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1.
Am J Physiol Heart Circ Physiol ; 323(5): H975-H982, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36149770

RESUMEN

Endothelial function (brachial artery flow-mediated dilation [FMD]) is reduced in estrogen-deficient postmenopausal women, mediated, in part, by reduced nitric oxide (NO) bioavailability, secondary to tetrahydrobiopterin (BH4) deficiency and oxidative stress. FMD is increased, but not fully restored, in postmenopausal women after acute intravenous vitamin C (VITC; superoxide scavenger) or oral BH4 supplementation. In vitro studies demonstrate that coadministration of VITC with BH4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite. To investigate mechanisms of endothelial dysfunction in women, we assessed the separate and combined effects of VITC and BH4 to determine whether coadministration of VITC + BH4 improves FMD in healthy postmenopausal women (n = 19, 58 ± 5 yr) to premenopausal (n = 14, 36 ± 9 yr) levels, with exploratory testing in perimenopausal women (n = 8, 51 ± 3 yr). FMD was measured during acute intravenous infusions of saline (control) and VITC (∼2-3 g) ∼3 h after a single dose of oral BH4 (KUVAN, 10 mg/kg body wt) or placebo (randomized crossover, separated by ∼1 mo). Under the placebo condition, FMD was reduced in postmenopausal compared with premenopausal women during the saline infusion (5.6 ± 0.7 vs. 11.6 ± 0.9%, P < 0.001) and increased in postmenopausal women during VITC (+3.5 [1.4, 5.6]%, P = 0.001) and acute BH4 (+1.8 [0.37, 3.2]%, P = 0.01) alone. Coadministration of VITC + BH4 increased FMD in postmenopausal women (+3.0 [1.7, 4.3]%, P < 0.001), but FMD remained reduced compared with premenopausal women (P = 0.02). Exploratory analyses revealed that VITC + BH4 did not restore FMD in perimenopausal women to premenopausal levels (P = 0.045). Coadministration of VITC + BH4 does not restore FMD in menopausal women, suggesting that additional mechanisms may be involved.NEW & NOTEWORTHY Endothelial function is reduced across the menopausal stages related to increased oxidative stress associated with estrogen deficiency. In vitro studies demonstrate that coadministration of VITC with BH4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite; however, this remains untested in humans. We demonstrate that the coadministration of BH4 + VITC does not restore endothelial function in perimenopausal and postmenopausal women to the level of premenopausal women, suggesting that other mechanisms contribute.


Asunto(s)
Óxido Nítrico Sintasa de Tipo III , Enfermedades Vasculares , Humanos , Femenino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Endotelio Vascular/metabolismo , Ácido Peroxinitroso/metabolismo , Biopterinas/metabolismo , Biopterinas/farmacología , Menopausia , Estrógenos/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo
2.
Circ Res ; 128(5): 585-601, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33494625

RESUMEN

RATIONALE: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype. OBJECTIVE: Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes. METHODS AND RESULTS: In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post-diabetes induction (streptozotocin, 42-45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31phosphorous magnetic resonance spectroscopy), and myocardial function. CONCLUSIONS: We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy. Graphic Abstract: A graphic abstract is available for this article.


Asunto(s)
Biopterinas/análogos & derivados , Cardiomiopatías Diabéticas/tratamiento farmacológico , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Disfunción Ventricular Izquierda/tratamiento farmacológico , Animales , Biopterinas/farmacología , Biopterinas/uso terapéutico , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , GTP Ciclohidrolasa/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Glutatión/metabolismo , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología
3.
Sci Rep ; 10(1): 19844, 2020 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-33199757

RESUMEN

This study aimed to investigate the influence of chronic ischemia on nitric oxide biosynthesis in the bladder and the effect of administering tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), on chronic ischemia-related lower urinary tract dysfunction (LUTD). This study divided male Sprague-Dawley rats into Control, chronic bladder ischemia (CBI) and CBI with oral BH4 supplementation (CBI/BH4) groups. In the CBI group, bladder capacity and bladder muscle strip contractility were significantly lower, and arterial wall was significantly thicker than in Controls. Significant improvements were seen in bladder capacity, muscle strip contractility and arterial wall thickening in the CBI/BH4 group as compared with the CBI group. Western blot analysis of bladder showed expressions of eNOS (p = 0.043), HIF-1α (p < 0.01) and dihydrofolate reductase (DHFR) (p < 0.01), which could regenerate BH4, were significantly higher in the CBI group than in Controls. In the CBI/BH4 group, HIF-1α (p = 0.012) and DHFR expressions (p = 0.018) were significantly decreased compared with the CBI group. Our results suggest that chronic ischemia increases eNOS and DHFR in the bladder to prevent atherosclerosis progression. However, DHFR could not synthesize sufficient BH4 relative to the increased eNOS, resulting in LUTD. BH4 supplementation protects lower urinary tract function by promoting eNOS activity.


Asunto(s)
Biopterinas/análogos & derivados , Isquemia/prevención & control , Óxido Nítrico/biosíntesis , Vejiga Urinaria/irrigación sanguínea , Animales , Disponibilidad Biológica , Biopterinas/administración & dosificación , Biopterinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isquemia/etiología , Isquemia/metabolismo , Masculino , Contracción Muscular/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Tetrahidrofolato Deshidrogenasa/metabolismo , Vejiga Urinaria/efectos de los fármacos
4.
Life Sci Alliance ; 3(9)2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32699151

RESUMEN

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.


Asunto(s)
Biopterinas/análogos & derivados , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Cardiomiopatías Diabéticas/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/genética , Animales , Biopterinas/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Diabetes Mellitus/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Corazón/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Contracción Miocárdica , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Biogénesis de Organelos , Fosforilación Oxidativa , Ratas , Ratas Long-Evans , Transducción de Señal/fisiología
5.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31356183

RESUMEN

High salt (HS) intake can lead to hypertension, probably the result of the predominance of vasoconstrictor reactive oxygen species over vasodilator nitric oxide (NO). We aimed to examine if the supposed NO deficiency and the resultant blood pressure increase could be corrected by supplementation of L-arginine, the substrate, and tetrahydrobiopterin (BH4), a co-factor of NO synthases. Wistar rats without known genetic background of salt sensitivity were exposed to HS diet (4%Na) for 10 or 26 days, without or with supplementation with oral L-arginine, 1.4 mg/kg b.w. daily, alone or together with intraperitoneal BH4, 10 mg/kg daily. Systolic blood pressure (SBP, tail-cuff method) was measured repeatedly and found to increase ~40 mmHg after 26 days; L-arginine and BH4 did not significantly attenuate this increase. At the end of chronic studies, in anaesthetized rats the diet- and treatment-induced changes in renal haemodynamics were assessed. HS diet selectively decreased (-30%, P < 0.03) the inner medullary blood flow (IMBF, laser-Doppler flux) without changing total or cortical renal perfusion. Arginine supplementation tended to raise all renal circulatory parameters, and distinctly increased IMBF, to 61% above the HS diet level (P < 0.05). In conclusion, unlike in confirmed genetically determined salt-dependent hypertension, L-arginine and BH4 supplementation failed to attenuate the SBP increase observed after exposure to HS diet. On the other hand, arginine increased total and regional renal perfusion, especially IMBF. This suggests that the delivery of arginine increased intrarenal NO synthesis, an action of renoprotective potential which presumably countered the harmful influence of the local tissue oxidative stress.


Asunto(s)
Arginina/farmacología , Biopterinas/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipotensión/inducido químicamente , Cloruro de Sodio Dietético/administración & dosificación , Animales , Arginina/efectos adversos , Biopterinas/efectos adversos , Biopterinas/farmacología , Suplementos Dietéticos , Hipertensión/metabolismo , Hipotensión/metabolismo , Riñón , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Circulación Renal/efectos de los fármacos
6.
Homeopathy ; 108(3): 183-187, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30836409

RESUMEN

INTRODUCTION: The authors had previously conducted an in-vitro study to observe the effect of homeopathic medicines on melanogenesis, demonstrating anti-vitiligo potential by increasing the melanin content in murine B16F10 melanoma cells. A similar experiment was performed using further homeopathic preparations sourced from kojic acid (KA), hydrogen peroxide (H2O2; HP), 6-biopterin (BP), and [Nle4, D-Phe7]-α-melanocyte-stimulating hormone (NLE), some of which are known to induce vitiligo or melano-destruction at physiological dose. MATERIALS AND METHODS: The homeopathic preparations of BP, KA, NLE, and HP were used in 30c potency. Alcohol and potentized alcohol were used as vehicle controls. Prior to starting the main experiment, the viability of B16F10 melanoma cells after treatment with study preparations was assayed. Melanin content (at 48 h and 96 h) and tyrosinase activity in melanocytes were determined. RESULTS: At the end of 48 hours, NLE and HP in 30c potency had a significantly greater melanin content (p = 0.015 and p = 0.039, respectively) compared with controls; BP and KA in 30c potency had no significant effects. No significant changes were seen at the end of 96 hours. KA, NLE, HP, and vehicle controls showed an inhibition of tyrosinase activity. CONCLUSION: The study demonstrated melanogenic effects of two homeopathic preparations. Further research to evaluate the therapeutic efficacy of these medicines is warranted.


Asunto(s)
Biopterinas/farmacología , Peróxido de Hidrógeno/farmacología , Melaninas/metabolismo , Melanocitos/efectos de los fármacos , Pironas/farmacología , Análisis de Varianza , Biopterinas/metabolismo , Supervivencia Celular/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Melaninas/análisis , Melanocitos/metabolismo , Melanocitos/fisiología , Pironas/metabolismo , Vitíligo/tratamiento farmacológico , Vitíligo/fisiopatología
7.
J Inherit Metab Dis ; 41(4): 709-718, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29520738

RESUMEN

Hyperphenylalaninemia (HPA) caused by hepatic phenylalanine hydroxylase (PAH) deficiency has severe consequences on brain monoamine neurotransmitter metabolism. We have studied monoamine neurotransmitter status and the effect of tetrahydrobiopterin (BH4) treatment in Pahenu1/enu2 (ENU1/2) mice, a model of partial PAH deficiency. These mice exhibit elevated blood L-phenylalanine (L-Phe) concentrations similar to that of mild hyperphenylalaninemia (HPA), but brain levels of L-Phe are still ~5-fold elevated compared to wild-type. We found that brain L-tyrosine, L-tryptophan, BH4 cofactor and catecholamine concentrations, and brain tyrosine hydroxylase (TH) activity were normal in these mice but that brain serotonin, 5-hydroxyindolacetic acid (5HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) content, and brain TH protein, as well as tryptophan hydroxylase type 2 (TPH2) protein levels and activity were reduced in comparison to wild-type mice. Parenteral L-Phe loading conditions did not lead to significant changes in brain neurometabolite concentrations. Remarkably, enteral BH4 treatment, which normalized brain L-Phe levels in ENU1/2 mice, lead to only partial recovery of brain serotonin and 5HIAA concentrations. Furthermore, indirect evidence indicated that the GTP cyclohydrolase I (GTPCH) feedback regulatory protein (GFRP) complex may be a sensor for brain L-Phe elevation to ameliorate the toxic effects of HPA. We conclude that BH4 treatment of HPA toward systemic L-Phe lowering reverses elevated brain L-Phe content but the recovery of TPH2 protein and activity as well as serotonin levels is suboptimal, indicating that patients with mild HPA and mood problems (depression or anxiety) treated with the current diet may benefit from supplementation with BH4 and 5-OH-tryptophan.


Asunto(s)
Biopterinas/análogos & derivados , Encéfalo/metabolismo , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/metabolismo , Serotonina/metabolismo , Animales , Biopterinas/farmacología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Humanos , Ratones , Ratones Mutantes , Neurotransmisores/metabolismo , Fenilalanina/sangre , Fenilalanina/metabolismo , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/genética , Triptófano Hidroxilasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismo
8.
PLoS One ; 11(10): e0164305, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27711248

RESUMEN

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS) and aromatic amino acid hydroxylases. BH4 and 7,8-dihydrobiopterin (BH2) are metabolically interchangeable at the expense of NADPH. Exogenously administered BH4 can be metabolized by the body, similar to vitamins. At present, synthetic BH4 is used as an orphan drug for patients with inherited diseases requiring BH4 supplementation. BH4 supplementation has also drawn attention as a means of treating certain cardiovascular symptoms, however, its application in human patients remains limited. Here, we tracked biopterin (BP) distribution in blood, bile, urine, liver, kidney and brain after BH4 administration (5 mg/kg rat, i.v.) with or without prior treatment with probenecid, a potent inhibitor of uptake transporters particularly including organic anion transporter families such as OTA1 and OAT3. The rapid excretion of BP in urine was driven by elevated blood concentrations and its elimination reached about 90% within 120 min. In the very early period, BP was taken up by the liver and kidney and gradually released back to the blood. BH4 administration caused a considerable decrease in the BH4% in blood BP as an inevitable compensatory process. Probenecid treatment slowed down the decrease in blood BP and simultaneously inhibited its initial rapid excretion in the kidney. At the same time, the BH4% was further lowered, suggesting that the probenecid-sensitive BP uptake played a crucial role in BH2 scavenging in vivo. This suggested that the overproduced BH2 was taken up by organs by means of the probenecid-sensitive process, and was then scavenged by counter-conversion to BH4 via the BH4 salvage pathway. Taken together, BH4 administration was effective at raising BP levels in organs over the course of hours but with extremely low efficiency. Since a high BH2 relative to BH4 causes NOS dysfunction, the lowering of the BH4% must be avoided in practice, otherwise the desired effect of the supplementation in ameliorating NOS dysfunction would be spoiled.


Asunto(s)
Biopterinas/análogos & derivados , Biopterinas/análisis , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Probenecid/farmacología , Animales , Bilis/química , Bilis/efectos de los fármacos , Bilis/metabolismo , Biopterinas/sangre , Biopterinas/química , Biopterinas/metabolismo , Biopterinas/farmacología , Biopterinas/orina , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclosporina/farmacología , Eritrocitos/química , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Riñón/química , Riñón/metabolismo , Hígado/química , Hígado/metabolismo , Masculino , Óxido Nítrico Sintasa/metabolismo , Ratas
9.
Gynecol Endocrinol ; 30(10): 691-3, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24927077

RESUMEN

PURPOSE: A woman with phenylketonuria (PKU) was diagnosed through neonatal screening, her PAH mutation was p.V388M/p.I65T, for which she received treatment with phenylalanine restriction, and was administered oral sapropterin dihydrochloride (6R-BH(4)) from the age of thirty. The purpose of this article is to describe the treatment with BH4 during her pregnancy and to evaluate a plan for its use. METHODS: The patient had an unplanned pregnancy at 34 years of age, for which she received a phenylalanine-free supplement enriched with essential fatty acids, vitamins and trace elements. RESULTS: The dose of 6R-BH(4) was reduced from 500 mg/day to 100 mg/day until its suspension in the 28th week of gestation, and was well tolerated. Blood phenylalanine control was easily accomplished during this pregnancy, and no nutritional deficiency was seen. CONCLUSION: The pregnancy had a normal outcome, and so we consider that adaptation of the dose of 6R-BH(4) to the prenatal periods aided a greater efficiency and a lower risk in the treatment of maternal PKU.


Asunto(s)
Biopterinas/análogos & derivados , Fenilcetonuria Materna/tratamiento farmacológico , Adulto , Biopterinas/administración & dosificación , Biopterinas/farmacología , Femenino , Humanos , Embarazo , Resultado del Tratamiento
10.
Free Radic Biol Med ; 67: 426-36, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24316196

RESUMEN

Tetrahydrobiopterin (BH4) is important for normal brain development as congenital BH4 deficiencies manifest movement disorders at various childhood ages. BH4 transitions from very low levels in fetal brains to higher "adult" levels postnatally, with the highest levels in the thalamus. Maternal supplementation with the BH4 precursor sepiapterin reduces postnatal motor deficits and perinatal deaths after 40-min fetal hypoxia-ischemia (HI) at 70% gestation, suggesting that brain BH4 is important in improving function after HI. We tested the hypothesis that the intrinsically low concentrations of BH4 made fetal neurons vulnerable to added insults. Brains were obtained from naïve fetal rabbits or after 40-min HI, at 70% (E22) and 92% gestation (E29). Neuronal cultures were prepared from basal ganglia, cortex, and thalamus, regions with different intrinsic levels of BH4. Cultures were grown with or without added BH4 for 48h. Cell survival and mitochondrial function were determined by flow cytometry. At E22, thalamic cells had the lowest survival rate in a BH4-free milieu, in both control and HI groups, whereas BH4 supplementation ex vivo increased neuronal survival only in HI cells. Neuronal survival was similar in all regions without BH4 at E29. BH4 supplementation increased cell survival and cells with intact mitochondrial membrane potential, from basal ganglia and cortex, but not thalamus. After E29 HI, however, the benefit of BH4 was limited to cortical neurons. We conclude that BH4 is important for fetal neuronal survival after HI especially in the premature thalamus. Supplementation of BH4 has a greater benefit at an earlier gestational age.


Asunto(s)
Biopterinas/análogos & derivados , Hipoxia-Isquemia Encefálica/metabolismo , Neuronas/metabolismo , Fenilcetonurias/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Ganglios Basales/metabolismo , Ganglios Basales/patología , Biopterinas/metabolismo , Biopterinas/farmacología , Supervivencia Celular/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Susceptibilidad a Enfermedades , Femenino , Feto , Edad Gestacional , Hipoxia-Isquemia Encefálica/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Especificidad de Órganos , Fenilcetonurias/patología , Embarazo , Cultivo Primario de Células , Conejos , Tálamo/metabolismo , Tálamo/patología
11.
Mol Nutr Food Res ; 58(1): 101-16, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23740826

RESUMEN

L-Arginine (L-Arg) is a conditionally essential amino acid in the human diet. The most common dietary sources of L-Arg are meat, poultry and fish. L-Arg is the precursor for the synthesis of nitric oxide (NO); a key signaling molecule via NO synthase (NOS). Endogenous NOS inhibitors such as asymmetric-dimethyl-L-Arg inhibit NO synthesis in vivo by competing with L-Arg at the active site of NOS. In addition, NOS possesses the ability to be "uncoupled" to produce superoxide anion instead of NO. Reduced NO bioavailability may play an essential role in cardiovascular pathologies and metabolic diseases. L-Arg deficiency syndromes in humans involve endothelial inflammation and immune dysfunctions. Exogenous administration of L-Arg restores NO bioavailability, but it has not been possible to demonstrate, that L-Arg supplementation improved endothelial function in cardiovascular disease such as heart failure or hypertension. L-Arg supplementation may be a novel therapy for obesity and metabolic syndrome. The utility of l-Arg supplementation in the treatment of L-Arg deficiency syndromes remains to be established. Clinical trials need to continue to determine the optimal concentrations and combinations of L-Arg, with other protective compounds such as tetrahydrobiopterin (BH4 ), and antioxidants to combat oxidative stress that drives down NO production in humans.


Asunto(s)
Arginina/metabolismo , Sistema Cardiovascular/metabolismo , Suplementos Dietéticos , Óxido Nítrico Sintasa/metabolismo , Tejido Adiposo/metabolismo , Arginina/farmacología , Transporte Biológico , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Biopterinas/farmacología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Citrulina/farmacología , Dieta , Humanos
12.
Curr Opin Clin Nutr Metab Care ; 17(1): 61-8, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24136088

RESUMEN

PURPOSE OF REVIEW: The purpose is to discuss advances in the nutritional and pharmacological management of phenylketonuria (PKU). RECENT FINDINGS: Glycomacropeptide (GMP), a whey protein produced during cheese production, is a low-phenylalanine (phe) intact protein that represents a new dietary alternative to synthetic amino acids for people with PKU. Skeletal fragility is a long-term complication of PKU that based on murine research, appears to result from both genetic and nutritional factors. Skeletal fragility in murine PKU is attenuated with the GMP diet, compared with an amino acid diet, allowing greater radial bone growth. Pharmacologic therapy with tetrahydrobiopterin, acting as a molecular chaperone for phenylalanine hydroxylase, increases tolerance to dietary phe in some individuals. Large neutral amino acids inhibit phe transport across the intestinal mucosa and blood-brain barrier, and are most effective for individuals unable to comply with the low-phe diet. SUMMARY: Although a low-phe synthetic amino acid diet remains the mainstay of PKU management, new nutritional and pharmacological treatment options offer alternative approaches to maintain lifelong low phe concentrations. GMP medical foods provide an alternative to amino acid formula that may improve bone health, and tetrahydrobiopterin permits some individuals with PKU to increase tolerance to dietary phe. Further research is needed to characterize the long-term efficacy of these new approaches for PKU management.


Asunto(s)
Fenilcetonurias/dietoterapia , Fenilcetonurias/tratamiento farmacológico , Aminoácidos/administración & dosificación , Biopterinas/análogos & derivados , Biopterinas/farmacología , Huesos/efectos de los fármacos , Huesos/metabolismo , Caseínas/análisis , Caseínas/farmacología , Suplementos Dietéticos , Humanos , Proteínas de la Leche/análisis , Proteínas de la Leche/farmacología , Mutación , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/farmacología , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilalanina Hidroxilasa/genética , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Tirosina/metabolismo , Proteína de Suero de Leche
13.
Mol Med ; 18: 1221-30, 2012 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-23212846

RESUMEN

Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays essential roles in neovascularization. During limb ischemia, decreased NO bioavailability occurs secondary to increased oxidant stress, decreased L-arginine and tetrahydrobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), L-arginine and vitamin C acts synergistically to decrease oxidant stress, increase NO and thereby increase blood flow recovery after hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or L-arginine (alone or in combination) or chow supplemented with BH4 + L-arginine + vitamin C for 1 wk before induction of hindlimb ischemia. In the is-chemic hindlimb, cosupplementation with BH4 + L-arginine resulted in greater eNOS and phospho-eNOS (P-eNOS) expression, Ca(2+)-dependent NOS activity and NO concentration in the ischemic calf region (gastrocnemius), as well as greater NO concentration in the region of collateral arteries (gracilis). Rats receiving cosupplementation of BH4 + L-arginine led to greater recovery of foot perfusion and greater collateral enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + L-arginine regimen further increased these dependent variables. In addition, rats given all three supplements showed significantly less Ca(2+)-independent activity, less nitrotyrosine accumulation, greater glutathione (GSH)-to-glutathione disulfide (GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, co-supplementation with BH4 + L-arginine + vitamin C significantly increased blood flow recovery after hindlimb ischemia by reducing oxidant stress, increasing NO bioavailability, enlarging collateral arteries and reducing muscle necrosis. Oral cosupplementation of BH4, L-arginine and vitamin C holds promise as a biological therapy to induce collateral artery enlargement.


Asunto(s)
Arginina/farmacología , Ácido Ascórbico/farmacología , Biopterinas/análogos & derivados , Miembro Posterior/irrigación sanguínea , Isquemia/patología , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Arginina/administración & dosificación , Arginina/uso terapéutico , Ácido Ascórbico/administración & dosificación , Ácido Ascórbico/uso terapéutico , Biopterinas/administración & dosificación , Biopterinas/farmacología , Biopterinas/uso terapéutico , Calcio/metabolismo , Sinergismo Farmacológico , Miembro Posterior/efectos de los fármacos , Miembro Posterior/patología , Miembro Posterior/fisiopatología , Isquemia/tratamiento farmacológico , Isquemia/fisiopatología , Masculino , Modelos Biológicos , Músculos/efectos de los fármacos , Músculos/enzimología , Músculos/patología , Músculos/fisiopatología , Nitratos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitritos/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos
14.
Circ Res ; 111(6): 718-27, 2012 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-22798524

RESUMEN

RATIONALE: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOS). Oral BH4 supplementation preserves cardiac function in animal models of cardiac disease; however, the mechanisms underlying these findings are not completely understood. OBJECTIVE: To study the effect of myocardial transgenic overexpression of the rate-limiting enzyme in BH4 biosynthesis, GTP cyclohydrolase 1 (GCH1), on NOS activity, myocardial function, and Ca2+ handling. METHODS AND RESULTS: GCH1overexpression significantly increased the biopterins level in left ventricular (LV) myocytes but not in the nonmyocyte component of the LV myocardium or in plasma. The ratio between BH4 and its oxidized products was lower in mGCH1-Tg, indicating that a large proportion of the myocardial biopterin pool was oxidized; nevertheless, myocardial NOS1 activity was increased in mGCH1-Tg, and superoxide release was significantly reduced. Isolated hearts and field-stimulated LV myocytes (3 Hz, 35°C) overexpressing GCH1 showed a faster relaxation and a PKA-mediated increase in the PLB Ser16 phosphorylated fraction and in the rate of decay of the [Ca2+]i transient. RyR2 S-nitrosylation and diastolic Ca2+ leak were larger in mGCH1-Tg and ICa density was lower; nevertheless the amplitude of the [Ca2+]i transient and contraction did not differ between genotypes, because of an increase in the SR fractional release of Ca2+ in mGCH1-Tg myocytes. Xanthine oxidoreductase inhibition abolished the difference in superoxide production but did not affect myocardial function in either group. By contrast, NOS1 inhibition abolished the differences in ICa density, Ser16 PLB phosphorylation, [Ca2+]i decay, and myocardial relaxation between genotypes. CONCLUSIONS: Myocardial GCH1 activity and intracellular BH4 are a limiting factor for constitutive NOS1 and SERCA2A activity in the healthy myocardium. Our findings suggest that GCH1 may be a valuable target for the treatment of LV diastolic dysfunction.


Asunto(s)
Biopterinas/análogos & derivados , GTP Ciclohidrolasa/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Animales , Biopterinas/metabolismo , Biopterinas/farmacología , Calcio/metabolismo , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Femenino , GTP Ciclohidrolasa/genética , Corazón/efectos de los fármacos , Corazón/fisiología , Humanos , Immunoblotting , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Miocardio/citología , Miocardio/enzimología , Miocitos Cardíacos/enzimología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Superóxidos/metabolismo
15.
Am J Hypertens ; 25(10): 1050-4, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22673017

RESUMEN

BACKGROUND: We performed a pilot study to test the hypothesis that acute oral ingestion of tetrahydrobiopterin (BH(4)), a key cofactor modulating vascular nitric oxide (NO) synthase activity, improves large elastic artery stiffness with aging in men. METHODS: Healthy older (63 ± 2 years; n = 8) and young (age 25 ± 1 years; n = 6) men were studied 3 h after ingestion of BH(4) (10 mg·kg(-1) body weight) or placebo on separate days in a randomized, placebo-controlled, double-blind study. RESULTS: Baseline carotid artery compliance was 37% lower (0.17 ± 0.02 vs. 0.22 ± 0.02 mm/mm Hg·10(-1)) and ß-stiffness was 42% higher (7.3 ± 1.1 vs. 4.2 ± 0.5 AU) in the older men (both P < 0.05). BH(4) ingestion markedly increased circulating BH(4) concentrations in both groups (17-19-fold, P < 0.05), but increased compliance (+39% to 0.23 ± 0.02 mm/mm Hg·10(-1), P < 0.01) and decreased ß-stiffness index (-27% to 5.3 ± 0.7 AU, P < 0.01) only in the older men. BH(4) also reduced carotid systolic blood pressure (SBP) in the older men (P < 0.05). CONCLUSIONS: These preliminary results support the possibility that limited BH(4) bioavailability contributes to impaired carotid artery compliance in healthy older men. Further studies are needed to determine if increasing BH(4) bioavailability though oral BH(4) supplementation may have therapeutic efficacy for improving large elastic artery compliance and reducing central SBP with aging.


Asunto(s)
Biopterinas/análogos & derivados , Arterias Carótidas/fisiología , Adulto , Anciano , Biopterinas/farmacología , Arterias Carótidas/efectos de los fármacos , Adaptabilidad/efectos de los fármacos , Suplementos Dietéticos , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Rigidez Vascular/efectos de los fármacos
16.
Mol Pharmacol ; 82(3): 420-7, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22648973

RESUMEN

Tetrahydrobiopterin (BH4) is a major endogenous vasoprotective agent that improves endothelial function by increasing nitric oxide (NO) synthesis and scavenging of superoxide and peroxynitrite. Therefore, administration of BH4 is considered a promising therapy for cardiovascular diseases associated with endothelial dysfunction and oxidative stress. Here we report on a novel function of BH4 that might contribute to the beneficial vascular effects of the pteridine. Treatment of cultured porcine aortic endothelial cells with nitroglycerin (GTN) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) resulted in heme oxidation of soluble guanylate cyclase (sGC), as evident from diminished NO-induced cGMP accumulation that was paralleled by increased cGMP response to a heme- and NO-independent activator of soluble guanylate cyclase [4-([(4-carboxybutyl)[2-(5-fluoro-2-([4'-(trifluoromethyl)biphenyl-4-yl]methoxy)phenyl)ethyl]amino]methyl)benzoic acid (BAY 60-2770)]. Whereas scavenging of superoxide and/or peroxynitrite with superoxide dismutase, tiron, Mn(III)tetrakis(4-benzoic acid)porphyrin, and urate had no protective effects, supplementation of the cells with BH4, either by application of BH4 directly or of its precursors dihydrobiopterin or sepiapterin, completely prevented the inhibition of NO-induced cGMP accumulation by GTN and ODQ. Tetrahydroneopterin had the same effect, and virtually identical results were obtained with RFL-6 fibroblasts, suggesting that our observation reflects a general feature of tetrahydropteridines that is unrelated to NO synthase function and not limited to endothelial cells. Protection of sGC against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress.


Asunto(s)
Biopterinas/análogos & derivados , Guanilato Ciclasa/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Biopterinas/farmacología , Enfermedades Cardiovasculares/metabolismo , Células Cultivadas , GMP Cíclico/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Hemo/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Nitroglicerina/farmacología , Oxidación-Reducción/efectos de los fármacos , Ácido Peroxinitroso/metabolismo , Pterinas/farmacología , Guanilil Ciclasa Soluble , Superóxidos/metabolismo , Porcinos
17.
Hum Mutat ; 33(10): 1464-73, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22644647

RESUMEN

The Pah(enu1/enu2) (ENU1/2) mouse is a heteroallelic orthologous model displaying blood phenylalanine (Phe) concentrations characteristic of mild hyperphenylalaninemia. ENU1/2 mice also have reduced liver phenylalanine hydroxylase (PAH) protein content (∼20% normal) and activity (∼2.5% normal). The mutant PAH protein is highly ubiquitinated, which is likely associated with its increased misfolding and instability. The administration of a single subcutaneous injection of l-Phe (1.1 mg l-Phe/g body weight) leads to an approximately twofold to threefold increase of blood Phe and phenylalanine/tyrosine (Phe/Tyr) ratio, and a 1.6-fold increase of both nonubiquitinated PAH protein content and PAH activity. It also results in elevated concentrations of liver 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), potentially through the influence of Phe on GTP cyclohydrolase I and its feedback regulatory protein. The increased BH(4) content seems to stabilize PAH. Supplementing ENU1/2 mice with BH(4) (50 mg/kg/day for 10 days) reduces the blood Phe/Tyr ratio within the mild hyperphenylalaninemic range; however, PAH content and activity were not elevated. It therefore appears that BH(4) supplementation of ENU1/2 mice increases Phe hydroxylation levels through a kinetic rather than a chaperone stabilizing effect. By boosting blood Phe concentrations, and by BH(4) supplementation, we have revealed novel insights into the processing and regulation of the ENU1/2-mutant PAH.


Asunto(s)
Biopterinas/análogos & derivados , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/genética , Animales , Biopterinas/metabolismo , Biopterinas/farmacología , Modelos Animales de Enfermedad , Femenino , Hidroxilación , Masculino , Ratones , Ratones Mutantes , Fenilalanina/genética , Fenilalanina/metabolismo , Fenilalanina Hidroxilasa/metabolismo
18.
Mol Med ; 18: 676-84, 2012 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-22371305

RESUMEN

Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays an essential role in vascular remodeling of collateral arteries and perfusion recovery in response to hindlimb ischemia. In ischemic conditions, decreased NO bioavailability was observed because of increased oxidative stress, decreased L-arginine and tetrahydrobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), L-arginine, and vitamin C acts synergistically to decrease oxidative stress, increase nitric oxide and improve blood flow in response to acute hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or L-arginine (alone or in combination) or chow supplemented with BH4 + L-arginine + vitamin C for 1 wk before induction of unilateral hindlimb ischemia. Cosupplementation with BH4 + L-arginine resulted in greater eNOS expression, Ca²âº-dependent NOS activity and NO concentration in gastrocnemius from the ischemic hindlimb, as well as greater recovery of foot perfusion and more collateral artery enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + L-arginine regimen did further increase these dependent variables, although only the increase in eNOS expression reached statistical significances. In addition, rats given all three supplements demonstrated significantly less Ca²âº-independent activity, less nitrotyrosine accumulation, greater glutathione:glutathione disulfide (GSH:GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, cosupplementation with BH4 + L-arginine + vitamin C significantly increased vascular perfusion after hindlimb ischemia by increasing eNOS activity and reducing oxidative stress and tissue necrosis. Oral cosupplementation of L-arginine, BH4 and vitamin C holds promise as a biological therapy to induce collateral artery enlargement.


Asunto(s)
Antioxidantes/farmacología , Arginina/farmacología , Ácido Ascórbico/farmacología , Biopterinas/análogos & derivados , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Flujo Sanguíneo Regional/efectos de los fármacos , Administración Oral , Animales , Antioxidantes/administración & dosificación , Arginina/administración & dosificación , Ácido Ascórbico/administración & dosificación , Biopterinas/administración & dosificación , Biopterinas/farmacología , Calcio/metabolismo , Sinergismo Farmacológico , Activación Enzimática , Miembro Posterior/irrigación sanguínea , Miembro Posterior/efectos de los fármacos , Isquemia/tratamiento farmacológico , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Necrosis , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Sprague-Dawley
19.
J Cereb Blood Flow Metab ; 32(5): 792-804, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22234336

RESUMEN

Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH(4)) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH(4) supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH(4) by GTP-CH induced by insulin promoted NOS uncoupling.


Asunto(s)
Circulación Cerebrovascular/efectos de los fármacos , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Insulina/farmacología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Biopterinas/análogos & derivados , Biopterinas/farmacología , Arterias Cerebrales/metabolismo , Arterias Cerebrales/fisiopatología , GTP Ciclohidrolasa , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes/metabolismo , Insulina/metabolismo , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Vasodilatación/efectos de los fármacos
20.
Aging Cell ; 10(3): 429-37, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21276184

RESUMEN

We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD) (71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ∼100-300% greater and SOD activity was ∼50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.


Asunto(s)
Acetilcolina/farmacología , Envejecimiento , Arterias Carótidas/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Nitrito de Sodio/farmacología , Vasodilatadores/farmacología , Acetofenonas/farmacología , Administración Oral , Animales , Biopterinas/análogos & derivados , Biopterinas/farmacología , Óxidos N-Cíclicos/farmacología , Citocinas/biosíntesis , Elasticidad/efectos de los fármacos , Endotelio Vascular/citología , Humanos , Masculino , Ratones , Miografía , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Óxido Nítrico/farmacología , Estrés Oxidativo/efectos de los fármacos , Nitrito de Sodio/metabolismo , Marcadores de Spin , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Vasodilatación/efectos de los fármacos
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