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1.
J Periodontal Res ; 58(5): 1006-1019, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37482954

RESUMO

OBJECTIVE: To determine whether Bifidobacterium animalis subspecies lactis HN019 (B. lactis HN019) can reduce the sequelae of experimental periodontitis (EP) in rats modulating systemic parameters. BACKGROUND: This study evaluated the effects of probiotic therapy (PROB) in the prevention of local and systemic damage resulting from EP. METHODS: Forty-eight rats were allocated into four groups: C (control), PROB, EP, and EP-PROB. PROB (1 × 1010 CFU/mL) administration lasted 8 weeks and PE was induced on the 7th week by placing ligature on the animals' lower first molars. All animals were euthanized in the 9th week of the experiment. Biomolecular analyses, RT-PCR, and histomorphometric analyses were performed. The data obtained were analyzed statistically (ANOVA, Tukey, p < .05). RESULTS: The EP group had higher dyslipidemia when compared to the C group, as well as higher levels of insulin resistance, proteinuria levels, percentages of systolic blood pressure, percentage of fatty hepatocytes in the liver, and expression of adipokines was up-regulated (LEPR, NAMPT, and FABP4). All these parameters (except insulin resistance, systolic blood pressure, LEPR and FABP4 gene expression) were reduced in the EP-PROB group when compared to the EP group. The EP group had lower villus height and crypt depth, as well as a greater reduction in Bacteroidetes and a greater increase in Firmicutes when compared to the EP-PROB group. Greater alveolar bone loss was observed in the EP group when compared to the EP-PROB group. CONCLUSION: Bifidobacterium lactis HN019 can reduce the sequelae of EP in rats modulating intestinal parameters, attenuating expression of lipogenic genes and hepatic steatosis.


Assuntos
Bifidobacterium animalis , Fígado Gorduroso , Resistência à Insulina , Periodontite , Probióticos , Ratos , Animais , Bifidobacterium animalis/fisiologia , Probióticos/uso terapêutico , Periodontite/prevenção & controle , Mucosa Intestinal
2.
Curr Issues Mol Biol ; 44(12): 6333-6345, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36547093

RESUMO

Anesthesia with propofol is frequently associated with hypotension. The TRPA1 gene contributes to the vasodilator effect of propofol. Hypotension is crucial for anesthesiologists because it is deleterious in the perioperative period. We tested whether the TRPA1 gene polymorphisms or haplotypes interfere with the hypotensive responses to propofol. PCR-determined genotypes and haplotype frequencies were estimated. Nitrite, nitrates, and NOx levels were measured. Propofol induced a more expressive lowering of the blood pressure (BP) without changing nitrite or nitrate levels in patients carrying CG+GG genotypes for the rs16937976 TRPA1 polymorphism and AG+AA genotypes for the rs13218757 TRPA1 polymorphism. The CGA haplotype presented the most remarkable drop in BP. Heart rate values were not impacted. The present exploratory analysis suggests that TRPA1 genotypes and haplotypes influence the hypotensive responses to propofol. The mechanisms involved are probably other than those related to NO bioavailability. With better genetic knowledge, planning anesthesia with fewer side effects may be possible.

3.
Eur J Clin Pharmacol ; 77(6): 869-877, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33410970

RESUMO

PURPOSE: Propofol anesthesia is usually accompanied by hypotensive responses, which are at least in part mediated by nitric oxide (NO). Arginase I (ARG1) and arginase II (ARG2) compete with NO synthases for their common substrate L-arginine, therefore influencing the NO formation. We examined here whether ARG1 and ARG2 genotypes and haplotypes affect the changes in blood pressure and NO bioavailability in response to propofol. METHODS: Venous blood samples were collected from 167 patients at baseline and after 10 min of anesthesia with propofol. Genotypes were determined by polymerase chain reaction. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. RESULTS: We found that patients carrying the AG + GG genotypes for the rs3742879 polymorphism in ARG2 gene and the ARG2 GC haplotype show lower increases in nitrite levels and lower decreases in blood pressure after propofol anesthesia. On the other hand, subjects carrying the variant genotypes for the rs10483801 polymorphism in ARG2 gene show more intense decreases in blood pressure (CA genotype) and/or higher increases in nitrite levels (CA and AA genotypes) in response to propofol. CONCLUSION: Our results suggest that ARG2 variants affect the hypotensive responses to propofol, possibly by modifying NO bioavailability. TRIAL REGISTRATION: NCT02442232.


Assuntos
Anestésicos Intravenosos/efeitos adversos , Arginase/genética , Hipotensão/induzido quimicamente , Óxido Nítrico/metabolismo , Propofol/efeitos adversos , Adulto , Idoso , Anestésicos Intravenosos/farmacocinética , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Nitritos/sangue , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Propofol/farmacocinética
4.
Nitric Oxide ; 74: 65-73, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29378249

RESUMO

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources.


Assuntos
Ácido Ascórbico/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Nitritos/administração & dosagem , Nitritos/farmacologia , Administração Oral , Animais , Hipertensão/induzido quimicamente , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar
5.
Nitric Oxide ; 75: 77-84, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29496565

RESUMO

Propofol anesthesia is usually accompanied by hypotension, which is at least in part related to enhanced endothelial nitric oxide synthase (NOS3)-derived NO bioavailability. We examined here whether NOS3 polymorphisms (rs2070744, 4b/4a VNTR, rs3918226 and rs1799983) and haplotypes affect the changes in blood pressure and NO bioavailability induced by propofol. Venous blood samples were collected from 168 patients at baseline and after 10 min of anesthesia with propofol 2 mg/kg administered intravenously by bolus injection. Genotypes were determined by polymerase chain reaction and haplotype frequencies were estimated. Nitrite concentrations were measured by using an ozone-based chemiluminescence assay, while NOx (nitrites + nitrates) levels were determined by using the Griess reaction. We found that CT + TT genotypes for the rs3918226 polymorphism, the ba + aa genotypes for the 4b/4a VNTR and the CTbT haplotype were associated with lower decreases in blood pressure and lower increases in nitrite levels after propofol anesthesia. On the other hand, the TCbT and CCbT haplotypes were associated with more intense decreases in blood pressure and higher increases in nitrite levels in response to propofol. Our results suggest that NOS3 polymorphisms and haplotypes influence the hypotensive responses to propofol, possibly by affecting NO bioavailability.


Assuntos
Pressão Sanguínea/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico/farmacocinética , Polimorfismo de Nucleotídeo Único , Propofol/farmacologia , Adulto , Idoso , Anestésicos Intravenosos/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Nitritos/sangue
7.
Nitric Oxide ; 40: 52-9, 2014 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-24878382

RESUMO

Nitrite-derived nitric oxide (NO) formation exerts antihypertensive effects. Because NO inhibits angiotensin converting enzyme (ACE) activity, we carried a comprehensive series of experiments in rats to test the hypothesis that sodium nitrite exerts antihypertensive effects by inhibiting ACE. We examined whether sodium nitrite (15 mg/kg; or vehicle; by gavage): (I) attenuates the pressor responses to angiotensin I at doses of 0.03, 0.1, 0.3, 1, 3, and 10 µg/kg intravenously; (II) attenuates the acute hypertension induced by L-NAME (100 mg/kg; or vehicle; by gavage); (III) attenuates the chronic hypertension induced by L-NAME (1 g/L in drinking water; or vehicle) administered for 6 weeks; (IV) attenuates the hypertension in the 2 kidney-1 clip (2K1C) chronic hypertension model. Blood samples were collected at the end of each study and plasma angiotensin converting enzyme (ACE) activity was measured with a fluorimetric assay using Hippuryl-His-Leu as substrate. ACE inhibitors were used as positive controls. Plasma nitrite concentrations were measured by ozone-based reductive chemiluminescence. The in vitro effects of sodium nitrite (0, 1, 3, 10, 30, 100 µmol/L) on plasma ACE activity were also determined. We found that sodium nitrite did not affect the pressor responses to angiotensin I. Moreover, while sodium nitrite exerted significant antihypertensive effects in acute and chronic hypertension models, no significant effects on plasma ACE activity were found. In vitro experiments showed no effects of sodium nitrite on plasma ACE activity. This is the first study to demonstrate that the acute and chronic antihypertensive effects of sodium nitrite are not associated with significant inhibition of circulating ACE activity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos/farmacologia , Peptidil Dipeptidase A/metabolismo , Nitrito de Sódio/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertensão/sangue , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Masculino , NG-Nitroarginina Metil Éster , Peptidil Dipeptidase A/sangue , Ratos , Ratos Wistar , Nitrito de Sódio/química , Relação Estrutura-Atividade
8.
Sci Adv ; 10(11): eadg9278, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38478616

RESUMO

Canonical Wnt and sphingosine-1-phosphate (S1P) signaling pathways are highly conserved systems that contribute to normal vertebrate development, with key consequences for immune, nervous, and cardiovascular system function; despite these functional overlaps, little is known about Wnt/ß-catenin-S1P cross-talk. In the vascular system, both Wnt/ß-catenin and S1P signals affect vessel maturation, stability, and barrier function, but information regarding their potential coordination is scant. We report an instance of functional interaction between the two pathways, including evidence that S1P receptor 1 (S1PR1) is a transcriptional target of ß-catenin. By studying vascular smooth muscle cells and arterial injury response, we find a specific requirement for the ß-catenin carboxyl terminus, which acts to induce S1PR1, and show that this interaction is essential for vascular remodeling. We also report that pharmacological inhibition of the ß-catenin carboxyl terminus reduces S1PR1 expression, neointima formation, and atherosclerosis. These findings provide mechanistic understanding of how Wnt/ß-catenin and S1P systems collaborate during vascular remodeling and inform strategies for therapeutic manipulation.


Assuntos
Aterosclerose , Cateninas , Lisofosfolipídeos , Esfingosina/análogos & derivados , Humanos , Cateninas/metabolismo , beta Catenina/metabolismo , Remodelação Vascular , Transdução de Sinais
9.
Biochem Pharmacol ; 212: 115571, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37127250

RESUMO

The unsatisfactory rates of adequate blood pressure control among patients receiving antihypertensive treatment calls for new therapeutic strategies to treat hypertension. Several studies have shown that oral sodium nitrite exerts significant antihypertensive effects, but the mechanisms underlying these effects remain unclear. While these mechanisms may involve nitrite-derived S-nitrosothiols, their implication in important alterations associated with hypertension, such as aberrant α1-adrenergic vasoconstriction, has not yet been investigated. Here, we examined the effects of oral nitrite treatment on vascular responses to the α1-adrenergic agonist phenylephrine in two-kidney, one clip (2K1C) hypertensive rats and investigated the potential underlying mechanisms. Our results show that treatment with oral sodium nitrite decreases blood pressure and prevents the increased α1-adrenergic vasoconstriction in 2K1C hypertensive rats. Interestingly, we found that these effects require vascular protein S-nitrosylation, and to investigate the specific S-nitrosylated proteins we performed an unbiased nitrosoproteomic analysis of vascular smooth muscle cells (VSMCs) treated with the nitrosylating compound S-nitrosoglutathione (GSNO). This analysis revealed that GSNO markedly increases the nitrosylation of calcium/calmodulin-dependent protein kinase II γ (CaMKIIγ), a multifunctional protein that mediates the α1-adrenergic receptor signaling. This result was associated with reduced α1-adrenergic receptor-mediated CaMKIIγ activity in VSMCs. We further tested the relevance of these findings in vivo and found that treatment with oral nitrite increases CaMKIIγ S-nitrosylation and blunts the increased CaMKIIγ activity induced by phenylephrine in rat aortas. Collectively, these results are consistent with the idea that oral sodium nitrite treatment increases vascular protein S-nitrosylation, including CaMKIIγ as a target, which may ultimately prevent the increased α1-adrenergic vasoconstriction induced by hypertension. These mechanisms may help to explain the antihypertensive effects of oral nitrite and hold potential implications in the therapy of hypertension and other cardiovascular diseases associated with abnormal α1-adrenergic vasoconstriction.


Assuntos
Hipertensão , Nitrito de Sódio , Ratos , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Vasoconstrição , Cálcio , Adrenérgicos/farmacologia , Adrenérgicos/uso terapêutico , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/prevenção & controle , Fenilefrina/farmacologia , Receptores Adrenérgicos/uso terapêutico , Receptores Adrenérgicos alfa 1/metabolismo
10.
J Periodontol ; 94(11): 1363-1375, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37057371

RESUMO

BACKGROUND: This study evaluated the systemic (intestine and adipose tissue) and local (periodontal tissues) impact of probiotic therapy in rats with metabolic syndrome (MS) associated or not with periodontitis (PE). METHODS: Forty-eight rats received a high-fat diet for induction of MS for 16 weeks. They were subdivided into groups with (+) and without (-) PE, receiving (*) or not (**) receiving probiotics (PROB): MS (-**), MSP (-*), MSPE (+**), and MSPEP (+*). PROB administration (Bifidobacterium animalis subsp. lactis HN019) started on the 8th week of the study and PE was induced on the 14th week by placing ligature on the animals' lower first molars. Euthanasia occurred in the 16th week. Biomolecular, immunoenzymatic assays, and histomorphometric analyses were performed. The data obtained were statistically analyzed (ANOVA, Tukey, p < 0.05). RESULTS: The MSPEP group exhibited reduced alveolar bone loss when compared with the MSPE group, as well as lower levels of hepatic steatosis and proteinuria (p < 0.05). In the intestinal environment, the MSPE group exhibited significantly lower villus height and crypt depth, as well as a greater increase in Bacillota when compared with the MSPEP group (p < 0.05). The MSPEP group showed lower adipokine gene expression (LEPR, NAMPT, and FABP4) in adipose tissue than the MSPE group (p < 0.05). CONCLUSION: The probiotic B. lactis HN019 reduced the severity of experimental periodontitis and modulated the expression of lipogenic genes and intestinal morphological and microbiological parameters in rats with MS.


Assuntos
Bifidobacterium animalis , Síndrome Metabólica , Periodontite , Probióticos , Ratos , Animais , Síndrome Metabólica/complicações , Periodontite/terapia , Periodontite/metabolismo , Intestinos/microbiologia , Probióticos/uso terapêutico , Probióticos/farmacologia
11.
J Periodontol ; 93(2): e1-e12, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34374081

RESUMO

BACKGROUND: This study evaluated the effects of Bifidobacterium animalis subsp. lactis HN019 (B. lactis HN019) in the development of periodontitis (PE), associated or not with metabolic syndrome, (MS) in rats. METHODS: Ninety-six rats were grouped according to a food protocol: high-fat diet for induction of MS or standard diet for the control groups (C). They were subdivided into groups with (+) and without (-) PE, receiving (*) or not (**) probiotic (PROB): C-**, CP-*, PE+**, PEP+*, MS- MSP-*, MSPE+**, and MSPEP+*. PROB administration started on the eighth week of the study and PE was induced on the 14th week by placing ligature on the animals' lower first molars. Euthanasia occurred in the 16th week. Biomolecular analyzes, immunoenzymatic assays, and microtomographic analyses were performed. The data obtained were analyzed statistically (P < 0.05). RESULTS: The PEP and MSPEP groups showed lower levels of alveolar bone loss when compared with the PE and MSPE groups, respectively (P < 0.05). The immunoenzymatic analysis showed higher levels of interleukin (IL)-1ß and a higher receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio in the MSPE group when compared with the MSPEP group (P < 0.05). The PEP group showed lower levels of tumor necrosis factor (TNF)-α and IL-6 when compared with the PE group. The use of PROB attenuated dyslipidemia parameters in animals with MS, with or without PE. CONCLUSION: B. lactis HN019 reduced more significantly the severity of PE in rats with MS, modulating both systemic metabolic and immunoinflammatory parameters in periodontal tissues.


Assuntos
Perda do Osso Alveolar , Bifidobacterium animalis , Síndrome Metabólica , Periodontite , Probióticos , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/metabolismo , Perda do Osso Alveolar/prevenção & controle , Animais , Bifidobacterium animalis/metabolismo , Síndrome Metabólica/complicações , Osteoprotegerina/análise , Periodontite/metabolismo , Probióticos/farmacologia , Probióticos/uso terapêutico , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
12.
Basic Clin Pharmacol Toxicol ; 130(2): 277-287, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34825477

RESUMO

Anaesthesia with propofol is frequently associated with hypotension, which is at least partially attributable to increased nitric oxide (NO) formation derived from the activation of protein kinase C (PKC)/endothelial NO synthase (NOS3) axis. In this cross-sectional study, we tested whether PRKCA (which encodes PKCα) polymorphisms, or haplotypes, and interactions among PRKCA and NOS3 polymorphisms affect the hypotensive responses to propofol. We collected venous blood samples from 164 patients before and 10 min after propofol administration. Genotypes were determined by PCR and haplotype frequencies were estimated. Nitrite and NOx (nitrites+nitrates) levels were measured by using an ozone-based chemiluminescence assay and the Griess reaction, respectively. We used multifactor dimensionality reduction to test interactions among PRKCA and NOS3 polymorphisms. Propofol promoted enhanced blood pressure-lowering effects and increased nitrite levels in subjects carrying GA + AA genotypes for the rs16960228 and TC + CC genotypes for the rs1010544 PRKCA polymorphisms, and the CCG haplotype. Moreover, genotypes for the rs1010544 PRKCA polymorphism were associated with higher or lower blood pressure decreases in response to propofol depending on the genotypes for the rs2070744 NOS3 polymorphism. Our findings suggest that PRKCA genotypes and haplotypes impact the hypotensive responses to propofol, possibly by modifying NO bioavailability, and that PRKCA-NOS3 interactions modify the blood pressure-lowering effects of propofol.


Assuntos
Hipotensão/induzido quimicamente , Óxido Nítrico Sintase Tipo III/genética , Propofol/efeitos adversos , Proteína Quinase C-alfa/genética , Adulto , Idoso , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/efeitos adversos , Estudos Transversais , Feminino , Genótipo , Haplótipos , Humanos , Hipotensão/genética , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Propofol/administração & dosagem
13.
Chem Biol Interact ; 349: 109658, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34543659

RESUMO

Nitric oxide (NO) metabolites have physiological and pharmacological importance and increasing their tissue concentrations may result in beneficial effects. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) has antioxidant properties that may improve NO bioavailability. Moreover, tempol increases oral nitrite-derived gastric formation of S-nitrosothiols (RSNO). We hypothesized that pretreatment with tempol may further increase tissue concentrations of NO-related species after oral nitrite administration and therefore we carried out a time-dependent analysis of how tempol affects the concentrations of NO metabolites in different tissues after oral nitrite administration to rats. NO metabolites (nitrate, nitrite and RSNO) were assessed by ozone-based reductive chemiluminescence assays in plasma, stomach, aorta, heart and liver samples obtained from anesthetized rats at baseline conditions and 15 min, 30 min, 2 h or 24 h after oral nitrite (15 mg/kg) was administered to rats pretreated with tempol (18 mg/kg) or vehicle 15 min prior to nitrite administration. Aortic protein nitrosation was assessed by resin-assited capture (SNO-RAC) method. We found that pretreatment with tempol transiently enhanced nitrite-induced increases in nitrite, RSNO and nitrate concentrations in the stomach and in the plasma (all P < 0.05), particularly for 15-30 min, without affecting aortic protein nitrosation. Pretreatment with tempol enhanced nitrite-induced increases in nitrite (but not RSNO or nitrate) concentrations in the heart (P < 0.05). In contrast, tempol attenuated nitrite-induced increases in nitrite, RSNO or nitrate concentrations in the liver. These findings show that pretreatment with tempol affects oral nitrite-induced changes in tissue concentrations of NO metabolites depending on tissue type and does not increase nitrite-induced vascular nitrosation. These results may indicate that oral nitrite therapy aiming at achieving increased nitrosation of cardiovascular targets requires appropriate doses of nitrite and is not optimized by tempol.


Assuntos
Antioxidantes/farmacologia , Óxidos N-Cíclicos/farmacologia , Óxido Nítrico/metabolismo , Nitritos/administração & dosagem , Administração Oral , Animais , Masculino , Nitratos/sangue , Nitritos/sangue , Ratos , Ratos Wistar , Marcadores de Spin
14.
Eur J Pharmacol ; 907: 174314, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245745

RESUMO

L-arginine supplementation increases nitric oxide (NO) formation and bioavailability in hypertension. We tested the possibility that many effects of L-arginine are mediated by increased formation of NO and enhanced nitrite, nitrate and nitrosylated species concentrations, thus stimulating the enterosalivary cycle of nitrate. Those effects could be prevented by antiseptic mouthwash. We examined how the derangement of the enterosalivary cycle of nitrate affects the improvement of endothelial dysfunction (assessed with isolated aortic ring preparation), the antihypertensive (assessed by tail-cuff blood pressure measurement) and the antioxidant effects (assessed with the fluorescent dye DHE) of L-arginine in two-kidney, one-clip hypertension model in rats by using chlorhexidine to decrease the number of oral bacteria and to decrease nitrate reductase activity assessed from the tongue (by ozone-based chemiluminiscence assay). Nitrite, nitrate and nitrosylated species concentrations were assessed (ozone-based chemiluminiscence). Chlorhexidine mouthwash reduced the number of oral bacteria and tended to decrease the nitrate reductase activity from the tongue. Antiseptic mouthwash blunted the improvement of the endothelial dysfunction and the antihypertensive effects of L-arginine, impaired L-arginine-induced increases in plasma nitrite and nitrosylated species concentrations, and blunted L-arginine-induced increases in aortic nitrate concentrations and vascular antioxidant effects. Our results show for the first time that the vascular and antihypertensive effects of L-arginine are prevented by antiseptic mouthwash. These findings show an important new mechanism that should be taken into consideration to explain how the use of antibacterial mouth rinse may affect arterial blood pressure and the risk of developing cardiovascular and other diseases.


Assuntos
Anti-Hipertensivos , Animais , Clorexidina , Nitritos , Ratos
15.
Redox Biol ; 38: 101769, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33126056

RESUMO

Nitrate and nitrite supplement deficient endogenous nitric oxide (NO) formation. While these anions may generate NO, recent studies have shown that circulating nitrite levels do not necessarily correlate with the antihypertensive effect of oral nitrite administration and that formation of nitrosylated species (RXNO) in the stomach is critically involved in this effect. This study examined the possibility that RXNO formed in the stomach after oral nitrite administration promotes target protein nitrosylation in the vasculature, inhibits vasoconstriction and the hypertensive responses to angiotensin II. Our results show that oral nitrite treatment enhances circulating RXNO concentrations (measured by ozone-based chemiluminescence methods), increases aortic protein kinase C (PKC) nitrosylation (measured by resin-assisted capture SNO-RAC method), and reduces both angiotensin II-induced vasoconstriction (isolated aortic ring preparation) and hypertensive (in vivo invasive blood pressure measurements) effects implicating PKC nitrosylation as a key mechanism for the responses to oral nitrite. Treatment of rats with the nitrosylating compound S-nitrosoglutathione (GSNO) resulted in the same effects described for oral nitrite. Moreover, partial depletion of thiols with buthionine sulfoximine prevented PKC nitrosylation and the blood pressure effects of oral nitrite. Further confirming a role for PKC nitrosylation, preincubation of aortas with GSNO attenuated the responses to both angiotensin II and to a direct PKC activator, and this effect was attenuated by ascorbate (reverses GSNO-induced nitrosylation). GSNO-induced nitrosylation also inhibited the increases in Ca2+ mobilization in angiotensin II-stimulated HEK293T cells expressing angiotensin type 1 receptor. Together, these results are consistent with the idea that PKC nitrosylation in the vasculature may underlie oral nitrite treatment-induced reduction in the vascular and hypertensive responses to angiotensin II.


Assuntos
Angiotensina II , Nitritos , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos , Células HEK293 , Humanos , Óxido Nítrico , Proteína Quinase C , Ratos
16.
Biochem Pharmacol ; 177: 113940, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224135

RESUMO

Proton pump inhibitors (PPI) are suppressors of gastric acid secretion (SGAS) that decrease gastric nitric oxide (NO) formation from nitrite and increase the cardiovascular risk. However, H2 receptor antagonists (H2RA) are considered safer than PPIs. We challenged this notion and hypothesized that both omeprazole (PPI) and ranitidine (H2RA) attenuate the responses to oral nitrite because both drugs increase gastric pH and therefore could decrease nitrite-derived NO formation in the stomach. We examined the blood pressure responses to oral nitrite in hypertensive rats treated with omeprazole, ranitidine, or vehicle. Chemiluminensce-based assays were used to measure gastric NO formation, plasma and gastric concentrations of nitrite, nitrate, and nitrosylated species (RXNO) to clarify the mechanism involved in the effects of SGAS on the responses to oral nitrite. Both drugs increased gastric pH, impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. These findings were reproduced in a second study using sodium acetate buffers at pH 3.5, 4.5, and 5.5 to mimic gastric pH found with vehicle, ranitidine, and omeprazole, respectively. Increasing gastric pH impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. Our results clearly indicate that SGAS impair nitrite-induced gastric formation of NO and vasoactive RXNO in a pH-dependent manner, thus resulting in impaired responses to oral nitrite. These findings may have several clinical implications, particularly to patients with cardiovascular diseases.


Assuntos
Anti-Hipertensivos/administração & dosagem , Ácido Gástrico/química , Ácido Gástrico/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Hipertensão/tratamento farmacológico , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Ranitidina/administração & dosagem , Nitrito de Sódio/administração & dosagem , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Mucosa Gástrica/metabolismo , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Masculino , Nitratos/análise , Nitratos/sangue , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Nitritos/análise , Nitritos/sangue , Ratos , Ratos Wistar , Resultado do Tratamento
17.
Free Radic Biol Med ; 152: 43-51, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32151744

RESUMO

Nitrite and nitrate are considered nitric oxide (NO) storage pools. The assessment of their tissue concentrations may improve our understanding of how they attenuate pathophysiological mechanisms promoting disease. We hypothesized that significant differences exist when the tissue concentrations of nitrite, nitrate, and nitrosylated species (RXNO) are compared among different tissues, particularly when nitrite is administered orally because nitrite generates various NO-related species in the stomach. We studied the different time-dependent changes in plasma and tissue concentrations of nitrite, nitrate, and RXNO after oral nitrite 15 mg/kg was administered rats, which were euthanized 15, 30, 60, 120, 240, 480 or 1440 min after nitrite administration. A control group received water. Arterial blood samples were collected and the rats were perfused with a PBS solution containing NEM/DTPA to prevent the destruction of RXNO. After perfusion, heart, aorta, mesenteric artery, brain, stomach, liver and femoral muscle were harvested and immediately stored at -70°C until analyzed for their nitrite, nitrate and RXNO contents using an ozone-based reductive chemiluminescence assay. While nitrite administration did not increase aortic nitrite or nitrate concentrations for at least 60 min, both aorta and mesenteric vessels stored nitrite from 8 to 24 h after its administration and their tissue concentrations increased from 10 to 40-fold those found in plasma. In contrast, the other studied tissues showed only transient increases in the concentrations of these NO metabolites, including RXNO. The differences among tissues may reflect differences in mechanisms regulating cellular influx of nitrite. These findings have important pharmacological and clinical implications.


Assuntos
Óxido Nítrico , Nitritos , Administração Oral , Animais , Nitratos , Ratos , Estômago
18.
Free Radic Biol Med ; 115: 10-17, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29138017

RESUMO

Propofol anesthesia is usually accompanied by hypotension. Studies have shown that the hypotensive effects of propofol increase in patients treated with angiotensin-converting enzyme inhibitors (ACEi). Given that both propofol and ACEi affect nitric oxide (NO) signaling, the present study tested the hypothesis that ACEi treatment induces pronounced hypotensive responses to propofol by increasing NO bioavailability. In this study we evaluated 65 patients, divided into three groups: hypertensive patients chronically treated with ACEi (HT-ACEi; n = 21), hypertensive patients treated with other antihypertensive drugs instead of ACEi, such as angiotensin II receptor blockers, ß-blockers or diuretics (HT; n = 21) and healthy normotensive subjects (NT; n = 23). Venous blood samples were collected at baseline and after 10min of anesthesia with propofol 2mg/kg administrated intravenously by bolus injection. Hemodynamic parameters were recorded at each blood sample collection. Nitrite levels were determined by using an ozone-based chemiluminescence assay, while NOx (nitrites+nitrates) levels were measured by using the Griess reaction. Additionally, experimental approaches were used to validate our clinical findings. Higher decreases in blood pressure after propofol anesthesia were observed in HT-ACEi group as compared with those found in NT and HT groups. Consistently, rats treated with the ACEi enalapril showed more intense hypotensive responses to propofol. The hypotensive effects of propofol were associated with increased NO production in both clinical and experimental approaches. Enhanced increases in nitrite levels after propofol anesthesia were observed in HT-ACEi patients compared with NT and HT groups. Accordingly, rats treated with enalapril showed increased vascular NO formation after propofol anesthesia compared with rats receiving vehicle. Our data show that ACEi enhance the hypotensive responses to propofol anesthesia and increase nitrite concentrations. These findings suggest that increased NO bioavailability may account for the enhanced hypotensive effects of propofol in ACEi-treated patients.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Hipotensão/metabolismo , Óxido Nítrico/metabolismo , Propofol/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Anestesia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Animais , Diuréticos/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Enalapril/uso terapêutico , Hemodinâmica , Humanos , Hipotensão/etiologia , Masculino , Propofol/efeitos adversos , Ratos , Ratos Wistar , Transdução de Sinais , Regulação para Cima
19.
Free Radic Biol Med ; 101: 226-235, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27769921

RESUMO

The nitric oxide (NO•) metabolites nitrite and nitrate exert antihypertensive effects by mechanisms that involve gastric formation of S-nitrosothiols. However, while the use of antiseptic mouthwash (AM) is known to attenuate the responses to nitrate by disrupting its enterosalivary cycle, there is little information about whether AM attenuates the effects of orally administered nitrite. We hypothesized that the antihypertensive effects of orally administered nitrite would not be prevented by AM because, in contrast to oral nitrate, oral nitrite could promote S-nitrosothiols formation in the stomach without intereference by AM. Chronic effects of oral nitrite or nitrate were studied in two-kidney, one-clip (2K1C) hypertensive rats (and normotensive controls) treated with AM (or vehicle) once/day. We found that orally administered nitrite exerts antihypertensive effects that were not affected by AM. This finding contrasts with lack of antihypertensive responses to oral nitrate in 2K1C hypertensive rats treated with AM. Nitrite and nitrate treatments increased plasma nitrites, nitrates, and S-nitrosothiols concentrations. However, while treatment with AM attenuated the increases in plasma nitrite concentrations after both nitrite and nitrate treatments, AM attenuated the increases in S-nitrosothiols in nitrate-treated rats, but not in nitrite-treated rats. Moreover, AM attenuated vascular S-nitrosylation (detected by the SNO-RAC method) after nitrate, but not after nitrite treatment. Significant correlations were found between the hypotensive responses and S-nitrosothiols, and vascular S-nitrosylation levels. These results show for the first time that oral nitrite exerts antihypertensive effects notwithstanding the fact that antiseptic mouthwash disrupts the enterosalivary circulation of nitrate. Our results support a major role for S-nitrosothiols formation resulting in vascular S-nitrosylation as a key mechanism for the antihypertensive effects of both oral nitrite and nitrate.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Antissépticos Bucais/farmacologia , Nitratos/farmacologia , Nitritos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Nitrosação , Ratos , Ratos Wistar , Artéria Renal/cirurgia , Obstrução da Artéria Renal/cirurgia , S-Nitrosotióis/metabolismo
20.
Redox Biol ; 5: 340-346, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26119848

RESUMO

Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin-angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8-isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Hipertensão/tratamento farmacológico , Nitrito de Sódio/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona/toxicidade , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/patologia , Peróxidos Lipídicos/sangue , Masculino , NADPH Oxidases/metabolismo , Nitritos/sangue , Óxidos de Nitrogênio/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Nitrito de Sódio/farmacologia , Xantina Oxidase/metabolismo
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