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1.
Life Sci ; 272: 119223, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33610574

RESUMO

AIMS: Hypertension underlies endothelial dysfunction, and activation of vasorelaxation signaling with low dependence on nitric oxide (NO) represents a good alternative for vascular modulation. C-type natriuretic peptide (CNP) causes relaxation by increasing cyclic guanosine 3',5'-monophosphate (cGMP) or Gi-protein activation through its natriuretic peptide receptor-B or -C, respectively. We have hypothesized that CNP could exerts its effects and could overcome endothelial dysfunction in two kidney-one clip (2K-1C) hypertensive rat aorta. Here, we investigate the intracellular signaling involved in CNP effects in hypertension. MATERIALS AND METHODS: The 2K-1C hypertension was induced in male Wistar rats (200 g). CNP-induced vascular relaxation and cGMP production were investigated in rat thoracic aortas. The natriuretic peptide receptor-B and -C localization was evaluated by immunofluorescence. Calcium mobilization was assessed in endothelial cells from rat aortas. KEY FINDINGS: CNP induced similar relaxation in normotensive and 2K-1C hypertensive rat aortas, which increased after endothelium removal. CNP-induced relaxation involved natriuretic peptide receptor-B and -C activation in 2K-1C rats. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) counter-regulated CNP-particulate GC (pGC) activation in aortas. CNP reduced endothelial calcium and increased cGMP production, which was lower in 2K-1C. CNP-induced cGMP-dependent protein kinase (PKG) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) activation was impaired in 2K-1C rat aorta. SIGNIFICANCE: Our results indicated CNP triggered relaxation through its natriuretic peptide receptor-B and -C in 2K-1C rat aortas, and that CNP-induced relaxation overcomes endothelial dysfunction in hypertension. In addition, NOS and sGC activities counter-regulate CNP-pGC activation to induce vascular relaxation.


Assuntos
Peptídeo Natriurético Tipo C/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Guanilato Ciclase/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Masculino , Peptídeo Natriurético Tipo C/metabolismo , Peptídeos Natriuréticos/metabolismo , Peptídeos Natriuréticos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Instrumentos Cirúrgicos , Vasodilatação/fisiologia
2.
J Ethnopharmacol ; 264: 113235, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32777518

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: DG is a herbal formula, containing the root of Salvia miltiorrhiza Bunge (Danshen) and the root of Pueraria lobate (Willd.) Ohwi (Gegen), has a history of usage in China for cardiovascular protection and anti-atherosclerosis. AIM OF THE STUDY: The present study aims to determine the beneficial effect of DG on the hind-limb ischemia rat model which mimics peripheral arterial disease (PAD) and its vasodilative effect on isolated femoral artery. MATERIALS AND METHODS: The vasodilatory effects were assessed by contractile responses to DG in the isolated femoral artery and its underlying mechanisms were evaluated by the involvement of endothelium, potassium channel and calcium channel. For hind-limb ischemia study, treatment outcomes were assessed by evaluating hind-limb blood flow, functional limb recovery, muscle histology and angiogenesis. RESULTS: Our results demonstrated positive dose-dependent vasodilatory response to DG via an endothelium-independent mechanism that involved inwardly rectifying K+ channels and Ca2+ channels. We also demonstrated significant improvement in blood perfusion and micro-vessel density in the ischemic limb and positive effects in functional limb recovery. CONCLUSION: In conclusion, our study supported the potential use of DG as a novel treatment for symptomatic PAD.


Assuntos
Marcha/efeitos dos fármacos , Doença Arterial Periférica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pueraria , Salvia miltiorrhiza , Vasodilatação/efeitos dos fármacos , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Marcha/fisiologia , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Masculino , Técnicas de Cultura de Órgãos , Doença Arterial Periférica/fisiopatologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Vasodilatação/fisiologia
3.
J Am Heart Assoc ; 9(24): e018327, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33307937

RESUMO

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium-dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium-dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium-dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium-dependent hyperpolarization (EDH)-mediated vasodilation was prominent in small distal PAs (fourth-fifth order). Chronic hypoxia abolished EDH-mediated relaxation in small distal PAs without affecting smooth muscle-dependent relaxation. RNA-sequencing data revealed that, among genes related to EDH, the levels of Cx37, Cx40, Cx43, and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH-mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH-mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia-induced downregulation of endothelial Cx40 results in impaired EDH-mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension.


Assuntos
Conexinas/metabolismo , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Animais , Fatores Biológicos , Conexina 43/metabolismo , Regulação para Baixo/genética , Endotélio Vascular/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Óxido Nítrico/metabolismo , Artéria Pulmonar/fisiopatologia , Vasodilatação/fisiologia
4.
Rev Cardiovasc Med ; 21(3): 315-319, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33070537

RESUMO

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.


Assuntos
Betacoronavirus , Transtornos da Coagulação Sanguínea/etiologia , Infecções por Coronavirus/complicações , Endotélio Vascular/fisiopatologia , Pneumonia Viral/complicações , Doenças Vasculares/etiologia , Vasodilatação/fisiologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Infecções por Coronavirus/epidemiologia , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Pandemias , Pneumonia Viral/epidemiologia , Doenças Vasculares/fisiopatologia
5.
Rev Cardiovasc Med ; 21(3): 339-344, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-33070539

RESUMO

There is emerging evidence to suggest that vitamin D deficiency is associated with adverse outcomes in COVID-19 patients. Conversely, vitamin D supplementation protects against an initial alveolar diffuse damage of COVID-19 becoming progressively worse. The mechanisms by which vitamin D deficiency exacerbates COVID-19 pneumonia remain poorly understood. In this review we describe the rationale of the putative role of endothelial dysfunction in this event. Herein, we will briefly review (1) anti-inflammatory and anti-thrombotic effects of vitamin D, (2) vitamin D receptor and vitamin D receptor ligand, (3) protective role of vitamin D against endothelial dysfunction, (4) risk of vitamin D deficiency, (5) vitamin D deficiency in association with endothelial dysfunction, (6) the characteristics of vitamin D relevant to COVID-19, (7) the role of vitamin D on innate and adaptive response, (8) biomarkers of endothelial cell activation contributing to cytokine storm, and (9) the bidirectional relationship between inflammation and homeostasis. Finally, we hypothesize that endothelial dysfunction relevant to vitamin D deficiency results from decreased binding of the vitamin D receptor with its ligand on the vascular endothelium and that it may be immune-mediated via increased interferon 1 α. A possible sequence of events may be described as (1) angiotensin II converting enzyme-related initial endothelial injury followed by vitamin D receptor-related endothelial dysfunction, (2) endothelial lesions deteriorating to endothelialitis, coagulopathy and thrombosis, and (3) vascular damage exacerbating pulmonary pathology and making patients with vitamin D deficiency vulnerable to death.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Endotélio Vascular/fisiopatologia , Pneumonia Viral/epidemiologia , Vasodilatação/fisiologia , Deficiência de Vitamina D/epidemiologia , Comorbidade , Infecções por Coronavirus/fisiopatologia , Humanos , Pandemias , Pneumonia Viral/fisiopatologia , Deficiência de Vitamina D/fisiopatologia
6.
PLoS One ; 15(9): e0238946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956397

RESUMO

BACKGROUND: The origin of low frequency cerebral hemodynamic fluctuations (CHF) in the resting state remains unknown. Breath-by breath O2-CO2 exchange ratio (bER) has been reported to correlate with the cerebrovascular response to brief breath hold challenge at the frequency range of 0.008-0.03Hz in healthy adults. bER is defined as the ratio of the change in the partial pressure of oxygen (ΔPO2) to that of carbon dioxide (ΔPCO2) between end inspiration and end expiration. In this study, we aimed to investigate the contribution of respiratory gas exchange (RGE) metrics (bER, ΔPO2 and ΔPCO2) to low frequency CHF during spontaneous breathing. METHODS: Twenty-two healthy adults were included. We used transcranial Doppler sonography to evaluate CHF by measuring the changes in cerebral blood flow velocity (ΔCBFv) in bilateral middle cerebral arteries. The regional CHF were mapped with blood oxygenation level dependent (ΔBOLD) signal changes using functional magnetic resonance imaging. Temporal features and frequency characteristics of RGE metrics during spontaneous breathing were examined, and the simultaneous measurements of RGE metrics and CHF (ΔCBFv and ΔBOLD) were studied for their correlation. RESULTS: We found that the time courses of ΔPO2 and ΔPCO2 were interdependent but not redundant. The oscillations of RGE metrics were coherent with resting state CHF at the frequency range of 0.008-0.03Hz. Both bER and ΔPO2 were superior to ΔPCO2 in association with CHF while CHF could correlate more strongly with bER than with ΔPO2 in some brain regions. Brain regions with the strongest coupling between bER and ΔBOLD overlapped with many areas of default mode network including precuneus and posterior cingulate. CONCLUSION: Although the physiological mechanisms underlying the strong correlation between bER and CHF are unclear, our findings suggest the contribution of bER to low frequency resting state CHF, providing a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.


Assuntos
Circulação Cerebrovascular/fisiologia , Taxa Respiratória/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Encéfalo/fisiologia , Dióxido de Carbono/sangue , Feminino , Voluntários Saudáveis , Hemodinâmica/fisiologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Artéria Cerebral Média/fisiologia , Oxigênio/sangue , Pressão Parcial , Respiração , Descanso/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Vasodilatação/fisiologia
7.
J Sports Med Phys Fitness ; 60(8): 1159-1166, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32955842

RESUMO

BACKGROUND: Endothelial function assessment may provide important insights into the cardiovascular function and long-term effects of exercise training. Many studies have investigated the possible negative effects on cardiovascular function due to extreme athletic performance, leading to undesirable effects. The purposes of this study were to investigate the acute effects of maximal intensity exercise on endothelium-dependent vasodilation, and to understand the patterns of flow-mediated dilation (FMD) change following maximal exercise in elite female athletes with a high-volume training history. METHODS: Twenty-six elite female soccer players (mean age, 22±4 years; BMI, 21±2 kg/m2; VO2max, 41±4 mL/kg/min) were evaluated. Brachial artery FMD was determined using high-resolution ultrasound at rest, and after 15 and 60 min of maximal cardiopulmonary exercise (CPX) testing on a treadmill. Flow velocity was measured at baseline and during reactive hyperemia at the same periods. RESULTS: Rest FMD was 12.4±5.5%. Peak diameter in response to reactive hyperemia was augmented after 15 min of CPX (3.5±0.4 vs. 3.6±0.4 mm, P<0.05), returning to resting values after 60 min. However, %FMD did not change among time periods. There were two characteristic patterns of FMD response following CPX. Compared to FMD at rest, half of the subjects responded with an increased FMD following maximum exercise (10.5±6.1 vs. 17.8±7.5%, P<0.05). The other subjects demonstrated a reduced FMD response following maximum exercise (14.2±4.3 vs. 10.9±3.2%, P<0.01). CONCLUSIONS: These results indicate that elite female soccer players presented robust brachial artery FMD at rest, with a heterogeneous FMD response to acute exercise with a 50% FMD improvement rate.


Assuntos
Endotélio Vascular/fisiologia , Exercício Físico/fisiologia , Condicionamento Físico Humano/fisiologia , Futebol/fisiologia , Vasodilatação/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiologia , Teste de Esforço , Feminino , Humanos , Fluxo Sanguíneo Regional/fisiologia , Adulto Jovem
8.
Nat Commun ; 11(1): 4883, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985528

RESUMO

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Modelos Biológicos , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Circulação Pulmonar/fisiologia , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Humanos , Hipóxia/terapia , Pneumopatias/terapia , Conceitos Matemáticos , Modelos Cardiovasculares , Oxigenoterapia , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Tempo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Relação Ventilação-Perfusão/fisiologia
9.
J Vis Exp ; (161)2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32804163

RESUMO

Coronary arterial tone along with the opening or closing of the capillaries largely determine the blood flow to cardiomyocytes at constant perfusion pressure. However, it is difficult to monitor the dynamic changes of the coronary arterioles and the capillaries in the whole heart, primarily due to its motion and non-stop beating. Here we describe a method that enables monitoring of arterial perfusion rate, pressure and the diameter changes of the arterioles and capillaries in mouse right ventricular papillary muscles. The mouse septal artery is cannulated and perfused at a constant flow or pressure with the other dynamically measured. After perfusion with a fluorescently labeled lectin (e.g., Alexa Fluor-488 or -633 labeled Wheat-Germ Agglutinin, WGA), the arterioles and capillaries (and other vessels) in right ventricle papillary muscle and septum could be readily imaged. The vessel-diameter changes could then be measured in the presence or absence of heart contractions. When genetically encoded fluorescent proteins were expressed, specific features could be monitored. For examples, pericytes were visualized in mouse hearts that expressed NG2-DsRed. This method has provided a useful platform to study the physiological functions of capillary pericytes in heart. It is also suitable for studying the effect of reagents on the blood flow in heart by measuring the vascular/capillary diameter and the arterial luminal pressure simultaneously. This preparation, combined with a state-of-the-art optic imaging system, allows one to study the blood flow and its control at cellular and molecular level in the heart under near-physiological conditions.


Assuntos
Arteríolas/diagnóstico por imagem , Capilares/diagnóstico por imagem , Imageamento Tridimensional , Pericitos/fisiologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiologia , Capilares/efeitos dos fármacos , Capilares/fisiologia , Cateterismo , Corantes Fluorescentes/metabolismo , Hemodinâmica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Perfusão , Pericitos/efeitos dos fármacos , Pinacidil/farmacologia , Pressão , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Aglutininas do Germe de Trigo/metabolismo
10.
Metabolism ; 111: 154340, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32791171

RESUMO

BACKGROUND: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function. PURPOSE: To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity. METHODS AND RESULTS: To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone. CONCLUSIONS: The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.


Assuntos
Células Endoteliais/patologia , Endotélio Vascular/patologia , Obesidade/patologia , Estado Pré-Diabético/patologia , Animais , Sinalização do Cálcio/fisiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Masculino , Óxido Nítrico/metabolismo , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Ratos , Ratos Wistar , Vasodilatação/fisiologia
11.
Am J Physiol Endocrinol Metab ; 319(2): E438-E446, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32691633

RESUMO

Understanding mouse thermal physiology informs the usefulness of mice as models of human disease. It is widely assumed that the mouse tail contributes greatly to heat loss (as it does in rat), but this has not been quantitated. We studied C57BL/6J mice after tail amputation. Tailless mice housed at 22°C did not differ from littermate controls in body weight, lean or fat content, or energy expenditure. With acute changes in ambient temperature from 19 to 39°C, tailless and control mice demonstrated similar body temperatures (Tb), metabolic rates, and heat conductances and no difference in thermoneutral point. Treatment with prazosin, an α1-adrenergic antagonist and vasodilator, increased tail temperature in control mice by up to 4.8 ± 0.8°C. Comparing prazosin treatment in tailless and control mice suggested that the tail's contribution to total heat loss was a nonsignificant 3.4%. Major heat stress produced by treatment at 30°C with CL316243, a ß3-adrenergic agonist, increased metabolic rate and Tb and, at a matched increase in metabolic rate, the tailless mice showed a 0.72 ± 0.14°C greater Tb increase and 7.6% lower whole body heat conductance. Thus, the mouse tail is a useful biomarker of vasodilation and thermoregulation, but in our experiments contributes only 5-8% of whole body heat dissipation, less than the 17% reported for rat. Heat dissipation through the tail is important under extreme scenarios such as pharmacological activation of brown adipose tissue; however, non-tail contributions to heat loss may have been underestimated in the mouse.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Modelos Animais , Cauda/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1 , Amputação , Animais , Composição Corporal/fisiologia , Superfície Corporal , Regulação da Temperatura Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Resposta ao Choque Térmico , Camundongos , Camundongos Endogâmicos C57BL , Prazosina/farmacologia , Ratos , Cauda/cirurgia , Vasodilatação/fisiologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-32708408

RESUMO

The current pool of data investigating the effects of a single resistance exercise session on endothelial function is divergent and inconclusive. Therefore, the purpose of the present study was to evaluate the effect of a single resistance exercise session on flow-mediated dilation (FMD) in trained individuals. Eleven healthy, young, recreationally resistance-trained individuals participated in the study. After determining the resistance exercise workload, the participants performed three sets of 10-12 repetition of leg press and leg extension exercises. By using ultrasound equipment, brachial artery FMD was assessed before (PRE) and 30 min after (POST) the resistance exercise protocol or resting (control) to evaluate endothelial function. A significant reduction in FMD response (PRE: 5.73% ± 1.21% vs. POST: 4.03% ± 1.94%, p < 0.01) after resistance exercise was observed, accompanied by a large effect size (d = 1.05). No significant difference was observed in FMD in the control condition (PRE: 5.82% ± 1.19% vs. POST: 5.66% ± 1.24%, p = 0.704). Additionally, no significant difference in baseline brachial artery diameter between resistance exercise (PRE: 3.30 ± 0.32 vs. POST: 3.40 ± 0.34 mm, p = 0.494) and resting (PRE: 3.64 ± 0.41 vs. POST: 3.67 ± 0.62 mm, p = 0.825) was observed. Our findings showed that a single resistance exercise session induced a reduction in FMD in resistance-trained individuals.


Assuntos
Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiologia , Endotélio Vascular/fisiologia , Exercício Físico/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Treinamento de Resistência , Vasodilatação/fisiologia , Adulto , Dilatação , Endotélio Vascular/diagnóstico por imagem , Feminino , Voluntários Saudáveis , Humanos , Masculino , Ultrassonografia , Adulto Jovem
13.
Sci Rep ; 10(1): 12220, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699285

RESUMO

Growing evidence supports the role of advanced glycation end products (AGEs) in the development of diabetic vascular complications and cardiovascular diseases (CVDs). We have shown that high-molecular-weight AGEs (HMW-AGEs), present in our Western diet, impair cardiac function. Whether HMW-AGEs affect vascular function remains unknown. In this study, we aimed to investigate the impact of chronic HMW-AGEs exposure on vascular function and structure. Adult male Sprague Dawley rats were daily injected with HMW-AGEs or control solution for 6 weeks. HMW-AGEs animals showed intracardiac pressure overload, characterized by increased systolic and mean pressures. The contraction response to PE was increased in aortic rings from the HMW-AGEs group. Relaxation in response to ACh, but not SNP, was impaired by HMW-AGEs. This was associated with reduced plasma cyclic GMP levels. SOD restored ACh-induced relaxation of HMW-AGEs animals to control levels, accompanied by a reduced half-maximal effective dose (EC50). Finally, collagen deposition and intima-media thickness of the aortic vessel wall were increased with HMW-AGEs. Our data demonstrate that chronic HMW-AGEs exposure causes adverse vascular remodelling. This is characterised by disturbed vasomotor function due to increased oxidative stress and structural changes in the aorta, suggesting an important contribution of HMW-AGEs in the development of CVDs.


Assuntos
Acetaldeído/análogos & derivados , Aorta/metabolismo , Aorta/fisiopatologia , Pressão Sanguínea/fisiologia , Coração/fisiopatologia , Remodelação Vascular/fisiologia , Acetaldeído/metabolismo , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Colágeno/metabolismo , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Produtos Finais de Glicação Avançada/metabolismo , Coração/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
14.
Wilderness Environ Med ; 31(3): 312-316, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32482519

RESUMO

INTRODUCTION: Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud's syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied. METHODS: A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orally twice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24 h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD). RESULTS: Twelve volunteers (age 29±3 [24-34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo). CONCLUSIONS: Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Temperatura Baixa/efeitos adversos , Dedos/fisiologia , Nifedipino/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Utah , Vasodilatação/efeitos dos fármacos , Adulto Jovem
15.
Am J Physiol Renal Physiol ; 319(1): F33-F40, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421350

RESUMO

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Sex differences in vascular function are common in clinical and nonclinical populations. However, no data exist in individuals with CKD. The present study tested the hypothesis that sex and/or aging differences exist in vascular function in patients with CKD. Endothelium-dependent dilation (EDD; measured via brachial artery flow-mediated dilation) and endothelium-independent dilation (EID; measured via nitroglycerin-mediated dilation) were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, cardiovascular disease, and blood pressure). Women, in general, had higher EDD values than men (6.5 ± 4.9% vs. 4.4 ± 3.4%); however, EID did not differ among these groups. In younger men and women (<55 yr old), EDD and EID were higher (P < 0.05) than their older (≥55 yr old) counterparts (EDD: 7.0 ± 4.1% vs. 4.4 ± 3.8% and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). Additionally, younger women exhibited higher (P < 0.05) EDD and EID compared with younger men (EDD: 9.5 ± 6.4% vs. 5.1 ± 3.8%, P = 0.01, and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). No differences in EDD and EID were present between older men and women with CKD. Diabetes independently predicted lower EID but not EDD in men and women. Blood pressure and cardiovascular disease did not predict EDD or EID. This is the first study to show significant sex differences in vascular function. Moreover, these differences are evident between younger men and women with CKD but are abolished with age. Additional studies are needed to better understand the mechanisms that may underlie sex differences in vascular dysfunction with CKD.


Assuntos
Artéria Braquial/fisiopatologia , Endotélio Vascular/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Insuficiência Renal Crônica/fisiopatologia , Vasodilatação/fisiologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais
16.
Invest Ophthalmol Vis Sci ; 61(5): 36, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32437549

RESUMO

Purpose: Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction. Methods: Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 ± 27 mg/dL) or age-matched control pigs (97 ± 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro. Results: Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner. Conclusions: Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.


Assuntos
Arginase/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Endotélio Vascular/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Retiniana/fisiologia , Vasodilatação/fisiologia , Animais , Arteríolas/fisiologia , Glicemia/metabolismo , Bradicinina/farmacologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Tipo 1/enzimologia , Inibidores Enzimáticos/farmacologia , Histamina/farmacologia , Hiperglicemia/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sus scrofa
17.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R33-R42, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401627

RESUMO

Cerebral blood flow (CBF) is commonly inferred from blood velocity measurements in the middle cerebral artery (MCA), using nonimaging, transcranial Doppler ultrasound (TCD). However, both blood velocity and vessel diameter are critical components required to accurately determine blood flow, and there is mounting evidence that the MCA is vasoactive. Therefore, the aim of this study was to employ imaging TCD (ITCD), utilizing color flow images and pulse wave velocity, as a novel approach to measure both MCA diameter and blood velocity to accurately quantify changes in MCA blood flow. ITCD was performed at rest in 13 healthy participants (7 men/6 women; 28 ± 5 yr) with pharmaceutically induced vasodilation [nitroglycerin (NTG), 0.8 mg] and without (CON). Measurements were taken for 2 min before and for 5 min following NTG or sham delivery (CON). There was more than a fivefold, significant, fall in MCA blood velocity in response to NTG (∆-4.95 ± 4.6 cm/s) compared to negligible fluctuation in CON (∆-0.88 ± 4.7 cm/s) (P < 0.001). MCA diameter increased significantly in response to NTG (∆0.09 ± 0.04 cm) compared with the basal variation in CON (∆0.00 ± 0.04 cm) (P = 0.018). Interestingly, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (∆144 ± 159 ml/min) compared with CON (∆-5 ± 130 ml/min) (P = 0.005). These juxtaposed findings highlight the importance of measuring both MCA blood velocity and diameter when assessing CBF and document ITCD as a novel approach to achieve this goal.


Assuntos
Circulação Cerebrovascular/fisiologia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Adulto , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/efeitos dos fármacos , Nitroglicerina/farmacologia , Análise de Onda de Pulso , Ultrassonografia Doppler em Cores , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Adulto Jovem
18.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R19-R25, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32401629

RESUMO

Microvascular endothelial dysfunction, a precursor to atherosclerotic cardiovascular disease, increases with aging. Endothelium-derived hyperpolarizing factors (EDHFs), which act through K+ channels, regulate blood flow and are important to vascular health. It is unclear how EDHFs change with healthy aging. To evaluate microvascular endothelial reliance on K+ channel-mediated dilation as a function of age in healthy humans. Microvascular function was assessed using intradermal microdialysis in healthy younger (Y; n = 7; 3 M/4 W; 26 ± 1 yr) and older adults (O; n = 12; 5 M/7 W; 64 ± 2 yr) matched for V̇o2peak (Y: 39.0 ± 3.8, O: 37.6 ± 3.1 mL·kg-1·min-1). Participants underwent graded local infusions of: the K+ channel activator Na2S (10-6 to 10-1 M), acetylcholine (ACh, 10-10 to 10-1 M), ACh + the K+ channel inhibitor tetraethylammonium (TEA; 25 or 50 mM), and ACh + the nitric oxide synthase-inhibitor l-NAME (15 mM). Red blood cell flux was measured with laser-Doppler flowmetry and used to calculate cutaneous vascular conductance (CVC; flux/mean arterial pressure) as a percentage of each site-specific maximum (%CVCmax, 43°C+28 mM sodium nitroprusside). The %CVCmax response to Na2S was higher in older adults (mean, O: 51.7 ± 3.9% vs. Y: 36.1 ± 5.3%; P = 0.03). %CVCmax was lower in the ACh+TEA vs. the ACh site starting at 10-5 M (ACh: 34.0 ± 5.7% vs. ACh+TEA: 19.4 ± 4.5%; P = 0.002) in older and at 10-4 M (ACh: 54.5 ± 9.4% vs. ACh+TEA: 31.2 ± 6.7%; P = 0.0002) in younger adults. %CVCmax was lower in the ACh+l-NAME vs. the ACh site in both groups starting at 10-4 M ACh (Y: P < 0.001; O: P = 0.02). Healthy active older adults have enhanced K+ channel-dependent endothelial vasodilatory mechanisms, suggesting increased responsiveness to EDHFs with age.


Assuntos
Endotélio Vascular/fisiologia , Envelhecimento Saudável/fisiologia , Canais de Potássio/fisiologia , Vasodilatação/fisiologia , Adulto , Idoso , Envelhecimento/fisiologia , Limiar Anaeróbio/fisiologia , Fatores Biológicos/fisiologia , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/fisiologia , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , NG-Nitroarginina Metil Éster/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/agonistas , Fluxo Sanguíneo Regional/fisiologia
19.
J Smooth Muscle Res ; 56(0): 1-18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32249242

RESUMO

Spontaneous rhythmic constrictions known as vasomotion are developed in several microvascular beds in vivo. Vasomotion in arterioles is considered to facilitate blood flow, while venular vasomotion would facilitate tissue metabolite drainage. Mechanisms underlying vasomotion periodically generate synchronous Ca2+ transients in vascular smooth muscle cells (VSMCs). In visceral organs, mural cells (pericytes and VSMCs) in arterioles, capillaries and venules exhibit synchronous spontaneous Ca2+ transients. Since sympathetic regulation is rather limited in the intra-organ microvessels, spontaneous activity of mural cells may play an essential role in maintaining tissue perfusion. Synchronous spontaneous Ca2+ transients in precapillary arterioles (PCAs)/capillaries appear to propagate to upstream arterioles to drive their vasomotion, while venules develop their own synchronous Ca2+ transients and associated vasomotion. Spontaneous Ca2+ transients of mural cells primarily arise from IP3 and/or ryanodine receptor-mediated Ca2+ release from sarcoendoplasmic reticulum (SR/ER) Ca2+ stores. The resultant opening of Ca2+-activated Cl- channels (CaCCs) causes a membrane depolarisation that triggers Ca2+ influx via T-type and/or L-type voltage-dependent Ca2+ channels (VDCCs). Mural cells are electrically coupled with each other via gap junctions, and thus allow the sequential spread of CaCC or VDCC-dependent depolarisations to develop the synchrony of Ca2+ transients within their network. Importantly, the synchrony of spontaneous Ca2+ transients also requires a certain range of the resting membrane potential that is maintained by the opening of Kv7 voltage-dependent K+ (Kv7) and inward rectifier K+ (Kir) channels. Thus, a depolarised membrane would evoke asynchronous, 'premature' spontaneous Ca2+ transients, while a hyperpolarised membrane prevents any spontaneous activity.


Assuntos
Cálcio/metabolismo , Microvasos/citologia , Microvasos/metabolismo , Músculo Liso Vascular/metabolismo , Arteríolas/metabolismo , Canais de Cálcio/metabolismo , Capilares/metabolismo , Canais de Cloreto/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Inositol 1,4,5-Trifosfato , Músculo Liso Vascular/citologia , Pericitos/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina , Vasoconstrição/fisiologia , Vasodilatação/fisiologia
20.
Am J Physiol Heart Circ Physiol ; 318(6): H1371-H1378, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32330091

RESUMO

Microvascular dysfunction often precedes other age-related macrovascular conditions and predicts future cardiovascular risk. Sirtuin 1 (Sirt1) has recently emerged as a protein that protects the vasculature and reduces the risk of cardiovascular diseases. We tested the hypothesis that lower Sirt1 during childhood is associated with a reduced microvascular function during adulthood. Thirty-four adults (34 ± 3 yr) from the Augusta Heart Study returned to participate in the present clinical observational study. Sirt1 was assessed in samples collected during both adulthood and participants' childhood (16 ± 3 yr), and data were divided based on childhood Sirt1 concentrations: <3 ng/dL (LowCS; n = 16) and ≥3 ng/dL (HighCS; n = 18). MVF was evaluated in all of the adults using laser-Doppler flowmetry coupled with three vascular reactivity tests: 1) local thermal hyperemia (LTH), 2) post-occlusive reactive hyperemia (PORH), and 3) iontophoresis of acetylcholine (ACh). The hyperemic response to LTH was significantly (P ≤ 0.044) lower in the LowCS than in the HighCS group. Similarly, the LowCS also exhibited an ameliorated (P ≤ 0.045) response to the PORH test and lower (P ≤ 0.008) vasodilation in response to iontophoresis of ACh when compared with the HighCS. Positive relationships were identified between childhood Sirt1 and all MVF reactivity tests (r≥0.367, P ≤ 0.004). Novel observations suggest that lower Sirt1 during childhood is associated with premature microvascular dysfunction in adulthood. These findings provide evidence that Sirt1 may play a critical role in microvascular function and have therapeutic potential for the prevention of age-associated vascular dysfunction in humans.NEW & NOTEWORTHY With a longitudinal cohort, novel observations from the present study demonstrate that individuals who had lower Sirt1 early in life exhibit premature microvascular dysfunction during adulthood and may be at higher risk to develop CVD. These results provide experimental evidence that Sirt1 may play an important role in microvascular function with age and represent a potential therapeutic target to prevent premature vascular dysfunction.


Assuntos
Hiperemia/fisiopatologia , Microcirculação/fisiologia , Microvasos/fisiologia , Sirtuína 1/sangue , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Adolescente , Adulto , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hiperemia/sangue , Fluxometria por Laser-Doppler , Masculino , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto Jovem
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