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BACKGROUND: Green leafy vegetables (GLV) contain inorganic nitrate, an anion with potential prebiotic effects on the oral microbiome. However, it remains unclear whether GLV and pharmacological supplementation [potassium nitrate (PN)] with a nitrate salt induce similar effects on the oral microbiome. OBJECTIVES: This study aimed to compare the effect of GLV with PN supplementation on the oral microbiome composition and salivary biomarkers in individuals with high blood pressure. METHODS: Seventy individuals were randomly allocated to 3 different groups to follow a 5-wk dietary intervention. Group 1 consumed 300 mg/d of nitrate in form of GLV. Group 2 consumed pills with 300 mg/d of PN and low-nitrate vegetables. Group 3 consumed pills with potassium chloride (placebo: PLAC) and low-nitrate vegetables. The oral microbiome composition and salivary biomarkers of oral health were analyzed before and after the dietary intervention. RESULTS: The GLV and PN groups showed similar microbial changes, probably nitrate-dependent, including an increase in the abundance of Neisseria, Capnocytophaga, Campylobacter species, and a decrease in Veillonella, Megasphaera, Actinomyces, and Eubacterium species after the treatment. Increased abundance of Rothia species, and reduced abundance of Streptococcus, Prevotella, Actinomyces, and Mogibacterium species were observed in the GLV group, which could be nitrate-independent. GLV and PN treatments increased salivary pH, but only GLV treatment showed an increase in the salivary buffering capacity and a reduction of lactate. CONCLUSION: The combination of nitrate-dependent and nitrate-independent microbial changes in the GLV group has a stronger effect to potentially improve oral health biomarkers compared with PN.
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Nitric oxide (NO) from endothelial NO synthase (eNOS) importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NOS system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species which can transfer between proteins, partition into a hydrophobic phase, and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and non-classical pathways for NO generation in the cardiovascular system, and how these can be modulated for therapeutic purposes. Significance Statement After four decades of intensive research, questions persist about the transduction and control of NO synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Non-classical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.
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Prolonged use of antibacterial mouthwash is linked to an increased risk of systemic disease. We aimed to investigate if disturbing the oral microbiota would impact the lower gut microbiome with functional effects in diet-induced obesity. Mice were exposed to oral chlorhexidine and fed a Western diet (WD). Food intake and weight gain were monitored, and metabolic function, blood pressure, and microbiota were analyzed. Chlorhexidine reduced the number of viable bacteria in the mouth and lowered species richness in the gut but with proportional enrichment of some bacteria linked to metabolic pathways. In mice fed a Western diet, chlorhexidine reduced weight gain, body fat, steatosis, and plasma insulin without changing caloric intake, while increasing colon triglycerides and proteins, suggesting reduced absorption of these nutrients. The mechanisms behind these effects as well as the link between the oral microbiome and small intestinal function need to be pinpointed. While the short-term effects of chlorhexidine in this model appear beneficial, potential long-term disruptions in the oral and gut microbiota and possible malabsorption should be considered.
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Microbioma Gastrointestinal , Ratones , Animales , Antisépticos Bucales/farmacología , Dieta Occidental/efectos adversos , Clorhexidina/farmacología , Dieta Alta en Grasa/efectos adversos , Aumento de Peso , Tejido Adiposo , Nutrientes , Ratones Endogámicos C57BLRESUMEN
Nanomaterials are currently being explored as novel antimicrobial agents. In this study, we first investigated the ability of two-dimensional (2D) molybdenum disulfide (MoS2) nanosheets to trigger neutrophil extracellular traps (NETs) using neutrophil-differentiated HL-60 cells as well as primary human peripheral blood neutrophils. We then addressed whether the MoS2 nanosheets themselves function as antibacterial agents. We found that MoS2 and Na2MoO4 both triggered NETs, as evidenced by the quantification of neutrophil elastase (NE) activity and immunofluorescence staining of extracellular NE, as well as scanning electron microscopy. The release of NETs was found to be nitric oxide (NO)-dependent. We also found that the MoS2 nanosheets but not the soluble salt prompted acellular NO production in the presence of NaNO2. The acellular generation of NO, suggestive of nanozyme properties of the MoS2 nanosheets, was demonstrated by electron paramagnetic resonance analysis. Electrochemical analysis using cyclic voltammetry confirmed the redox transition of the MoS2 nanosheets. Finally, MoS2 nanosheets inhibited the growth of Escherichia coli in the presence of sodium nitrate. Taken together, MoS2 nanosheets triggered cellular effects as well as acellular antibacterial effects, and we provided evidence for nitrite reductase-like properties of MoS2.
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Molibdeno , Óxido Nítrico , Humanos , Molibdeno/farmacología , Molibdeno/química , Antibacterianos/farmacología , Antibacterianos/química , Disulfuros/farmacología , Disulfuros/químicaRESUMEN
Goitre is commonly caused by a lack of iodine in the diet. This condition is particularly prevalent in high-altitude areas where iodine deficiency is common. Here we speculate that inorganic nitrate, the oxidation product of nitric oxide, which is generated endogenously at very high levels in highlanders, further increases the risk of goitre and thyroid dysfunction in this population by inhibiting the transport of iodide into the thyroid gland. Indeed, it is well-known that nitrate and iodide compete for such transport. While iodine scarcity is a primary cause of goitre, the excessive nitrate levels in highlanders may further hinder iodide transport, exacerbating the problem.
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Reduced nitric oxide (NO) bioactivity in red blood cells (RBCs) is critical for augmented myocardial ischemia-reperfusion injury in type 2 diabetes. This study identified the nature of "NO bioactivity" by stimulating the intracellular NO receptor soluble guanylyl cyclase (sGC) in RBCs. sGC stimulation in RBCs from patients with type 2 diabetes increased export of cyclic guanosine monophosphate from RBCs and activated cardiac protein kinase G, thereby attenuating ischemia-reperfusion injury. These results provide novel insight into RBC signaling by identifying cyclic guanosine monophosphate from RBC as a mediator of protection against cardiac ischemia-reperfusion injury induced by sGC stimulation in RBCs.
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BACKGROUND: The efficacy of dietary nitrate supplementation to lower blood pressure (BP) in pregnant women is highly variable. We aimed to investigate whether differences in oral microbiota profiles and oral nitrate-reducing capacity may explain interindividual differences in BP lowering following nitrate supplementation. METHODS: Participants recruited for this study were both pregnant and nonpregnant women, with or without hypertension (n=55). Following an overnight fast, plasma, saliva, and tongue scraping samples were collected for measurement of nitrate/nitrite concentrations, oral NaR (nitrate reductase) activity, and microbiota profiling using 16S rRNA gene sequencing. Baseline BP was measured, followed by the administration of a single dose of dietary nitrate (400 mg nitrate in 70 mL beetroot juice). Post-nitrate intervention, plasma and salivary nitrate/nitrite concentrations and BP were determined 2.5 hours later. RESULTS: Women with hypertension had significantly lower salivary nitrite concentrations (P=0.006) and reduced abundance of the nitrate-reducing taxa Veillonella(P=0.007) compared with normotensive women. Oral NaR activity was not significantly different in pregnant versus nonpregnant women (P=0.991) but tended to be lower in hypertensive compared with normotensive women (P=0.099). Oral NaR activity was associated with both baseline diastolic BP (P=0.050) and change in diastolic BP following acute nitrate intake (P=0.01, adjusted for baseline BP). CONCLUSIONS: The abundance and activity of oral nitrate-reducing bacteria impact both baseline BP as well as the ability of dietary nitrate supplementation to lower BP. Strategies to increase oral nitrate-reducing capacity could lower BP and enhance the efficacy of dietary nitrate supplementation, in pregnancy as well as in nonpregnant adults. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03930693.
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Beta vulgaris , Hipertensión , Adulto , Humanos , Femenino , Embarazo , Nitratos , Presión Sanguínea , Nitritos , ARN Ribosómico 16S , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Bacterias , Suplementos DietéticosRESUMEN
Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.
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Eritrocitos , Óxido Nítrico , Hemo , Transducción de SeñalRESUMEN
Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.
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Cardiotónicos , GMP Cíclico , Eritrocitos , Guanilil Ciclasa Soluble , Animales , Ratones , Hipoxia , Miocitos Cardíacos , Nitratos , Óxido Nítrico , Ratas , HumanosRESUMEN
Distance running requires a high absolute oxygen consumption, while for a breath-hold diver the opposite is preferable. We compared physiological exercise parameters and mitochondrial function in a competitive triathlete with those seen in an accomplished breath-hold diver and notice some remarkable differences, possibly explaining why both have become successful.
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Buceo , Liebres , Tortugas , Animales , Humanos , Buceo/fisiología , Contencion de la Respiración , Consumo de Oxígeno/fisiologíaRESUMEN
BACKGROUND & AIMS: Nitric oxide bioactivity (NO) from endothelial NO synthase (eNOS) importantly contributes to the maintenance of vascular homeostasis, and reduced eNOS activity has been associated with cardiovascular disease. Emerging evidence suggests interaction(s) between red blood cells (RBCs) and the endothelium in vascular control; however, the specific role of RBC eNOS is less clear. We aimed to investigate the hypothesis that a lack of RBC eNOS induces endothelial dysfunction. METHODS & RESULTS: RBCs from global eNOS knockout (KO) and wildtype (WT) mice were co-incubated ex vivo overnight with healthy mouse aortic rings, followed by functional and mechanistic analyses of endothelium-dependent and independent relaxations. RBCs from eNOS KO mice induced endothelial dysfunction and vascular oxidative stress, whereas WT RBC did not. No differences were observed for endothelium-independent relaxations. This eNOS KO RBC-induced endothelial dysfunctional phenotype was prevented by concomitant co-incubation with reactive oxygen species scavenger (TEMPOL), arginase inhibitor (nor-NOHA), NO donor (detaNONOate) and NADPH oxidase 4 (NOX4) inhibitor. Moreover, vessels from endothelial cell-specific arginase 1 KO mice were resistant to eNOS KO-RBC-induced endothelial dysfunction. Finally, in mice aortae co-incubated with RBCs from women with preeclampsia, we observed a significant reduction in endothelial function compared to when using RBCs from healthy pregnant women or from women with uncomplicated gestational hypertension. CONCLUSIONS: RBCs from mice lacking eNOS, and patients with preeclampsia, induce endothelial dysfunction in adjacent blood vessels. Thus, RBC-derived NO bioactivity acts to prevent induction of vascular oxidative stress occurring via RBC NOX4-derived ROS in a vascular arginase-dependent manner. Our data highlight the intrinsic protective role of RBC-derived NO bioactivity in preventing the damaging potential of RBCs. This provides novel insight into the functional relationship between RBCs and the vasculature in health and cardiovascular disease, including preeclampsia.
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Enfermedades Cardiovasculares , Preeclampsia , Enfermedades Vasculares , Ratones , Femenino , Humanos , Embarazo , Animales , Endotelio Vascular/metabolismo , Enfermedades Cardiovasculares/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Arginasa/genética , Arginasa/metabolismo , Preeclampsia/metabolismo , Estrés Oxidativo , Óxido Nítrico/metabolismo , Eritrocitos/metabolismoRESUMEN
The surprising discovery that the diatomic gas nitric oxide (NO) is generated by mammalian cells and serves to regulate a multitude of physiological processes has continued to fascinate biologists for almost four decades. The biochemistry of NO is complex, and novel insights into the control of NO biosynthesis and mechanisms of signal transduction are continuously emerging. NO is a key regulator of cardiovascular function, metabolism, neurotransmission, immunity, and more, and aberrant NO signaling is a central feature of many major disorders including cardiovascular disease, diabetes, and cancer. Here, we discuss the basics of NO biology emphasizing recent advances in the field including novel means of increasing NO bioactivity with therapeutic and nutritional implications.
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Enfermedades Cardiovasculares , Nitritos , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Fenómenos Fisiológicos Cardiovasculares , Humanos , Mamíferos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Nitritos/uso terapéutico , Transducción de SeñalRESUMEN
Arginase 1 (Arg1) is a ubiquitous enzyme belonging to the urea cycle that catalyzes the conversion of l-arginine into l-ornithine and urea. In endothelial cells (ECs), Arg1 was proposed to limit the availability of l-arginine for the endothelial nitric oxide synthase (eNOS) and thereby reduce nitric oxide (NO) production, thus promoting endothelial dysfunction and vascular disease. The role of EC Arg1 under homeostatic conditions is in vivo less understood. The aim of this study was to investigate the role of EC Arg1 on the regulation of eNOS, vascular tone, and endothelial function under normal homeostatic conditions in vivo and ex vivo. By using a tamoxifen-inducible EC-specific gene-targeting approach, we generated EC Arg1 KO mice. Efficiency and specificity of the gene targeting strategy was demonstrated by DNA recombination and loss of Arg1 expression measured after tamoxifen treatment in EC only. In EC Arg1 KO mice we found a significant decrease in Arg1 expression in heart and lung ECs and in the aorta, however, vascular enzymatic activity was preserved likely due to the presence of high levels of Arg1 in smooth muscle cells. Moreover, we found a downregulation of eNOS expression in the aorta, and a fully preserved systemic l-arginine and NO bioavailability, as demonstrated by the levels of l-arginine, l-ornithine, and l-citrulline as well as nitrite, nitrate, and nitroso-species. Lung and liver tissues from EC Arg1 KO mice showed respectively increase or decrease in nitrosyl-heme species, indicating that the lack of endothelial Arg1 affects NO bioavailability in these organs. In addition, EC Arg1 KO mice showed fully preserved acetylcholine-mediated vascular relaxation in both conductance and resistant vessels but increased phenylephrine-induced vasoconstriction. Systolic, diastolic, and mean arterial pressure and cardiac performance in EC Arg1 KO mice were not different from the wild-type littermate controls. In conclusion, under normal homeostatic conditions, lack of EC Arg1 expression is associated with a down-regulation of eNOS expression but a preserved NO bioavailability and vascular endothelial function. These results suggest that a cross-talk exists between Arg1 and eNOS to control NO production in ECs, which depends on both L-Arg availability and EC Arg1-dependent eNOS expression.
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Arginasa , Óxido Nítrico Sintasa de Tipo III , Animales , Arginasa/genética , Arginasa/metabolismo , Arginina/metabolismo , Regulación hacia Abajo , Células Endoteliales/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ornitina , Tamoxifeno/metabolismo , Urea/metabolismoRESUMEN
Red blood cells (RBCs) were shown to transport and release nitric oxide (NO) bioactivity and carry an endothelial NO synthase (eNOS). However, the pathophysiological significance of RBC eNOS for cardioprotection in vivo is unknown. Here we aimed to analyze the role of RBC eNOS in the regulation of coronary blood flow, cardiac performance, and acute myocardial infarction (AMI) in vivo. To specifically distinguish the role of RBC eNOS from the endothelial cell (EC) eNOS, we generated RBC- and EC-specific knock-out (KO) and knock-in (KI) mice by Cre-induced inactivation or reactivation of eNOS. We found that RBC eNOS KO mice had fully preserved coronary dilatory responses and LV function. Instead, EC eNOS KO mice had a decreased coronary flow response in isolated perfused hearts and an increased LV developed pressure in response to elevated arterial pressure, while stroke volume was preserved. Interestingly, RBC eNOS KO showed a significantly increased infarct size and aggravated LV dysfunction with decreased stroke volume and cardiac output. This is consistent with reduced NO bioavailability and oxygen delivery capacity in RBC eNOS KOs. Crucially, RBC eNOS KI mice had decreased infarct size and preserved LV function after AMI. In contrast, EC eNOS KO and EC eNOS KI had no differences in infarct size or LV dysfunction after AMI, as compared to the controls. These data demonstrate that EC eNOS controls coronary vasodilator function, but does not directly affect infarct size, while RBC eNOS limits infarct size in AMI. Therefore, RBC eNOS signaling may represent a novel target for interventions in ischemia/reperfusion after myocardial infarction.
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Animales , Eritrocitos , Corazón , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infarto del Miocardio/genética , Daño por Reperfusión Miocárdica/genética , Óxido Nítrico , Óxido Nítrico Sintasa de Tipo III/genética , VasodilatadoresRESUMEN
Nitric oxide (NO) contributes to maintaining normal cardiovascular and renal function. This bioactive signalling molecule is generally formed enzymatically by NO synthase in the vascular endothelium. NO bioactivity can also be attributed to dietary intake of inorganic nitrate, which is abundant in our diet, especially in green leafy vegetables and beets. Ingested nitrate is reduced to nitrite by oral commensal bacteria and further to NO systemically. Previous studies have shown that dialysis, by means of removing nitrate and nitrite from the body, can reduce NO bioactivity. Hence, dietary intervention approaches aimed to boost the nitrate-nitrite-NO pathway may be of benefit in dialysis patients. The purpose of this study was to examine the kinetics of plasma nitrate and nitrite after a single intake of nitrate-rich concentrated beetroot juice (BJ) in adult hemodialysis (HD) patients and in age-matched healthy volunteers (HV). Eight HD patients and seven HV participated in this single center, randomized, single-blind, placebo-controlled, crossover study. Each participant received a sequential single administration of active BJ (70 mL, 400 mg nitrate) and placebo BJ (70 mL, 0 mg nitrate) in a random order separated by a washout period of seven days. For the kinetic analysis, blood samples were collected at different time-points before and up to 44 h after BJ intake. Compared with placebo, active BJ significantly increased plasma nitrate and nitrite levels both in HD patients and HV. The area under the curve and the maximal concentration of plasma nitrate, but not of nitrite, were significantly higher in HD patients as compared with HV. In both groups, active BJ ingestion did not affect blood pressure or plasma potassium levels. Both BJs were well tolerated in all participants with no adverse events reported. Our data provide useful information in planning dietary nitrate supplementation efficacy studies in patients with reduced NO bioactivity.
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Beta vulgaris , Nitritos , Adulto , Antioxidantes/análisis , Presión Sanguínea , Estudios Cruzados , Suplementos Dietéticos , Jugos de Frutas y Vegetales/análisis , Humanos , Cinética , Nitratos , Óxido Nítrico/metabolismo , Diálisis Renal , Método Simple CiegoRESUMEN
BACKGROUND: Renal fibrosis, associated with oxidative stress and nitric oxide (NO) deficiency, contributes to the development of chronic kidney disease and renal failure. As major energy source in maintaining renal physiological functions, tubular epithelial cells with decreased fatty acid oxidation play a key role in renal fibrosis development. Inorganic nitrate, found in high levels in certain vegetables, can increase the formation and signaling by bioactive nitrogen species, including NO, and dampen oxidative stress. In this study, we evaluated the therapeutic value of inorganic nitrate treatment on development of kidney fibrosis and investigated underlying mechanisms including regulation of lipid metabolism in tubular epithelial cells. METHODS: Inorganic nitrate was supplemented in a mouse model of complete unilateral ureteral obstruction (UUO)-induced fibrosis. Inorganic nitrite was applied in transforming growth factor ß-induced pro-fibrotic cells in vitro. Metformin was administrated as a positive control. Fibrosis, oxidative stress and lipid metabolism were evaluated. RESULTS: Nitrate treatment boosted the nitrate-nitrite-NO pathway, which ameliorated UUO-induced renal dysfunction and fibrosis in mice, represented by improved glomerular filtration and morphological structure and decreased renal collagen deposition, pro-fibrotic marker expression, and inflammation. In human proximal tubule epithelial cells (HK-2), inorganic nitrite treatment prevented transforming growth factor ß-induced pro-fibrotic changes. Mechanistically, boosting the nitrate-nitrite-NO pathway promoted AMP-activated protein kinase (AMPK) phosphorylation, improved AKT-mediated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) activity and restored mitochondrial function. Accordingly, treatment with nitrate (in vivo) or nitrite (in vitro) decreased lipid accumulation, which was associated with dampened NADPH oxidase activity and mitochondria-derived oxidative stress. CONCLUSIONS: Our findings indicate that inorganic nitrate and nitrite treatment attenuates the development of kidney fibrosis by targeting oxidative stress and lipid metabolism. Underlying mechanisms include modulation of AMPK and AKT-PGC1α pathways.
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Enfermedades Renales , Obstrucción Ureteral , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Femenino , Fibrosis , Humanos , Riñón/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Obstrucción Ureteral/metabolismoRESUMEN
Current knowledge regarding mechanisms underlying cardiovascular complications in patients with COVID-19 is limited and urgently needed. We shed light on a previously unrecognized mechanism and unravel a key role of red blood cells, driving vascular dysfunction in patients with COVID-19 infection. We establish the presence of profound and persistent endothelial dysfunction in vivo in patients with COVID-19. Mechanistically, we show that targeting reactive oxygen species or arginase 1 improves vascular dysfunction mediated by red blood cells. These translational observations hold promise that restoring the redox balance in red blood cells might alleviate the clinical complications of COVID-19-associated vascular dysfunction.
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Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 µM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 µM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle.
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Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Arterias Mesentéricas/efectos de los fármacos , Nitratos/uso terapéutico , Donantes de Óxido Nítrico/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Antihipertensivos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Hipertensión/metabolismo , Masculino , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/metabolismo , Canales de Potasio/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Guanilil Ciclasa Soluble/metabolismo , Vasodilatadores/metabolismo , Xantina Deshidrogenasa/metabolismoRESUMEN
RATIONALE: Dietary nitrate and nitrite have a notoriously bad reputation because of their proposed association with disease, in particular cancer. However, more recent lines of research have challenged this dogma suggesting that intake of these anions also possess beneficial effects after in vivo conversion to the vital signaling molecule nitric oxide. Such effects include improvement in cardiovascular, renal and metabolic function, which is partly mediated via reduction of oxidative stress. A recent study even indicates that low dose of dietary nitrite extends life span in fruit flies. METHODS: In this study, 200 middle-aged Wistar rats of both sexes were supplemented with nitrate or placebo in the drinking water throughout their remaining life and we studied longevity, biochemical markers of disease, vascular reactivity along with careful determination of the cause of death. RESULTS: Dietary nitrate did not affect life span or the age-dependent changes in markers of oxidative stress, kidney and liver function, or lipid profile. Ex vivo examination of vascular function, however, showed improvements in endothelial function in rats treated with nitrate. Neoplasms were not more common in the nitrate group. CONCLUSION: We conclude that chronic treatment with dietary nitrate does not affect life span in rats nor does it increase the incidence of cancer. In contrast, vascular function was improved by nitrate, possibly suggesting an increase in health span.