Tetrahydrobiopterin Improves Endothelial Function in Patients with Coronary Artery Disease

Maier, Willibald; Cosentino, Francesco; Lütolf, Roland; Fleisch, Martin; Seiler, Christian; Hess, Otto M.; Meier, Bernhard; Lüscher, Thomas F.

doi:10.1097/00005344-200002000-00001

Cited by 200 publications

(86 citation statements)

References 24 publications

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“…12 Acute infusion of BH 4 improved endothelial function in angiographically normalappearing segments of coronary arteries in subjects with coronary artery disease or hypercholesterolaemia. 13,14 A similar improvement was observed in the forearm circulation of diabetics and smokers. [15][16][17] These studies have used either parenteral infusion of BH 4 or a single oral dose, and it has not been shown that chronic oral administration of BH 4 could cause a sustained improvement in endothelial function.…”

Section: Introductionsupporting

confidence: 69%

Tetrahydrobiopterin: a novel antihypertensive therapy

et al. 2008

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Tetrahydrobiopterin (BH 4 ) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH 4 will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH 4 was given to subjects with poorly controlled hypertension (BP 4135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg À1 day À1 of BH 4 (n ¼ 8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH 4 (n ¼ 16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P ¼ 0.005) and mean BP (P ¼ 0.01) were observed with both doses of BH 4 . Systolic BP was 15 ± 15 mm Hg (P ¼ 0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH 4 had decreased systolic (P ¼ 0.03) and mean BP (P ¼ 0.04), with a peak decline of 16±19 mm Hg (P ¼ 0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH 4 . There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH 4 at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.

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Section: Introductionsupporting

confidence: 69%

Tetrahydrobiopterin: a novel antihypertensive therapy

et al. 2008

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“…The coupling/uncoupling of eNOS activity is reported to be regulated by BH4 availability [23,24]. CRP treatment resulted in a significant decrease in intracellular BH4 levels (reduced form) as compared to control cells (Fig 2a).…”

Section: Resultsmentioning

confidence: 90%

“…Various clinical studies have also demonstrated that administration of BH4 improves endothelial dysfunction in conditions characterized by reduced availability of NO and increased production of reactive oxygen species, such as hypercholesterolemia [38], coronary artery disease [24] and smoking [39]. BH4 is synthesized through 2 distinct pathways [16].…”

Section: Discussionmentioning

confidence: 99%

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C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

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C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). In this study, we examined the mechanisms by which CRP decreases eNOS activity in HAECs. To this end, we explored different strategies such as availability of tetrahydrobiopterin (BH4) -a critical cofactor for eNOS, superoxide (O 2 -) production resulting in uncoupling of eNOS and phosphorylation/dephosphorylation of eNOS. CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. Pretreatment with sepiapterin, a BH4 precursor, prevented CRP-mediated effects on BH 4 levels, superoxide production as well as eNOS activity. The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH 4 , was significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP mediated pathway. In the present study, CRP mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. Furthermore, CRP-induced O 2 -production was reversed by pharmacologic inhibition and siRNAs to p47 phox and p22 phox. Additionally, CRP treatment significantly decreased the eNOS dimer:monomer ratio confirming CRP-mediated eNOS uncoupling. The pretreatment of cells with NO synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]) also prevented CRP-mediated O 2 -production further strengthening CRP-mediated eNOS uncoupling. Additionally, CRP decreased eNOS phosphorylation at Ser1177 as well as increased phosphorylation at Thr495. CRP appears to mediate these effects through the Fcγ receptors, CD32 and CD64.To conclude, CRP uncouples eNOS resulting in increased superoxide production, decreased NO production, altered eNOS phosphorylation.

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“…Administration of BH4 improves endothelial function in patients with or without CAD (11,12). In addition, decreased BH4/BH2 ratio, a marker of BH4 oxidation, is also an independent factor of impaired vasorelaxation responses to acetylcholine, suggesting that this factor may exert adverse effects on the endothelial function of the coronary artery.…”

mentioning

confidence: 99%

Reply to letter to the editor: coronary flow velocity reserve was impaired in chronic hyperhomocysteinemic patients: why?

Wang¹,

Hong³

2011

American Journal of Physiology-Endocrinology and Metabolism

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TO THE EDITOR: Hyperhomocysteinemia (HHcy) is considered a potentially modifiable risk factor for coronary artery disease (CAD) and atherosclerosis. The possible mechanisms of accelerated CAD in HHcy include endothelial dysfunction and enhanced oxidative stress (13). However, the precise mechanism by which homocysteine (Hcy) promotes atherosclerosis is not well understood. Hcy could impair coronary microvascular dilated function in healthy individuals. Endothelium-dependent dilation was significantly impaired in acute methionine-induced HHcy patients (1).Noninvasive transthoracic ultrasound imaging of coronary blood flow has been increasingly used to assessment of coronary microcirculation in individuals free of epicardial coronary stenosis (2). Coronary flow velocity reserve (CFVR), which is derived from the ratio of maximal hyperemic to basal coronary blood flow, is an accepted index for assessment of the coronary microcirculation and provides important information about coronary endothelial function. We thank Dr. Kietadisorn et al. (10a) for their interest in our paper (9). We fully agree that CFVR as an independent index of coronary microvascular function has multiple limitations. CFVR is influenced by both epicardial and microvascular factors of the coronary artery. It is also influenced by serious epicardial coronary stenosis, previous myocardial infarction, etc. Pharmacological hyperemic vasodilatation induced by adenosine is a reliable and reproducible technique with which CFVR is evaluated by Doppler echocardiography (3, 10). Adenosine is often used to assess microcirculatory function on the basis of their ability to induce maximal vasodilatation of coronary resistance vessels. This vasodilatation is primarily achieved through effects of adenosine on vascular smooth muscle cells. However, adenosine-induced vasodilatation is partly dependent on the release of nitric oxide (NO) from endothelial cells through the effect of adenosine on endothelial cells and/or via flow-induced shearing force (4, 8). Hence, adenosine-derived CFVR may involve both endothelium-dependent and -independent microcirculatory function. CFVR in response to adenosine may be partly endothelium dependent. In our study, we investigated whether CFVR was damaged in patients with chronic HHcy and, if so, whether this impaired effect was associated with the endothelial dysfunction. Quantification of CFVR was after rest and after adenosine administration by noninvasive Doppler echocardiography. Our results showed that CFVR was significantly lower in the HHcy patients than in the control group (2.76 Ϯ 0.49 vs. 3.09 Ϯ 0.52). In addition, the plasma level of Hcy was negatively correlated with CFVR. Regarding the potential effect of multiple factors on CFVR, the patients with myocardial infarction, CAD (Ͼ50% stenosis as shown on angiography), heart failure, renal function impairment, or a serious illness or who were undergoing nitrate or vitamin treatment that would affect their participation were excluded from our study. Consistent with our f...

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Tetrahydrobiopterin Improves Endothelial Function in Patients with Coronary Artery Disease

Cited by 200 publications

References 24 publications

Tetrahydrobiopterin: a novel antihypertensive therapy

Tetrahydrobiopterin: a novel antihypertensive therapy

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Reply to letter to the editor: coronary flow velocity reserve was impaired in chronic hyperhomocysteinemic patients: why?

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