Tetrahydrobiopterin: a novel antihypertensive therapy

Porkert, M; Sher, Salman; Reddy, Utkarsh A.; Cheema, Faiz A.; Niessner, Christina; Kolm, Paul; Jones, Dean P.; Hooper, C. W.; Taylor, W. Robert; Harrison, David G.; Quyyumi, Arshed A.

doi:10.1038/sj.jhh.1002329

Cited by 92 publications

(72 citation statements)

References 32 publications

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“…57 Furthermore, FIR rays have been applied in treating various chronic diseases, such as hypertension, heart failure, and vascular endothelial dysfunction, which are associated with the depletion of tetrahydrobiopterin (BH4), a critical cofactor for NO synthases. 90,91 FIR therapy improves blood flow in heated surface areas, causing an increase in vascular shear stress and enhancement of the activity of GTP cyclohydrolase I, which benefits BH4 synthesis. 92,93 Thus, the increased availability of BH4 may provide key insight into the underlying mechanisms of sauna therapy.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Far-infrared therapy for cardiovascular, autoimmune, and other chronic health problems: A systematic review

Shui

Wang

Chiang

et al. 2015

Exp Biol Med (Maywood)

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Physical therapy (physiotherapy), a complementary and alternative medicine therapy, has been widely applied in diagnosing and treating various diseases and defects. Increasing evidence suggests that convenient and non-invasive far-infrared (FIR) rays, a vital type of physiotherapy, improve the health of patients with cardiovascular disease, diabetes mellitus, and chronic kidney disease. Nevertheless, the molecular mechanisms by which FIR functions remain elusive. Hence, the purpose of this study was to review and summarize the results of previous investigations and to elaborate on the molecular mechanisms of FIR therapy in various types of disease. In conclusion, FIR therapy may be closely related to the increased expression of endothelial nitric oxide synthase as well as nitric oxide production and may modulate the profiles of some circulating miRNAs; thus, it may be a beneficial complement to treatments for some chronic diseases that yields no adverse effects.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Far-infrared therapy for cardiovascular, autoimmune, and other chronic health problems: A systematic review

Shui

Wang

Chiang

et al. 2015

Exp Biol Med (Maywood)

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“…To improve management of these conditions, intense efforts are being focused on the development of ROS-detoxifying interventions. For example, nonenzymatic antioxidants, including scavengers of ROS or donors of reducing equivalents (e.g., glutathione precursors), may help alleviate subtle chronic oxidative stress, but these consumable agents provide rather marginal protection against severe oxidative stresses Porkert et al, 2008). …”

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confidence: 99%

Targeted Detoxification of Selected Reactive Oxygen Species in the Vascular Endothelium

Shuvaev¹,

Christofidou‐Solomidou²,

Bhora³

et al. 2009

J Pharmacol Exp Ther

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Oxidative stress underlies diverse vascular diseases, but its management remains elusive, in part because of our inability to selectively detoxify reactive oxygen species (ROS) in pathological sites and our limited understanding which species need to be eliminated. The antioxidant enzymes (AOEs) superoxide dismutase (SOD) and catalase (which decompose O 2. and H 2 O 2 , respectively), conjugated with an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1), bind to endothelial cells and alleviate oxidative stress in cell culture models. Here, we studied the effects of these antioxidant conjugates in mouse models of vascular oxidative stress. Anti-PECAM/catalase and anti-PECAM/SOD conjugates, in contrast to control IgG/AOE conjugates, accumulated in the lungs and vascularized organs after intravenous injection in wild-type, but not PECAM KO mice. Anti-PECAM/catalase, but not anti-PECAM/SOD, protected mice from lung injury induced by H 2 O 2 produced by glucose oxidase deposited in the pulmonary vasculature. Anti-PECAM/catalase also reduced alveolar edema and attenuated decline in arterial oxygen in mice that underwent unilateral lung ischemia/reperfusion, whereas anti-PECAM/SOD was not effective, implying the key role of H 2 O 2 in tissue damage in this pathology. In contrast, anti-PECAM/SOD, but not anti-PECAM/ catalase prevented oxidation of tetrahydrobiopterin and normalized vasoreactivity in the vessels of mice rendered hypertensive by pretreatment with angiotensin-II. This outcome agrees with reports implicating superoxide and peroxynitrite in altered endothelium-dependent vasodilatation in hypertension. Therefore, the use of endothelial cell-targeted antioxidants identifies the key specific species of ROS involved in various forms of vascular disease and holds promise for the mechanistically tailored treatment of these pathologies.Oxidative stress induced by an excess of reactive oxygen species (ROS) plays an important role in a number of vascular pathologies including hypertension, ischemia, stroke, acute myocardial infarction, and inflammation (Cai et al., 2003;Krause and Bedard, 2008). To improve management of these conditions, intense efforts are being focused on the development of ROS-detoxifying interventions. For example, nonenzymatic antioxidants, including scavengers of ROS or donors of reducing equivalents (e.g., glutathione precursors), may help alleviate subtle chronic oxidative stress, but these consumable agents provide rather marginal protection against severe oxidative stresses Porkert et al., 2008).

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“…BH4 exerts vasodilating effects through enhanced NO synthesis and may decrease BP. 44 We chose doses in the range previously used in studies of chronic BH4 supplementation in patients with hypercholesterolemia (400 mg BID 45 ) or ischemic heart disease (400-700 mg QD 46 ) to achieve daily averages of 5 mg/kg. These doses were deemed safe to avoid excessive BP decrease in CADASIL patients, who frequently …”

Section: Discussionmentioning

confidence: 99%

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL

Maria

Campolo

Frontali

et al. 2014

Stroke

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Background and Purpose-Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. Methods-In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. Results-The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, −0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. Conclusions-Sapropterin

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Tetrahydrobiopterin: a novel antihypertensive therapy

Cited by 92 publications

References 32 publications

RETRACTED: Far-infrared therapy for cardiovascular, autoimmune, and other chronic health problems: A systematic review

RETRACTED: Far-infrared therapy for cardiovascular, autoimmune, and other chronic health problems: A systematic review

Targeted Detoxification of Selected Reactive Oxygen Species in the Vascular Endothelium

Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL

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