recently been characterized to possess novel pharmacotherapeutic actions such as modulation of vasodilation under hypoxic conditions, thereby providing protection in ischemia-reperfusion injury. Administration of NO2-/NO3- has also been shown to improve myocardial function in heart failure and to lower blood pressure. Despite these positive aspects there is still a great need to study inOrganic Nitrate and nitrite therapy in various cardiovascular diseases in prospective outcome directed studies. In case being successful, this kind of therapy would indeed represent a cheap, therefore affordable, effective cardiovascular therapy without major side effects as observed in response to therapy with Organic Nitrates.
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Organic Nitrate therapy Nitrate tolerance and Nitrate induced endothelial dysfunction emphasis on redox biology and oxidative stress
Antioxidants & Redox Signaling, 2015Co-Authors: Andreas Daiber, Thomas MünzelAbstract:Abstract Organic Nitrates, such as nitroglycerin (GTN), isosorbide-5-monoNitrate and isosorbide diNitrate, and pentaerithrityl tetraNitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of Organic Nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial ...
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Nitrate reductase activity of mitochondrial aldehyde dehydrogenase aldh 2 as a redox sensor for cardiovascular oxidative stress
Methods of Molecular Biology, 2010Co-Authors: Andreas Daiber, Thomas MünzelAbstract:In 2002, mitochondrial aldehyde dehydrogenase (ALDH-2) was identified as an Organic Nitrate bioactivating enzyme. This so-called Nitrate reductase activity deNitrates nitroglycerin (glycerol triNitrate) to its 1,2-glycerol diNitrate metabolite and nitrite. This reaction relies on reduced thiols at the active site of the enzyme and on the presence of reduced dithiols as the electron source. During bioconversion of nitroglycerin, and also in the presence of reactive oxygen and nitrogen species, the active site thiols of ALDH-2 are oxidized and the enzyme looses its activity. We, therefore, speculated that ALDH-2 activity could be a useful marker for cardiovascular oxidative stress. Indeed, this hypothesis was supported by a number of studies, indicating that ALDH-2 activity is impaired in experimental animal models of increased oxidative stress and may be used for detection of an imbalance of mitochondrial and cellular redox state.
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New insights into bioactivation of Organic Nitrates, Nitrate tolerance and cross-tolerance
Clinical Research in Cardiology, 2008Co-Authors: Andreas Daiber, Philip Wenzel, Matthias Oelze, Thomas MünzelAbstract:Organic Nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with Organic Nitrates, however, results in a rapid development of Nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of Nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of Nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for Organic Nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various Organic Nitrates. Finally, we would like to draw the reader’s attention to the protective properties of the Organic Nitrate pentaerithrityl tetraNitrate (PETN), which, in contrast to all other Organic Nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
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role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase aldh 2 activity implications for mitochondrial oxidative stress and Nitrate tolerance
Journal of Biological Chemistry, 2007Co-Authors: Philip Wenzel, Matthias Oelze, Thomas Münzel, Ulrich Hink, Swaantje Schuppan, Karin Schaeuble, Stefan Schildknecht, Henry Weiner, Markus Bachschmid, Andreas DaiberAbstract:Chronic therapy with nitroglycerin results in a rapid development of Nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 microg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to Organic Nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to Nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves Nitrate tolerance.
Matthias Oelze - One of the best experts on this subject based on the ideXlab platform.
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tetraNitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. Hypertension 2010
2016Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Christian Mang, Susanne KarbachAbstract:Abstract—The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythrito
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vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetraNitrate but not isosorbide 5 monoNitrate therapy
Diabetes, 2011Co-Authors: Swenja Schuhmacher, Matthias Oelze, Maike Knorr, Franziska Bollmann, Hartmut Kleinert, Christian Otto, Tjebo Heeren, Sebastian Steven, Michael Hausding, Andrea PautzAbstract:OBJECTIVE Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetraNitrate (PETN) is an Organic Nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-monoNitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was assessed by isometric tension recordings, protein expression was assessed by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was assessed by luciferase assays. RESULTS PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both Organic Nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S -glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS In contrast to ISMN, the Organic Nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
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vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetraNitrate but not isosorbide 5 monoNitrate therapy
Diabetes, 2011Co-Authors: Swenja Schuhmacher, Matthias Oelze, Maike Knorr, Franziska Bollmann, Hartmut Kleinert, Christian Otto, Sebastian Steven, Michael Hausding, Tjebo F C Heeren, Andrea PautzAbstract:OBJECTIVE Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetraNitrate (PETN) is an Organic Nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-monoNitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was assessed by isometric tension recordings, protein expression was assessed by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was assessed by luciferase assays. RESULTS PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both Organic Nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S -glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS In contrast to ISMN, the Organic Nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
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pentaerythritol tetraNitrate improves angiotensin ii induced vascular dysfunction via induction of heme oxygenase 1
Hypertension, 2010Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Christian F Mang, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Susanne KarbachAbstract:The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythritol tetraNitrate largely depends on the induction of the antioxidant enzyme HO-1 and identifies pentaerythritol tetraNitrate, in contrast to isosorbide-5 monoNitrate, as an Organic Nitrate able to improve rather than to worsen endothelial function.
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New insights into bioactivation of Organic Nitrates, Nitrate tolerance and cross-tolerance
Clinical Research in Cardiology, 2008Co-Authors: Andreas Daiber, Philip Wenzel, Matthias Oelze, Thomas MünzelAbstract:Organic Nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with Organic Nitrates, however, results in a rapid development of Nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of Nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of Nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for Organic Nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various Organic Nitrates. Finally, we would like to draw the reader’s attention to the protective properties of the Organic Nitrate pentaerithrityl tetraNitrate (PETN), which, in contrast to all other Organic Nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
Philip Wenzel - One of the best experts on this subject based on the ideXlab platform.
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tetraNitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. Hypertension 2010
2016Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Christian Mang, Susanne KarbachAbstract:Abstract—The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythrito
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pentaerythritol tetraNitrate improves angiotensin ii induced vascular dysfunction via induction of heme oxygenase 1
Hypertension, 2010Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Christian F Mang, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Susanne KarbachAbstract:The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythritol tetraNitrate largely depends on the induction of the antioxidant enzyme HO-1 and identifies pentaerythritol tetraNitrate, in contrast to isosorbide-5 monoNitrate, as an Organic Nitrate able to improve rather than to worsen endothelial function.
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New insights into bioactivation of Organic Nitrates, Nitrate tolerance and cross-tolerance
Clinical Research in Cardiology, 2008Co-Authors: Andreas Daiber, Philip Wenzel, Matthias Oelze, Thomas MünzelAbstract:Organic Nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with Organic Nitrates, however, results in a rapid development of Nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of Nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of Nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for Organic Nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various Organic Nitrates. Finally, we would like to draw the reader’s attention to the protective properties of the Organic Nitrate pentaerithrityl tetraNitrate (PETN), which, in contrast to all other Organic Nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.
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role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase aldh 2 activity implications for mitochondrial oxidative stress and Nitrate tolerance
Journal of Biological Chemistry, 2007Co-Authors: Philip Wenzel, Matthias Oelze, Thomas Münzel, Ulrich Hink, Swaantje Schuppan, Karin Schaeuble, Stefan Schildknecht, Henry Weiner, Markus Bachschmid, Andreas DaiberAbstract:Chronic therapy with nitroglycerin results in a rapid development of Nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 microg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of isolated aortic rings in response to nitroglycerin. Chronic nitroglycerin infusion lead to impaired vascular responses to nitroglycerin and decreased dehydrogenase activity, which was corrected by dihydrolipoic acid co-incubation. Superoxide, peroxynitrite, and nitroglycerin itself were highly efficient in inhibiting mitochondrial and yeast aldehyde dehydrogenase activity, which was restored by dithiol compounds such as dihydrolipoic acid and dithiothreitol. Hydrogen peroxide and nitric oxide were rather insensitive inhibitors. Our observations indicate that mitochondrial oxidative stress (especially superoxide and peroxynitrite) in response to Organic Nitrate treatment may inactivate aldehyde dehydrogenase thereby leading to Nitrate tolerance. Glutathionylation obviously amplifies oxidative inactivation of the enzyme providing another regulatory pathway. Furthermore, the present data demonstrate that the mitochondrial dithiol compound dihydrolipoic acid restores mitochondrial aldehyde dehydrogenase activity via reduction of a disulfide at the active site and thereby improves Nitrate tolerance.
Swenja Schuhmacher - One of the best experts on this subject based on the ideXlab platform.
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tetraNitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. Hypertension 2010
2016Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Christian Mang, Susanne KarbachAbstract:Abstract—The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythrito
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vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetraNitrate but not isosorbide 5 monoNitrate therapy
Diabetes, 2011Co-Authors: Swenja Schuhmacher, Matthias Oelze, Maike Knorr, Franziska Bollmann, Hartmut Kleinert, Christian Otto, Sebastian Steven, Michael Hausding, Tjebo F C Heeren, Andrea PautzAbstract:OBJECTIVE Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetraNitrate (PETN) is an Organic Nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-monoNitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was assessed by isometric tension recordings, protein expression was assessed by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was assessed by luciferase assays. RESULTS PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both Organic Nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S -glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS In contrast to ISMN, the Organic Nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
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vascular dysfunction in experimental diabetes is improved by pentaerithrityl tetraNitrate but not isosorbide 5 monoNitrate therapy
Diabetes, 2011Co-Authors: Swenja Schuhmacher, Matthias Oelze, Maike Knorr, Franziska Bollmann, Hartmut Kleinert, Christian Otto, Tjebo Heeren, Sebastian Steven, Michael Hausding, Andrea PautzAbstract:OBJECTIVE Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetraNitrate (PETN) is an Organic Nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-monoNitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was assessed by isometric tension recordings, protein expression was assessed by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was assessed by luciferase assays. RESULTS PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both Organic Nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S -glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS In contrast to ISMN, the Organic Nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
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pentaerythritol tetraNitrate improves angiotensin ii induced vascular dysfunction via induction of heme oxygenase 1
Hypertension, 2010Co-Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Eberhard Schulz, Christian F Mang, Jens Kamuf, Tommaso Gori, Thomas Jansen, Maike Knorr, Susanne KarbachAbstract:The Organic Nitrate pentaerythritol tetraNitrate is devoid of Nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetraNitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 monoNitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetraNitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)–treated rats. The antioxidant features of pentaerythritol tetraNitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetraNitrate but not isosorbide-5 monoNitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II–treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetraNitrate in angiotensin II–treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetraNitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythritol tetraNitrate largely depends on the induction of the antioxidant enzyme HO-1 and identifies pentaerythritol tetraNitrate, in contrast to isosorbide-5 monoNitrate, as an Organic Nitrate able to improve rather than to worsen endothelial function.