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1.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32614178

RESUMO

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipotensão/fisiopatologia , Pulmão/irrigação sanguínea , Microvasos/fisiopatologia , Pneumonia Viral/fisiopatologia , Edema Pulmonar/fisiopatologia , Núcleo Solitário/fisiopatologia , Trombose/fisiopatologia , Betacoronavirus , Permeabilidade Capilar/fisiologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Nervo Facial , Nervo Glossofaríngeo , Humanos , Inflamação , Pulmão/imunologia , Microvasos/imunologia , Pandemias , Sistema Nervoso Parassimpático/fisiopatologia , Pneumonia Viral/imunologia , Edema Pulmonar/imunologia , Núcleo Solitário/imunologia , Nervo Vago , Vasoconstrição
2.
Prague Med Rep ; 121(2): 107-113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32553094

RESUMO

Reversible cerebral vasoconstriction syndrome (RCVS) is characterised by severe thunderclap headaches (with or without the presence of acute neurological symptoms) and segmental vasoconstriction of cerebral arteries that resolves spontaneously in a period of three months. Cases have been described in the literature with producing and non-producing masses of metanephrines. Within these reports, associations with cavernous haemangioma, medulloblastoma, colon cancer, paraganglioma, pheochromocytoma, uterine fibroids, among others were found. However, no association with adrenal masses which do not produce metanephrines was found. In this context, we reported the case of a woman with this type of tumour associated with RCVS which provided a treatment challenge, as well as we reviewed the literature on cases of RCVS associated with masses.


Assuntos
Transtornos da Cefaleia Primários , Paraganglioma , Vasoespasmo Intracraniano , Feminino , Humanos , Vasoconstrição
4.
Life Sci ; 254: 117819, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32442451

RESUMO

AIMS: Vascular dysfunction plays a key role in sepsis but the role of perivascular adipose tissue (PVAT) in this condition is relatively unknown. MAIN METHODS: Sepsis was induced by cecal ligation and puncture (CLP). The responses of the aorta and superior mesenteric artery to norepinephrine in the presence or absence of PVAT were evaluated. Fluorescent probes measured the production of nitric oxide (NO) and reactive oxygen species (ROS). NO synthases (NOS) and ß3-adrenoceptor expression were detected by immunofluorescence and S-nitrosylation by the biotin switch assay. KEY FINDINGS: Aorta and superior mesenteric arteries from septic animals with intact PVAT showed a worsened response to the vasoconstrictor compared to vessels without PVAT. PVAT from the aorta (APVAT) produced NO and ROS whereas PVAT from the superior mesenteric artery (MPVAT) produced only ROS. Septic APVAT exhibited a higher density of NOS-1 and NOS-3. S-nitrosylation was found in APVAT. Donor (PVAT obtained from normal or septic rats):Host (normal vessel without PVAT) experiments showed that L-NAME, ODQ and ß3-adrenergic receptor antagonist blocked the septic APVAT anti-contractile effect. None of these compounds affected MPVAT; tempol, but not apocynin, blocked its anti-contractile effect. SIGNIFICANCE: PVAT contributes to the anti-contractile effect in the aorta and mesenteric artery of septic rats through different pathways. ß3-Adrenergic receptor and NO appear to be key mediators of this effect in APVAT, but not in MPVAT where ROS seem to be a relevant mediator. Therefore, PVAT is a relevant player of sepsis vascular dysfunction.


Assuntos
Aorta/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos beta 3/fisiologia , Sepse/fisiopatologia , Acetofenonas/farmacologia , Tecido Adiposo/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Óxidos N-Cíclicos/farmacologia , Feminino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Norepinefrina/farmacologia , Oxidiazóis/farmacologia , Fenótipo , Quinoxalinas/farmacologia , Ratos , Receptores Adrenérgicos beta 3/biossíntese , Marcadores de Spin , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
6.
Am J Physiol Heart Circ Physiol ; 318(5): H1233-H1244, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275471

RESUMO

An important physiological role of the aorta is to convert the pulsatile blood flow that originates in the heart to a nearly continuous flow in the peripheral vessels. Previously, we demonstrated that basal, unstimulated nitric oxide (NO) production is more abundant in large as compared with muscular arteries and that it is an important regulator of arterial (aortic) stiffness. Hence, endothelial function and NO bioavailability are important determinants of aortic biomechanics, and mouse models with altered NO signaling might be of interest to investigate the (patho)physiological role of the NO signaling as a dynamic regulator of arterial stiffness. We aimed to characterize the ex vivo biomechanical properties of aortic segments from mice with no (eNOS-/-), normal [wild type (WT)], or high (eNOS-tg) endothelial NO synthase (eNOS) expression. Isobaric aortic diameter and compliance were lower in eNOS-/- mice and increased in eNOS-tg mice as compared with WT mice. Interestingly, these differences remained when NO levels were pharmacologically restored ex vivo, suggesting that they were not merely the result of a lack or excess of the vasodilator effects of NO. Analysis of basal vascular smooth muscle cell tone and the phasic as well as the tonic contraction in response to α1-adrenergic stimulation with phenylephrine revealed that the chronic lack of eNOS expression affected aortic reactivity similarly but with different magnitude as compared with acute eNOS blockade using Nω-nitro-l-arginine methyl ester in WT and eNOS-tg mice, suggesting that chronical distortion of NO signaling triggered several compensatory mechanisms that reflect the organism's attempt to restore the contractile imbalance and maintain optimal central hemodynamics.NEW & NOTEWORTHY Endothelial function and NO bioavailability are important determinants of aortic biomechanics and function. With a new technique we investigated the ex vivo aortic segment biomechanics of different mouse models with altered NO signaling. Our experiments clearly show that chronic distortion of NO signaling triggered several compensatory mechanisms that reflect the organism's attempt to maintain optimal central hemodynamics.


Assuntos
Aorta/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Rigidez Vascular , Animais , Aorta/metabolismo , Fenômenos Biomecânicos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Transdução de Sinais , Vasoconstrição
7.
Am J Physiol Heart Circ Physiol ; 318(5): H1346-H1355, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302491

RESUMO

Renovascular hypertension is characterized by activation of the renin-angiotensin-aldosterone system, blunted natriuretic responses, and elevated sympathetic nerve activity. Excess dietary salt intake exaggerates arterial blood pressure (ABP) in multiple models of experimental hypertension. The present study tested whether a high-salt diet exaggerated ABP and vascular dysfunction in a 2-kidney, 1-clip (2K1C) murine model. Male C57BL/6J mice (8-12 wk) were randomly assigned, and fed a 0.1% or 4.0% NaCl diet, and instrumented with telemetry units to measure ABP. Then, the 2K1C model was produced by placing a cuff around the right renal artery. Systolic, diastolic, and mean ABP were significantly higher in mice fed 4.0% vs. 0.1% NaCl at 1 wk but not after 3 wk. Interestingly, 2K1C hypertension progressively increased arterial pulse pressure in both groups; however, the magnitude was significantly greater in mice fed 4.0% vs. 0.1% NaCl at 3 wk. Moreover, pulse wave velocity was significantly greater in 2K1C mice fed 4.0% vs. 0.1% NaCl diet or sham-operated mice fed either diet. Histological assessment of aortas indicated no structural differences among groups. Finally, endothelium-dependent vasodilation was significantly and selectively attenuated in the aorta but not mesenteric arteries of 2K1C mice fed 4.0% NaCl vs. 0.1% NaCl or sham-operated control mice. The findings suggest that dietary salt loading transiently exaggerates 2K1C renovascular hypertension but promotes chronic aortic stiffness and selective aortic vascular dysfunction.NEW & NOTEWORTHY High dietary salt exaggerates hypertension in multiple experimental models. Here we demonstrate that a high-salt diet produces a greater increase in arterial blood pressure at 1 wk after induction of 2-kidney, 1-clip (2K1C) hypertension but not at 3 wk. Interestingly, 2K1C mice fed a high-salt diet displayed an exaggerated pulse pressure, elevated pulse wave velocity, and reduced endothelium-dependent vasodilation of the aorta but not mesenteric arteries. These findings suggest that dietary salt may interact with underlying cardiovascular disease to promote selective vascular dysfunction and aortic stiffness.


Assuntos
Hipertensão Renovascular/etiologia , Cloreto de Sódio na Dieta/efeitos adversos , Rigidez Vascular , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Sódio na Dieta/toxicidade , Vasoconstrição
8.
Am J Physiol Heart Circ Physiol ; 318(5): H1296-H1307, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302494

RESUMO

Haptoglobin (Hp) is the plasma protein that binds and clears cell-free hemoglobin (Hb), whereas apohemoglobin (apoHb, i.e., Hb devoid of heme) can bind heme. Therefore, the apoHb-Hp protein complex should facilitate holoHb-apoHb αß-dimer exchange and apoHb-heme intercalation. Thus, we hypothesized that apoHb-Hp could facilitate both Hb and heme clearance, which, if not alleviated, could have severe microcirculatory consequences. In this study, we characterized apoHb-Hp and Hb/heme ligand interactions and assessed their in vivo consequences. Hb exchange and heme binding with the apoHb-Hp complex was studied with transfer assays using size-exclusion high-performance liquid chromatography coupled with UV-visible spectrophotometry. Exchange/transfer experiments were conducted in guinea pigs dosed with Hb or heme-albumin followed by a challenge with equimolar amounts of apoHb-Hp. Finally, systemic and microcirculatory parameters were studied in hamsters instrumented with a dorsal window chamber via intravital microscopy. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. Dosing with the apoHb-Hp complex reversed Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, reduced microvascular blood flow, and diminished functional capillary density. Therefore, this study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure.NEW & NOTEWORTHY This study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.


Assuntos
Apoproteínas/metabolismo , Haptoglobinas/metabolismo , Heme/metabolismo , Hemoglobinas/metabolismo , Hipertensão/sangue , Animais , Apoproteínas/sangue , Transfusão de Sangue/métodos , Cricetinae , Cobaias , Humanos , Hipertensão/fisiopatologia , Hipertensão/terapia , Masculino , Mesocricetus , Microcirculação , Ligação Proteica , Vasoconstrição
9.
PLoS One ; 15(4): e0230953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271814

RESUMO

OBJECTIVE: We sought to examine whether the effect of treatment modality and drugs for cerebral vasospasm on clinical outcomes differs between elderly and non-elderly subarachnoid hemorrhage (SAH) patients in Japan. METHODS: We analyzed the J-ASPECT Study Diagnosis Procedure Combination database (n = 17,343) that underwent clipping or coiling between 2010 and 2014 in 579 hospitals. We stratified patients into two groups according to their age (elderly [≥75 years old], n = 3,885; non-elderly, n = 13,458). We analyzed the effect of treatment modality and anti-vasospasm agents (fasudil hydrochloride, ozagrel sodium, cilostazol, statin, eicosapentaenoic acid [EPA], and edaravone) on in-hospital poor outcomes (mRS 3-6 at discharge) and mortality using multivariable analysis. RESULTS: The elderly patients were more likely to be female, have impaired levels of consciousness and comorbidity, and less likely to be treated with clipping and anti-vasospasm agents, except for ozagrel sodium and statin. In-hospital mortality and poor outcomes were higher in the elderly (15.8% vs. 8.5%, 71.7% vs. 36.5%). Coiling was associated with higher mortality (odds ratio 1.43, 95% confidence interval 1.2-1.7) despite a lower proportion of poor outcomes (0.84, 0.75-0.94) in the non-elderly, in contrast to no effect on clinical outcomes in the elderly. A comparable effect of anti-vasospasm agents on mortality was observed between non-elderly and elderly for fasudil hydrochloride (non-elderly: 0.20, 0.17-0.24), statin (0.63, 0.50-0.79), ozagrel sodium (0.72, 0.60-0.86), and cilostazol (0.63, 0.51-0.77). Poor outcomes were inversely associated with fasudil hydrochloride (0.59, 0.51-0.68), statin (0.84, 0.75-0.94), and EPA (0.83, 0.72-0.94) use in the non-elderly. No effect of these agents on poor outcomes was observed in the elderly. CONCLUSIONS: In contrast to the non-elderly, no effect of treatment modality on clinical outcomes were observed in the elderly. A comparable effect of anti-vasospasm agents was observed on mortality, but not on functional outcomes, between the non-elderly and elderly.


Assuntos
Hemorragia Subaracnóidea/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Resultado do Tratamento
11.
Am J Physiol Renal Physiol ; 318(4): F1053-F1065, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174139

RESUMO

We first tested the hypothesis that consuming a high-fructose corn syrup (HFCS)-sweetened soft drink augments kidney vasoconstriction to sympathetic stimulation compared with water (study 1). In a second study, we examined the mechanisms underlying these observations (study 2). In study 1, 13 healthy adults completed a cold pressor test, a sympathoexcitatory maneuver, before (preconsumption) and 30 min after drinking 500 mL of decarbonated HFCS-sweetened soft drink or water (postconsumption). In study 2, venous blood samples were obtained in 12 healthy adults before and 30 min after consumption of 500 mL water or soft drinks matched for caffeine content and taste, which were either artificially sweetened (Diet trial), sucrose-sweetened (Sucrose trial), or sweetened with HFCS (HFCS trial). In both study 1 and study 2, vascular resistance was calculated as mean arterial pressure divided by blood velocity, which was measured via Doppler ultrasound in renal and segmental arteries. In study 1, HFCS consumption increased vascular resistance in the segmental artery at rest (by 0.5 ± 0.6 mmHg·cm-1·s-1, P = 0.01) and during the cold pressor test (average change: 0.5 ± 1.0 mmHg·cm-1·s-1, main effect: P = 0.05). In study 2, segmental artery vascular resistance increased in the HFCS trial (by 0.8 ± 0.7 mmHg·cm-1·s-1, P = 0.02) but not in the other trials. Increases in serum uric acid were greater in the HFCS trial (0.3 ± 0.4 mg/dL, P ≤ 0.04) compared with the Water and Diet trials, and serum copeptin increased in the HFCS trial (by 0.8 ± 1.0 pmol/L, P = 0.06). These findings indicate that HFCS acutely increases vascular resistance in the kidneys, independent of caffeine content and beverage osmolality, which likely occurs via simultaneous elevations in circulating uric acid and vasopressin.


Assuntos
Bebidas Adoçadas Artificialmente/efeitos adversos , Xarope de Milho Rico em Frutose/efeitos adversos , Rim/irrigação sanguínea , Artéria Renal/inervação , Circulação Renal/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo , Cafeína/administração & dosagem , Feminino , Voluntários Saudáveis , Xarope de Milho Rico em Frutose/administração & dosagem , Humanos , Masculino , Distribuição Aleatória , Artéria Renal/diagnóstico por imagem , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo , Regulação para Cima , Ácido Úrico/sangue , Vasopressinas/sangue , Adulto Jovem
12.
Am J Physiol Heart Circ Physiol ; 318(5): H1219-H1232, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32216612

RESUMO

Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young Sprague-Dawley (SD) rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared with males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared with males. The MCA of females failed to constrict compared with a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4 and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100 to 180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause.NEW & NOTEWORTHY Using perfusion fixation of the middle cerebral artery (MCA) in calcium-free solution at physiological pressure and systematically randomly sampling the sections prepared from the same M2 segments of MCA, we found that there are structural differences that are associated with altered cerebral blood flow (CBF) autoregulation but not neurovascular coupling and cognition in young, healthy Sprague-Dawley (SD) rats. Understanding the intrinsic differences in cerebrovascular structure and function in males and females is essential to develop new pharmaceutical treatments for cerebrovascular disease (CVD).


Assuntos
Artéria Cerebral Média/fisiologia , Músculo Liso Vascular/fisiologia , Caracteres Sexuais , Vasoconstrição , Animais , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Células Cultivadas , Cognição , Feminino , Masculino , Artéria Cerebral Média/citologia , Tono Muscular , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley
13.
Nat Biomed Eng ; 4(3): 286-297, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32165736

RESUMO

The monitoring of vascular-targeted therapies using magnetic resonance imaging, computed tomography or ultrasound is limited by their insufficient spatial resolution. Here, by taking advantage of the intrinsic optical properties of haemoglobin, we show that raster-scanning optoacoustic mesoscopy (RSOM) provides high-resolution images of the tumour vasculature and of the surrounding tissue, and that the detection of a wide range of ultrasound bandwidths enables the distinction of vessels of differing size, providing detailed insights into the vascular responses to vascular-targeted therapy. Using RSOM to examine the responses to vascular-targeted photodynamic therapy in mice with subcutaneous xenografts, we observed a substantial and immediate occlusion of the tumour vessels followed by haemorrhage within the tissue and the eventual collapse of the entire vasculature. Using dual-wavelength RSOM, which distinguishes oxyhaemoglobin from deoxyhaemoglobin, we observed an increase in oxygenation of the entire tumour volume immediately after the application of the therapy, and a second wave of oxygen reperfusion approximately 24 h thereafter. We also show that RSOM enables the quantification of differences in neoangiogenesis that predict treatment efficacy.


Assuntos
Diagnóstico por Imagem/métodos , Neovascularização Patológica/diagnóstico , Técnicas Fotoacústicas/métodos , Ultrassonografia/métodos , Neoplasias Vasculares/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/patologia , Craniotomia , Modelos Animais de Doenças , Endotelina-1 , Epinefrina , Feminino , Xenoenxertos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Oxigênio , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia , Neoplasias Vasculares/patologia , Vasoconstrição
14.
Arterioscler Thromb Vasc Biol ; 40(4): 943-957, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32075416

RESUMO

OBJECTIVE: HuR (human antigen R)-an RNA-binding protein-is involved in regulating mRNA stability by binding adenylate-uridylate-rich elements. This study explores the role of HuR in the regulation of smooth muscle contraction and blood pressure. Approach and Results: Vascular HuRSMKO (smooth muscle-specific HuR knockout) mice were generated by crossbreeding HuRflox/flox mice with α-SMA (α-smooth muscle actin)-Cre mice. As compared with CTR (control) mice, HuRSMKO mice showed hypertension and cardiac hypertrophy. HuR levels were decreased in aortas from hypertensive patients and SHRs (spontaneously hypertensive rats), and overexpression of HuR could lower the blood pressure of SHRs. Contractile response to vasoconstrictors was increased in mesenteric artery segments isolated from HuRSMKO mice. The functional abnormalities in HuRSMKO mice were attributed to decreased mRNA and protein levels of RGS (regulator of G-protein signaling) protein(s) RGS2, RGS4, and RGS5, which resulted in increased intracellular calcium increase. Consistently, the degree of intracellular calcium ion increase in HuR-deficient smooth muscle cells was reduced by overexpression of RGS2, RGS4, or RGS5. Finally, administration of RGS2 and RGS5 reversed the elevated blood pressure in HuRSMKO mice. CONCLUSIONS: Our findings indicate that HuR regulates vascular smooth muscle contraction and maintains blood pressure by modulating RGS expression.


Assuntos
Pressão Sanguínea/fisiologia , Proteína Semelhante a ELAV 1/fisiologia , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiologia , Vasoconstrição , Animais , Cálcio/metabolismo , Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Proteínas RGS/genética , RNA Mensageiro/metabolismo , Ratos Endogâmicos SHR , Ratos Wistar
16.
Science ; 367(6483)2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32001524

RESUMO

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies.


Assuntos
Edema Encefálico/líquido cefalorraquidiano , Edema Encefálico/etiologia , Sistema Glinfático/fisiopatologia , Acidente Vascular Cerebral/líquido cefalorraquidiano , Acidente Vascular Cerebral/complicações , Animais , Aquaporina 5/metabolismo , Edema Encefálico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/diagnóstico por imagem , Vasoconstrição
17.
Am J Physiol Heart Circ Physiol ; 318(2): H470-H483, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31922892

RESUMO

Reactive oxygen species (ROS), mitochondrial dysfunction, and excessive vasoconstriction are important contributors to chronic hypoxia (CH)-induced neonatal pulmonary hypertension. On the basis of evidence that PKCß and mitochondrial oxidative stress are involved in several cardiovascular and metabolic disorders, we hypothesized that PKCß and mitochondrial ROS (mitoROS) signaling contribute to enhanced pulmonary vasoconstriction in neonatal rats exposed to CH. To test this hypothesis, we examined effects of the PKCß inhibitor LY-333,531, the ROS scavenger 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (TEMPOL), and the mitochondrial antioxidants mitoquinone mesylate (MitoQ) and (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) on vasoconstrictor responses in saline-perfused lungs (in situ) or pressurized pulmonary arteries from 2-wk-old control and CH (12-day exposure, 0.5 atm) rats. Lungs from CH rats exhibited greater basal tone and vasoconstrictor sensitivity to 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α (U-46619). LY-333,531 and TEMPOL attenuated these effects of CH, while having no effect in lungs from control animals. Basal tone was similarly elevated in isolated pulmonary arteries from neonatal CH rats compared with control rats, which was inhibited by both LY-333,531 and mitochondria-targeted antioxidants. Additional experiments assessing mitoROS generation with the mitochondria-targeted ROS indicator MitoSOX revealed that a PKCß-mitochondrial oxidant signaling pathway can be pharmacologically stimulated by the PKC activator phorbol 12-myristate 13-acetate in primary cultures of pulmonary artery smooth muscle cells (PASMCs) from control neonates. Finally, we found that neonatal CH increased mitochondrially localized PKCß in pulmonary arteries as assessed by Western blotting of subcellular fractions. We conclude that PKCß activation leads to mitoROS production in PASMCs from neonatal rats. Furthermore, this signaling axis may account for enhanced pulmonary vasoconstrictor sensitivity following CH exposure.NEW & NOTEWORTHY This research demonstrates a novel contribution of PKCß and mitochondrial reactive oxygen species signaling to increased pulmonary vasoconstrictor reactivity in chronically hypoxic neonates. The results provide a potential mechanism by which chronic hypoxia increases both basal and agonist-induced pulmonary arterial smooth muscle tone, which may contribute to neonatal pulmonary hypertension.


Assuntos
Hipóxia/metabolismo , Proteína Quinase C beta/metabolismo , Animais , Animais Recém-Nascidos , Doença Crônica , Óxidos N-Cíclicos/farmacologia , Inibidores Enzimáticos , Feminino , Depuradores de Radicais Livres , Indóis/farmacologia , Maleimidas/farmacologia , Compostos Organofosforados/farmacologia , Estresse Oxidativo , Gravidez , Proteína Quinase C beta/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Circulação Pulmonar , Ratos , Espécies Reativas de Oxigênio , Marcadores de Spin , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Vasoconstrição , Vasoconstritores/farmacologia
18.
Kidney Int ; 97(1): 31-33, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31901353

RESUMO

Cardiovascular and renal outcome trials demonstrate nephroprotection with sodium-glucose cotransporter-2 inhibitors in people with type 2 diabetes. Attenuation of hyperfiltration is believed to be responsible for the nephroprotection, and studies in young adults with type 1 diabetes suggest that afferent arteriolar vasoconstriction induced by a tubuloglomerular feedback mechanism may be responsible for this effect. The study by van Bommel et al. suggests that this mechanism may not hold true in older adults with type 2 diabetes, who instead attenuate elevated glomerular filtration rate via post-glomerular vasodilation.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Compostos Benzidrílicos , Método Duplo-Cego , Taxa de Filtração Glomerular , Glucosídeos , Hemodinâmica , Humanos , Transportador 2 de Glucose-Sódio , Vasoconstrição , Vasodilatação , Adulto Jovem
19.
Stroke ; 51(1): 143-148, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31694506

RESUMO

Background and Purpose- Symptomatic vasospasm is an important factor that affects the outcomes of aneurysmal subarachnoid hemorrhage. Subarachnoid blood volume can predict symptomatic vasospasm, and we postulated that the blood clot density would also be an important factor involved in such events. The present study aimed to determine the relationship between the incidence of symptomatic vasospasm and the Hounsfield unit (HU) value of the interpeduncular cistern that reflects the density of hematomas. Methods- Data from 323 patients admitted and treated at a single center between 2008 and 2017 within 24 hours of subarachnoid hemorrhage onset were retrospectively analyzed. Initial HU values of the interpeduncular cistern were measured using CT, then correlations with the incidence of symptomatic vasospasm and HU values as well as other variables were assessed. Results- Symptomatic vasospasm developed in 54 (16.7%) of the 323 patients. The incidence of symptomatic vasospasm was low (1.8%, 2/166) for HU <50, but this incidence increased greatly when the HU value exceeded 50 (23.7%, 22/93 for HU >50 to ≤60, and 45.3%, 29/64 for HU >60). The odds ratio for symptomatic vasospasm was 2.0 (95% CI, 1.6-2.4) per 5 HU increase. Symptomatic vasospasm correlated significantly with intraventricular hemorrhage (P=0.05) and with intracerebral hematoma (P=0.046) but even more significantly with the HU value of the interpeduncular cistern (P<0.0001). Conclusions- The HU value of the interpeduncular cistern on initial CT is an accurate and reliable predictor of symptomatic vasospasm.


Assuntos
Hematoma/epidemiologia , Aneurisma Intracraniano/epidemiologia , Hemorragia Subaracnóidea/etiologia , Vasoespasmo Intracraniano/etiologia , Idoso , Encéfalo/fisiopatologia , Feminino , Hematoma/complicações , Humanos , Incidência , Aneurisma Intracraniano/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemorragia Subaracnóidea/diagnóstico , Vasoconstrição/fisiologia , Vasoespasmo Intracraniano/diagnóstico
20.
World Neurosurg ; 135: e427-e434, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31837497

RESUMO

OBJECTIVE: Pharmacologically induced electroencephalogram (EEG) silence increases tolerance of ischemic period by reducing cerebral metabolism. We hypothesized that sevoflurane, a cerebral vasodilator, will maintain cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) better than propofol, a cerebral vasoconstrictor, during EEG silence. To validate this, we compared the effect of sevoflurane and propofol on CBF and CMRO2 during surgical plane of anasthesia (SP) and burst suppression on EEG (BS). METHODS: We conducted a prospective, double-blinded trial where patients undergoing neurosurgery were randomized to receive propofol or sevoflurane. Mean velocity (MV) and pulsatility index (PI) of bilateral middle cerebral arteries (MCA) were measured as surrogate of CBF. Jugular venous oxygen saturation (SjvO2) and arteriovenous oxygen difference (AjvDO2) were obtained to assess CMRO2. The values were compared between groups using Student t test and within the group with analysis of variance at SP and BS. RESULTS: BS decreased MV and increased PI in propofol group (P < 0.001 and P < 0.02 on normal side, P < 0.004 and P < 0.001 on tumor side). There was no significant change in sevoflurane group. BS with sevoflurane increased SjvO2 (P < 0.001) and decreased AjvDO2 (P < 0.001). Change in SjvO2 and AjvDO2 with propofol at SP and BS was variable. CONCLUSIONS: In our study, sevoflurane had a safer profile on cerebral oxygenation during BS while not altering the CBF, suggesting increased availability of oxygen. Propofol, on the other hand, produced cerebral vasoconstriction with BS. The effect of propofol on oxygenation was unpredictable, with low SjvO2 and high AjvDO2 even at surgical plane of anesthesia.


Assuntos
Anestésicos Intravenosos/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Propofol/farmacologia , Sevoflurano/farmacologia , Vasodilatadores/farmacologia , Adulto , Método Duplo-Cego , Eletroencefalografia , Feminino , Humanos , Masculino , Procedimentos Neurocirúrgicos/métodos , Oxigênio/sangue , Estudos Prospectivos , Vasoconstrição/efeitos dos fármacos
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