Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase: Evidence for a Dysfunctional Nitric Oxide S...

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Zeitschriftentitel:	Circulation Research
Personen und Körperschaften:	Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas
In:	Circulation Research, 86, 2000, 2
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	Ovid Technologies (Wolters Kluwer Health)
Schlagwörter:	Cardiology and Cardiovascular Medicine Physiology

author_facet	Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas
author	Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas
spellingShingle	Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas Circulation Research Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase Cardiology and Cardiovascular Medicine Physiology
author_sort	heitzer, thomas
spelling	Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas 0009-7330 1524-4571 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine Physiology http://dx.doi.org/10.1161/01.res.86.2.e36 <jats:p> <jats:italic>Abstract</jats:italic> —Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) <jats:italic>N</jats:italic> <jats:sup>G</jats:sup> -monomethyl- <jats:sc>l</jats:sc> -arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers. The full text of this article is available at http://www.circresaha.org. </jats:p> Evidence for a Dysfunctional Nitric Oxide Synthase Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase Circulation Research
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title_sub	Evidence for a Dysfunctional Nitric Oxide Synthase
title	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_unstemmed	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_full	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_fullStr	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_full_unstemmed	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_short	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_sort	tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase
topic	Cardiology and Cardiovascular Medicine Physiology
url	http://dx.doi.org/10.1161/01.res.86.2.e36
publishDate	2000
physical
description	<jats:p> <jats:italic>Abstract</jats:italic> —Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) <jats:italic>N</jats:italic> <jats:sup>G</jats:sup> -monomethyl- <jats:sc>l</jats:sc> -arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers. The full text of this article is available at http://www.circresaha.org. </jats:p>
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author	Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas
author_facet	Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas, Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas
author_sort	heitzer, thomas
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description	<jats:p> <jats:italic>Abstract</jats:italic> —Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) <jats:italic>N</jats:italic> <jats:sup>G</jats:sup> -monomethyl- <jats:sc>l</jats:sc> -arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers. The full text of this article is available at http://www.circresaha.org. </jats:p>
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spelling	Heitzer, Thomas Brockhoff, Carsten Mayer, Bernd Warnholtz, Ascan Mollnau, Hanke Henne, Simone Meinertz, Thomas Münzel, Thomas 0009-7330 1524-4571 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine Physiology http://dx.doi.org/10.1161/01.res.86.2.e36 <jats:p> <jats:italic>Abstract</jats:italic> —Conditions associated with impaired nitric oxide (NO) activity and accelerated atherosclerosis have been shown to be associated with a reduced bioavailability of tetrahydrobiopterin (BH4). We therefore hypothesized that BH4 supplementation may improve endothelial dysfunction of chronic smokers. Forearm blood flow (FBF) responses to the endothelium-dependent vasodilators acetylcholine (ACh; 0.75, 1.5, and 3.0 μg/100 mL tissue/min) or serotonin (5-HT; 0.7, 2.1, and 6.3 ng/100 mL tissue/min), to the inhibitor of endothelial nitric oxide synthase (NOS) <jats:italic>N</jats:italic> <jats:sup>G</jats:sup> -monomethyl- <jats:sc>l</jats:sc> -arginine (L-NMMA; 2, 4, and 8 μmol/min), and to the endothelium-independent vasodilator sodium nitroprusside (SNP; 0.1, 0.3, and 1.0 μg/100 mL tissue/min) were measured by venous occlusion plethysmography in controls and chronic smokers. Drugs were infused into the brachial artery, and FBF was measured before and during concomitant intra-arterial infusion of BH4, tetrahydroneopterin (NH4; another reduced pteridine), or the antioxidant vitamin C (6 and 18 mg/min). In control subjects, BH4 had no effect on FBF in response to ACh, 5-HT, and SNP. In contrast, in chronic smokers, the attenuated FBF responses to ACh and 5-HT were markedly improved by concomitant administration of BH4, whereas the vasodilator responses to SNP were not affected. L-NMMA-induced vasoconstriction was significantly reduced in smokers compared with controls, suggesting impaired basal NO bioactivity. BH4 improved L-NMMA responses in smokers while having no effect on L-NMMA responses in controls. Pretreatment with vitamin C abolished BH4 effects on ACh-dependent vasodilation. In vitro, NH4 scavenged superoxide created by the xanthine/xanthine oxidase reaction equipotent like BH4 but failed to modify ACh-induced changes in FBF in chronic smokers in vivo. These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional NOS III due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers. The full text of this article is available at http://www.circresaha.org. </jats:p> Evidence for a Dysfunctional Nitric Oxide Synthase Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase Circulation Research
spellingShingle	Heitzer, Thomas, Brockhoff, Carsten, Mayer, Bernd, Warnholtz, Ascan, Mollnau, Hanke, Henne, Simone, Meinertz, Thomas, Münzel, Thomas, Circulation Research, Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase, Cardiology and Cardiovascular Medicine, Physiology
title	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_full	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_fullStr	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_full_unstemmed	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_short	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
title_sort	tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase
title_sub	Evidence for a Dysfunctional Nitric Oxide Synthase
title_unstemmed	Tetrahydrobiopterin Improves Endothelium-Dependent Vasodilation in Chronic Smokers : Evidence for a Dysfunctional Nitric Oxide Synthase
topic	Cardiology and Cardiovascular Medicine, Physiology
url	http://dx.doi.org/10.1161/01.res.86.2.e36