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1.
Expert Opin Investig Drugs ; 29(1): 49-61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31778609

RESUMO

Introduction: Pharmacotherapy for the acute respiratory distress syndrome (ARDS) has been tested in preclinical and clinical studies. However, to date, no pharmacological interventions have proven effective. This may be attributed to lack of proper identification of different ARDS phenotypes.Areas covered: We designed inclusive search strings and searched four bibliographic databases (Cochrane Database of Systematic Reviews, PubMed, Web of Science, and clinicaltrials.gov) to identify relevant research. Search results were mainly restricted to papers published from 2009 through 2019. ARDS is a heterogeneous syndrome, and its different phenotypes - defined according to clinical, radiological, and biological parameters - may affect response to therapy. The most promising pharmacological approaches to date have been based on ARDS pathophysiology. They focus on reducing inflammation and pulmonary edema, promoting selective vasodilation, and repairing alveolar epithelial and endothelial cells.Expert opinion: Pharmacotherapeutic approaches targeting ARDS pathophysiology have failed to exert beneficial effects. Personalized medicine targeting the different ARDS phenotypes has emerged as an option to improve survival. Identification of specific ARDS patient phenotypes that respond to specific therapies seems to be the most important challenge for the next decade. Additional research is warranted before personalized medicine approaches can be applied at bedside for ARDS patients.


Assuntos
Medicina de Precisão/métodos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Fenótipo , Edema Pulmonar/tratamento farmacológico , Edema Pulmonar/fisiopatologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Vasodilatação/efeitos dos fármacos
2.
Mayo Clin Proc ; 94(12): 2455-2466, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806099

RESUMO

OBJECTIVE: To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia-peripheral arterial tonometry (RH-PAT) from the index finger. RESULTS: The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11). CONCLUSION: Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02086526.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Feminino , Humanos , Manometria , Síndrome do Ovário Policístico/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
3.
JAMA ; 322(23): 2288-2289, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31846001
4.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683362

RESUMO

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Assuntos
Acetilcolina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Oxigenação Hiperbárica , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal , Sistema Enzimático do Citocromo P-450/fisiologia , Primers do DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Oxigenação Hiperbárica/métodos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Vasodilatação/fisiologia
5.
Kardiologiia ; 59(9S): 42-50, 2019 Jul 23.
Artigo em Russo | MEDLINE | ID: mdl-31644416

RESUMO

AIM: The study assesses the effects of therapy based on the use of telmisartan in patients with arterial hypertension and stable angina on the clinical and functional indicators of the cardiovascularvascular system. MATERIAL AND METHODS: 52 patients with a combination of arterial hypertension (AH) I and II stages and coronary artery disease II with the mean age 63.5 ± 5.4 years (79% males and 21% of females) were enrolled in the trial. The duration of AH and CAD were 17.5±3.8 and 12.5±3.1 accordingly. All patients took a daily 80 mg dose of telmisartan. The efficacy of treatment was estimated in 3,6 and 12 months. RESULTS: The use of telmisartan in complex treatment of high-risk patients with AH has led to decreasing blood pressure to the target level, increasing exercise tolerance (walking the distance from 315.5 m to 410.2 m in 6 minutes). 12 months of therapy based on telmisartan showed significant decrease in left hy­ pertrophy ventricle (LV myocardial mass index on average by 10.4%), a decrease in the total duration of depression ST segment from 9.6±2.9 to 2.7±1.5 mm and a decrease in the depth of depression from 1.5±0.3 mm to 0.3±0.09 mm, with a trend towards decrease in the number of episodes of ST-segment depression, as well as the absence of a significant change in heart rate. After 12 months of en­ dothelium-dependent vasodilation therapy, the condition of 31 (60%) patients improved, and 18 (35%) patients showed the tendency to improvement. The tests with reactive hyperemia conducted after 12 months of treatment revealed decreased linear velocity of blood flow in the brachial artery on average by 17%. CONCLUSION: The use of telmisartan in complex therapy improves the quality of life according to the EQ-VAS questionnaire by 25 points after 12 months of therapy, contributes to lowering blood pressure in 96% of patients, reduc­ ing myocardial hypertrophy, endothelial dysfunction and severity of ischemic manifestations (reducing the need for nitroglycerin intake to an average of 0,5 inhalations, as well as a decrease in the ST segment depression of 40% after 12 months of therapy).


Assuntos
Hipertensão/tratamento farmacológico , Telmisartan/uso terapêutico , Idoso , Pressão Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Vasodilatação
6.
Sheng Li Xue Bao ; 71(5): 783-791, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646332

RESUMO

Circadian rhythms widely exist in living organisms, and they are regulated by the biological clock. Growing evidence has shown that circadian rhythms are tightly related to the physiological function of the cardiovascular system, including blood pressure, heart rate, metabolism of cardiomyocytes, function of endothelial cells, and vasoconstriction and vasodilation. In addition, disruption of circadian rhythms has been considered as one of the important risk factors for cardiovascular diseases, such as myocardial infarction. This review summarizes the recent research advances in the relationship between circadian clock and cardiovascular diseases, hoping to improve treatment strategies for patients with cardiovascular diseases according to the theory of biological clock.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Relógios Circadianos , Ritmo Circadiano , Pressão Sanguínea , Células Endoteliais/citologia , Frequência Cardíaca , Humanos , Miócitos Cardíacos/metabolismo , Vasoconstrição , Vasodilatação
7.
Gen Physiol Biophys ; 38(6): 505-512, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31588917

RESUMO

In a previous study, we produced antibodies from rats immunized with human umbilical vein endothelial cells (HUVECs) and determined the vascular function of the monoclonal antibodies. However, unanswered question remains still about their role in vascular function. The current study explored vasoreactivity, in particular, focusing on the vascular contractility of a functional antibody against proteins expressed on the plasma membrane of HUVECs developed in a previous study. Among the antibodies developed, A-7 significantly attenuated endothelium-dependent vasorelaxation in response to acetylcholine (ACh) but not to sodium nitroprusside or histamine. In addition, the A-7 antibody did not affect norepinephrine-stimulated contraction in both endothelium-intact and -denuded aorta. Immunocytochemical and immunoblotting analyses showed that A-7 attenuated ACh-increased expression of ACh receptor on the plasma membrane of HUVECs. These findings suggest that the monoclonal A-7 antibody may act as an inhibitor of endothelium-dependent vasorelaxation, probably in part via downregulation of ACh receptor expression.


Assuntos
Células Endoteliais , Veias Umbilicais , Vasodilatação , Animais , Anticorpos Monoclonais , Endotélio Vascular , Humanos , Óxido Nítrico , Ratos , Receptores Colinérgicos
8.
Clin Exp Rheumatol ; 37 Suppl 119(4): 97-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31573479

RESUMO

OBJECTIVES: The fingers, toes, and tips of the nose and ears have specialised structural and functional features for thermoregulation, and are the most common areas of Raynaud's phenomenon in systemic sclerosis. Digital thermal monitoring (DTM) of vascular reactivity assesses Doppler ultrasound hyperemic, low frequency, blood velocity of radial artery and fingertip vascular function. Flow mediated dilation (FMD) is an indirect measure of endothelial function, perfusion, and vasodilator ability. In this study, we investigated the cross-sectional correlation of FMD and DTM variables to inform an optimised noninvasive study of SSc endothelial function. A student's T-test was used to compare means of DTM across binary variables. METHODS: Consented SSc registry patients were included in this analysis. The subjects were prepared for FMD and DTM per standardised guidelines. The SSc clinical features were recorded. Spearman's Rank Correlation was used to assess the strength of a relationship FMD and DTM variables. RESULTS: Thirty-four SSc subjects had FMD and DTM performed on the same day. Relative (0.42, p=<0.02), absolute FMD (0.41, p<0.02), and shear rate (0.32, p<0.07) were weakly, but significantly correlated with the DTM. Reactive hyperemia (-0.44, p=0.000) was weakly inversely, but significantly related with DTM. Baseline diameter and flow were not significantly related to the DTM. CONCLUSIONS: This non-invasive study of SSc endothelial function suggests that macrocirculation (including relative and absolute FMD, shear rate, and peak hyperemia) and microcirculatory thermoregulation (characterised by DTM) are significantly correlated, thus warrants further prospective study.


Assuntos
Microcirculação/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Escleroderma Sistêmico , Pele/irrigação sanguínea , Artéria Braquial , Estudos Transversais , Dilatação , Endotélio Vascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/fisiopatologia , Vasodilatação
9.
Clin Interv Aging ; 14: 1579-1587, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564840

RESUMO

Background: Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose: The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (KCa2.3) channel signaling in this process. Methods: Male Sprague-Dawley rats aged 19-21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results: We found that TRPV4 and KCa2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or KCa2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and KCa2.3-mediated EDHF responses. Conclusion: These results suggest an important role for the TRPV4-KCa2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.


Assuntos
Fatores Biológicos/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Doenças Cardiovasculares/fisiopatologia , Endotélio Vascular/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Vasodilatação/fisiologia
10.
Fitoterapia ; 139: 104365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647954

RESUMO

As a folk medicine, Phlomis likiangensis is traditionally used in China to activate collaterals and protect cardiovascular system. We hypothesized that the beneficial effects of Phlomis likiangensis may be related to vasodilatation. In the present study, twelve known iridoid glucosides (1-12) were isolated from Phlomis likiangensis. The vasodilatory effects and the underlying mechanisms of the main components (iridoid glucosides) of Phlomis likiangensis on rat aortic rings were investigated. The result showed that iridoid glucosides significantly increased the vasodilatation in rat aortic rings, which was abolished by removing the endothelium of the vessels or by eliminating the generation of nitric oxide. Finally, the structure-activity relationship of compounds 1-12 was also speculated. Our findings provide the first evidence that the iridoid glucosides of Phlomis likiangensis may be the pharmacodynamic basis for its traditional efficacy.


Assuntos
Glucosídeos Iridoides/farmacologia , Phlomis/química , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , China , Células Endoteliais/efeitos dos fármacos , Técnicas In Vitro , Glucosídeos Iridoides/química , Masculino , Estrutura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Plantas Medicinais/química , Ratos , Ratos Sprague-Dawley , Rizoma/química , Relação Estrutura-Atividade , Vasodilatação , Vasodilatadores/química
11.
Plast Reconstr Surg ; 144(4): 669e-681e, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568315

RESUMO

BACKGROUND: Physiologic studies show that tissue perfusion increases during moderate amounts of tissue compression. This is attributed to sensory nerves initiating a vasodilatory cascade referred to as pressure-induced vasodilation. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies investigating perfusion during pressure exposure longer than 10 minutes. Retrieved studies were assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. Results were pooled with random effects models. The body of evidence was rated using the Office of Health Assessment and Translation approach. RESULTS: Twenty-nine articles were included, of which 19 articles were included in meta-analyses. The evidence indicates that moderate amounts of tissue compression have the capacity to increase perfusion in healthy humans by 46 percent (95 percent CI, 30 to 62 percent). Using the Office of Health Assessment and Translation approach, the authors found a high level of confidence in the body of evidence. Pressure-induced vasodilation blockade was associated with increased pressure ulcer formation. Pressure-induced vasodilation was impaired by neuropathy and by the drugs diclofenac and amiloride. CONCLUSIONS: This systematic review and meta-analysis indicates that healthy humans have the capacity to increase local perfusion in response to mechanical stress resulting from tissue compression. Because pressure-induced vasodilation is mediated by sensory nerves, pressure-induced vasodilation emphasizes the importance of sensory innervation for durable tissue integrity. Pressure-induced vasodilation impairment seems to provide a complementary explanation for the susceptibility of neuropathic tissues to pressure-induced lesions.


Assuntos
Lesão por Pressão/etiologia , Vasodilatação , Humanos , Pressão , Vasodilatação/fisiologia
12.
Adv Exp Med Biol ; 1161: 219-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562632

RESUMO

Accumulating evidence suggests that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) offer protection against vascular inflammation, neuroinflammation, hypertension, and thrombosis. Recently, biochemical studies have demonstrated that these benefits are partially mediated by their conversion to ω-3 endocannabinoid epoxide metabolites. These lipid metabolites originate from the epoxidation of ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by cytochrome P450 (CYP) epoxygenases to form epoxydocosapentaenoic acid-ethanolamides (EDP-EAs) and epoxyeicosatetraenoic acid-ethanolamides (EEQ-EAs), respectively. The EDP-EAs and EEQ-EAs are endogenously produced in rat brain and peripheral organs. Additionally, EDP-EAs and EEQ-EAs dose-dependently decrease pro-inflammatory IL-6 cytokine and increased anti-inflammatory IL-10 cytokine. Furthermore, the EEQ-EAs and EDP-EAs attenuate angiogenesis and cell migration in cancer cells, induce vasodilation in bovine coronary arteries, and reciprocally regulate platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides represent a new class of dual acting molecules that display unique pharmacological properties.


Assuntos
Endocanabinoides , Compostos de Epóxi , Ácidos Graxos Ômega-3 , Animais , Anti-Inflamatórios/metabolismo , Endocanabinoides/metabolismo , Compostos de Epóxi/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Humanos , Vasodilatação , Vasodilatadores/metabolismo
13.
J Vasc Res ; 56(6): 320-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550717

RESUMO

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artérias Mesentéricas/metabolismo , Comunicação Parácrina , Receptores Adrenérgicos beta 3/metabolismo , Vasoconstrição , Vasodilatação , Tecido Adiposo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Estimulação Elétrica , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
14.
Hypertension ; 74(5): 1104-1112, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31522618

RESUMO

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO3 dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na+/HCO3- cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, P<0.05) in response to NaHCO3 (44 mmol/L). Whereas, NaCl solution containing the same Na+ concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; P<0.05) in the presence of NaHCO3, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 µM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; P<0.005) and increases NO generation by 22±3% (n=7; P<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO3 increased NO generation in Af-Art by 19±4% (n=5; P<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; P<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO3-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO3 dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.


Assuntos
Arteríolas/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Bicarbonato de Sódio/farmacologia , Simportadores de Sódio-Bicarbonato/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Arteríolas/fisiologia , Modelos Animais de Doenças , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Perfusão/métodos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Sensibilidade e Especificidade , Simportadores de Sódio-Bicarbonato/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Vasodilatação/fisiologia
16.
Biol Pharm Bull ; 42(9): 1456-1463, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474707

RESUMO

α-Lipoic acid (ALA) is used as a dietary supplement and known as an anti-oxidant. The present study aimed to examine whether ALA improves endothelial dysfunction in high-fat diet-fed obese mice. After feeding a high-fat diet to Institute of Cancer Research (ICR) mice for 4 weeks, the mice were maintained with a high-fat diet (group HF) or a high-fat diet containing ALA (25 mg/d, group HF + ALA) for an additional 20 weeks. Age-matched normal diet-fed mice were also used (group Normal). Chronic oral treatment with ALA did not affect various plasma parameters or body weights. As compared with the aortas of Normal mice, those from HF mice showed impaired endothelium-dependent relaxation in response to clonidine. However, such an impairment was not observed in the aortas from HF + ALA mice. The plasma levels of thiobarbituric acid reactive substances, an indicator of oxidative stress, were significantly decreased in HF + ALA mice compared with HF mice, confirming the anti-oxidative effects of ALA. In addition, when the impaired clonidine-induced vasorelaxation of aortas from normal mice under high glucose conditions was used as a model of acute oxidative stress, the vasorelaxation responses were improved in the presence of ALA at 100 µM. Our results suggested that the chronic oral administration of ALA improves endothelial dysfunction in high-fat diet-fed obese mice possibly through the reduction in oxidative stress in vivo.


Assuntos
Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Dieta Hiperlipídica , Endotélio Vascular/efeitos dos fármacos , Obesidade/tratamento farmacológico , Ácido Tióctico/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos ICR , Obesidade/sangue , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/administração & dosagem
17.
J Agric Food Chem ; 67(35): 9805-9811, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407895

RESUMO

Stachydrine (STA) is a constituent of citrus fruits and Leonurus heterophyllus Sweet. In the present study, we established that STA caused acute endothelium-dependent relaxation. The vascular action of STA was mediated by nitric oxide (NO) via cyclic guanosine monophosphate. Mechanistically, STA activated AMP-activated protein kinase (AMPK), protein kinase B/Akt, and endothelial NO synthase (eNOS) in vascular endothelial cells (ECs). AMPK inhibition by compound C blocked STA-induced Akt/eNOS phosphorylation, suggesting that AMPK is the upstream of Akt and eNOS. Inhibition of Akt by MK2206 blocked STA-stimulated eNOS phosphorylation without altering AMPK phosphorylation. Furthermore, we showed that STA activated AMPK via the induction of liver kinase B1 phosphorylation. These results indicated that STA can induce eNOS phosphorylation and vasorelaxation by regulating the interplay between AMPK and Akt pathways in ECs. These findings further highlighted the potential of STA as a nutritional factor in the beneficial effects of fruit intake in preventing the endothelial dysfunction-related metabolic cardiovascular diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aorta Torácica/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Prolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vasodilatadores/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Bovinos , Citrus/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Técnicas In Vitro , Leonurus/química , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação/efeitos dos fármacos , Prolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
18.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370156

RESUMO

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.


Assuntos
Fatores Biológicos/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Canais de Potássio Cálcio-Ativados/genética , Animais , Fatores Biológicos/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Canais de Potássio Cálcio-Ativados/metabolismo , Fatores de Risco , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
19.
Kidney Blood Press Res ; 44(4): 835-847, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430746

RESUMO

OBJECTIVES: We aimed to assess whether a 7-day high-salt (HS) diet affects endothelium-dependent and/or endothelium-independent microvascular function in the absence of changes in arterial blood pressure (BP), and to determine whether such microvascular changes are associated with changes in body composition and fluid status in healthy young humans. MATERIALS AND METHODS: Fifty-three young healthy individuals (28 women and 25 men) were assigned to a 7-day low-salt diet (<3.5 g salt/day) followed by a 7-day HS diet (∼14 g salt/day). Skin microvascular blood flow in response to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) was assessed by laser Doppler flowmetry, and BP, heart rate (HR), plasma renin activity (PRA), serum aldosterone, serum and 24 h-urine sodium, potassium, urea and creatinine levels, together with body composition and fluid status measurement with a 4-terminal portable impedance analyzer were measured before and after diet protocols. RESULTS: BP, HR, body composition and fluid status were unchanged, and PRA and serum aldosterone level were significantly suppressed after HS diet. ACh-induced dilation (AChID) was significantly impaired, while SNP-induced dilation was not affected by HS diet. Impaired AChID and increased salt intake, as well as impaired AChID and suppressed renin-angiotensin system were significantly positively correlated. Changes in body composition and fluid status parameters were not associated with impaired AChID. CONCLUSION: 7-day HS diet impairs microvascular reactivity by affecting its endothelium-dependent vasodilation in young healthy individuals. Changes are independent of BP, body composition changes or fluid retention, but are the consequences of the unique effect of HS on endothelial function.


Assuntos
Cloreto de Sódio na Dieta/farmacologia , Vasodilatação/efeitos dos fármacos , Adolescente , Pressão Sanguínea/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Líquidos Corporais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Microcirculação , Microvasos/citologia , Fatores de Tempo , Adulto Jovem
20.
Kidney Blood Press Res ; 44(4): 792-809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430751

RESUMO

OBJECTIVE: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). METHODS: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). RESULTS: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. CONCLUSION: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.


Assuntos
Angiotensina II/efeitos adversos , Insuficiência Cardíaca/complicações , Hipertensão/induzido quimicamente , Circulação Renal/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Fístula Artério-Arterial/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Artéria Pulmonar/anormalidades , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Transgênicos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
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