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1.
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
2.
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
3.
Hypertension ; 74(4): 936-946, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378107

RESUMO

Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)-induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher in Tie-2-Cre-mediated regulatory associated protein of mTOR (mammalian target of rapamycin; Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired in Tie2Cre-RaptorKD mice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation in Raptorflox/- mice to a similar extent as in Tie2Cre-RaptorKD mice. Metabolomic profiling revealed that the plasma content of prostaglandin E2 was reduced in Tie2Cre-RaptorKD mice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) with siRNA-mediated RPTOR deficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension in Tie2Cre-RaptorKD mice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E2 production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Pressão Sanguínea/fisiologia , Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais/fisiologia , Angiotensina II , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ciclo Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Hipertensão/induzido quimicamente , Indometacina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Prostaglandina-E Sintases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
4.
Hypertension ; 74(4): 817-825, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422694

RESUMO

The BBSome-a complex consisting of 8 Bardet-Biedl syndrome proteins-is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of Bbs1 gene-a critical component of the BBSome complex-reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle Bbs1 gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced ET-1 (endothelin-1)-induced contractility of mesenteric arteries-an effect reversed by blockade of the AT1 (angiotensin type 1 receptor) with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of renin-angiotensin system signaling.


Assuntos
Pressão Sanguínea/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Rigidez Vascular/fisiologia , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Aorta/fisiologia , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/genética , Vasodilatação/fisiologia
5.
Int Heart J ; 60(4): 854-861, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31257335

RESUMO

The aim of this single-arm pilot study was to determine the effects of whole-body vibration training (WBVT) on endothelial function in elderly patients with cardiovascular diseases, as well as its safety. A total of 20 elderly patients with stable cardiovascular diseases underwent WBVT, which consisted of five static resistance training exercises (squats, wide stance squats, toe-stands, squats + band, and front lunges). The parameters of WBVT included vertical vibrations, 30 Hz frequency, and a 3-mm peak-to-peak amplitude. Each vibration session lasted 30 seconds, with 120 seconds of rest between sessions. Before and after WBVT, the reactive hyperemia peripheral arterial tonometry index (RH-PAT index) and transcutaneous oxygen pressure (tcPO2) were recorded as a measure of endothelial function and peripheral blood circulation. Systolic blood pressure, diastolic blood pressure, heart rate, and arterial oxygen saturation of pulse oximetry (SpO2) were measured at each rest interval as well as before and after WBVT. All patients completed our WBVT protocol without adverse events. The RH-PAT index significantly increased following WBVT (1.42 to 2.06, P < 0.001). There were no significant changes in heart rate (P = 0.777), systolic blood pressure (P = 0.183), diastolic blood pressure (P = 0.925), or SpO2 (P = 0.248) during WBVT. In conclusion, we demonstrated the acute effects of WBVT on endothelial function, with no reports of adverse events. These findings support the need for further randomized controlled studies to investigate the long-term effects of WBVT.


Assuntos
Artérias/fisiopatologia , Doenças Cardiovasculares/terapia , Endotélio Vascular/fisiopatologia , Modalidades de Fisioterapia/instrumentação , Vasodilatação/fisiologia , Idoso , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Masculino , Força Muscular/fisiologia , Projetos Piloto , Pletismografia , Estudos Retrospectivos , Resultado do Tratamento , Vibração
7.
Hypertension ; 74(1): 208-215, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31055952

RESUMO

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 µg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.


Assuntos
Acetilcolina/administração & dosagem , Artéria Braquial/efeitos dos fármacos , Cateterismo Cardíaco/métodos , Doença da Artéria Coronariana/diagnóstico , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Idoso , Artéria Braquial/fisiopatologia , Estudos de Coortes , Circulação Coronária/fisiologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Infusões Intralesionais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Medição de Risco , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
8.
J Headache Pain ; 20(1): 47, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053059

RESUMO

BACKGROUND: Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action. METHODS: Human blood vessel segments (middle meningeal artery, proximal and distal coronary arteries, and saphenous vein) were mounted in organ baths and concentration response curves to isometheptene were constructed. Calcitonin gene-related peptide (CGRP)-induced neurogenic dural vasodilation was elicited in the presence of the enantiomers using a rat closed cranial window model. RESULTS: The isometheptene enantiomers did not induce any significant contraction in human blood vessels, except in the middle meningeal artery, when they were administered at the highest concentration (100 µM). Interestingly in rats, (S)-isometheptene induced more pronounced vasopressor responses than (R)-isometheptene. However, none of these compounds affected the CGRP-induced vasodilator responses. CONCLUSION: The isometheptene enantiomers displayed a relatively safe peripheral vascular profile, as they failed to constrict the human coronary artery. These compounds do not appear to modulate neurogenic dural CGRP release, therefore, their antimigraine site of action remains to be determined.


Assuntos
Vasos Coronários/efeitos dos fármacos , Artérias Meníngeas/efeitos dos fármacos , Metilaminas/farmacologia , Transtornos de Enxaqueca , Veia Safena/efeitos dos fármacos , Adulto , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Artérias Meníngeas/fisiologia , Metilaminas/química , Metilaminas/uso terapêutico , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Veia Safena/fisiologia , Estereoisomerismo , Vasoconstritores/química , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/química , Vasodilatadores/farmacologia
9.
Wilderness Environ Med ; 30(2): 141-149, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30979538

RESUMO

INTRODUCTION: We tested the hypothesis that individual susceptibility to freezing cold injury might be reflected in an attenuated cold-induced vasodilatation (CIVD) response by comparing the CIVD responses of an elite alpinist with a history of freezing cold injury in the feet (case alpinist) with those of an age- and ability- matched noninjured alpinists control group (controls). According to this hypothesis, the vasomotor responses to a CIVD test of the case alpinist would represent a pathophysiological response when compared with the normal physiological response of a noninjured cohort. METHODS: The case alpinist and the controls in the cohort group conducted a cold water immersion test comprising sequential immersion of a hand and foot for 5 min in 35°C water, followed by a 30-min immersion in 8°C water and a 10-min recovery period in room air. During this test we monitored the finger and toe skin temperatures. RESULTS: The case alpinist had a significantly attenuated CIVD response and a lower skin temperature in all injured and noninjured digits during immersion (∼2°C lower than in the control group) and an attenuated recovery of finger skin temperatures (∼6°C lower than in the control group). CONCLUSIONS: The attenuated CIVD response of the case alpinist may reflect a previously unrecognized enhanced susceptibility to frostbite. In addition to the poor vasomotor response observed in the injured toes, he also exhibited a poor vasomotor response in his noninjured fingers. The results of the present study indicate that a test of vasomotor activity during thermal stress may identify individuals predisposed to cold injury.


Assuntos
Temperatura Baixa/efeitos adversos , Temperatura Cutânea/fisiologia , Vasodilatação/fisiologia , Adulto , Estudos de Casos e Controles , Dedos/fisiologia , Congelamento das Extremidades/fisiopatologia , Humanos , Imersão/fisiopatologia , Masculino , Montanhismo/fisiologia , Dedos do Pé/lesões , Dedos do Pé/fisiologia
10.
Hypertension ; 73(6): 1327-1335, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006327

RESUMO

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P<0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P=0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r2=0.303; P<0.001) and Hb ( r2=0.230; P=0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P<0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P=0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.


Assuntos
Altitude , Viscosidade Sanguínea/fisiologia , Artéria Braquial/fisiopatologia , Hemoglobinas/metabolismo , Policitemia/sangue , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Adulto , Artéria Braquial/diagnóstico por imagem , Endotélio Vascular/fisiopatologia , Humanos , Masculino , Policitemia/etiologia , Policitemia/fisiopatologia , Fatores de Risco , Ultrassonografia Doppler
11.
Hypertension ; 73(6): 1319-1326, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006328

RESUMO

The chronic hypoxia of high-altitude (HA) residence reduces uterine artery blood flow during pregnancy, likely contributing to an increased frequency of preeclampsia and intrauterine growth restriction. We hypothesized that this lesser pregnancy blood flow rise was due, in part, to reduced vasodilation of myometrial arteries (MAs). Here, we assessed MA vasoreactivity in healthy residents of high (2902±39 m) or low altitude (LA; 1669±10 m). MA contractile responses to potassium chloride, phenylephrine, or the thromboxane A2 agonist U46619 did not differ between LA and HA women. Acetylcholine vasodilated phenylephrine or U466119 preconstricted MAs at LA, yet had no effect on HA MAs. In contrast, another vasodilator, bradykinin, relaxed MAs from both altitudes similarly. At LA, the NO synthase inhibitor L-NG-nitroarginine methyl ester decreased both acetylcholine and bradykinin vasodilation by 56% and 33%, respectively. L-NG-nitroarginine methyl ester plus the COX (cyclooxygenase) inhibitor indomethacin had similar effects on acetylcholine and bradykinin vasodilation (68% and 42% reduction, respectively) as did removing the endothelium (78% and 50% decrease, respectively), suggesting a predominantly NO-dependent vasodilation at LA. However, at HA, L-NG-nitroarginine methyl ester did not change bradykinin vasodilation, whereas indomethacin or endothelium removal decreased it by 28% and 72%, respectively, indicating impaired NO signaling at HA. Suggesting that the impairment was downstream of eNOS (endothelial NO synthase), HA attenuated the vasodilation elicited by the NO donor sodium nitroprusside. We concluded that reduced NO-dependent MA vasodilation likely contributes to diminished uteroplacental perfusion in HA pregnancies.


Assuntos
Altitude , Endotélio Vascular/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Pré-Eclâmpsia/etiologia , Artéria Uterina/fisiopatologia , Vasodilatação/fisiologia , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Adulto Jovem
12.
J Headache Pain ; 20(1): 27, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866804

RESUMO

Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Sistema Cardiovascular/fisiopatologia , Humanos , Transtornos de Enxaqueca/etiologia , Transtornos de Enxaqueca/fisiopatologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Fatores Sexuais , Vasodilatação/fisiologia
13.
Hypertension ; 73(4): 849-858, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827147

RESUMO

Obesity is characterized by enhanced MR (mineralocorticoid receptor) activation, vascular stiffness, and associated cardiovascular and kidney disease. Consumption of a Western-style diet (WD), high in saturated fat and refined carbohydrates, by female mice, leads to obesity and vascular stiffening. Use of ECMR (endothelial cell-specific MR) knockout mice supports that ECMR activation is critical for development of vascular and cardiac fibrosis and stiffening. However, the role of ECMR activation in kidney inflammation and fibrosis remains unknown. We hypothesized that cell-specific deletion of ECMR would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Four-week-old female ECMR KO and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding increased body weight and fat mass, proteinuria, as well as vascular stiffness indices (pulse wave velocity and kidney artery stiffening) and impaired endothelial-dependent vasodilatation without blood pressure changes. The WD-induced kidney arterial stiffening was associated with attenuated eNOS (endothelial NO synthase) activation, increased oxidative stress, proinflammatory immune responses, alterations in extracellular matrix degradation pathways, and fibrosis. ECMR deletion prevented these abnormalities by improving eNOS activation and reducing macrophage proinflammatory M1 polarization, expression of TG2 (transglutaminase 2), and MMP (matrix metalloproteinase)-9. Our data support the concept that ECMR activation contributes to endothelial dysfunction, increased kidney artery fibrosis/stiffening, and impaired NOS (NO synthase) activation, processes associated with macrophage infiltration and polarization, inflammation, and oxidative stress, collectively resulting in tubulointerstitial fibrosis in females consuming a WD.


Assuntos
Endotélio Vascular/metabolismo , Nefropatias/patologia , Obesidade/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Artéria Renal/patologia , Rigidez Vascular/fisiologia , Vasodilatação/fisiologia , Animais , Dieta Ocidental/efeitos adversos , Endotélio Vascular/fisiopatologia , Feminino , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia
14.
Acta Ophthalmol ; 97(5): 441-450, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30801973

RESUMO

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels in vitro and ex vivo. Subsequently, the in vitro findings are translated to clinical studies in normal persons in vivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor-specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.


Assuntos
Fluxo Sanguíneo Regional/fisiologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Vasos Retinianos/fisiopatologia , Pesquisa Médica Translacional/métodos , Vasodilatação/fisiologia , Animais , Capilares/diagnóstico por imagem , Capilares/fisiopatologia , Humanos , Vasos Retinianos/diagnóstico por imagem
15.
Biomed Pharmacother ; 112: 108666, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30784936

RESUMO

OBJECTIVE: This work aimed to investigate whether G protein-coupled estrogen receptor (GPER) can improve the renal interlobular artery vascular function by increasing the NO content, thereby protecting against renal ischemia-reperfusion (IR) injury. METHODS: This study classified ovariectomised (OVX) female Sprague-Dawley rats into OVX, OVX + IR, OVX + IR + G1 (the GPER agonist G1), OVX + IR + G1+G15 (GPER blocker) and OVX + IR + G1+L-NAME (eNOS blocker) groups. Enzyme-linked immunosorbent assay was performed to detect the estrogen levels in the body and eliminate interference from endogenous estrogens. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) and HE staining, renal function test and Paller scoring were performed to identify the successful model and detect the degree of renal and renal interlobular arteries injury. The in vitro microvascular pressure diameter measurement technique was used to detect the contraction and diastolic activities of the renal interlobular arteries in each group. Immunofluorescence technique was used to observe the localisation and expression levels of GPER and eNOS in renal interlobular arteries. The GPER and eNOS protein expression levels in each group were detected by Western blot. The NO content in the serum of each group was detected by the nitrate reductase method. RESULT: After OVX, the estrogen level in the body decreased significantly (P < 0.01), and TUNEL staining showed a significant increase in the degree of renal tubular epithelial cell apoptosis in the IR group. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were significantly increased in the IR group (P < 0.01), and the Paller score showed significantly increased kidney damage. When performing drug treatment, the G1 intervention group significantly decreased serum BUN and SCr levels after IR injury (P < 0.01). The Paller score showed significantly decreased the degree of renal injury (P < 0.01). After IR, the renal interlobular artery contraction rate and systolic velocity of blood vessels were significantly decreased (P < 0.01). The G1 intervention group significantly restored contraction rate and systolic velocity of blood vessels (P < 0.01), and G15 and L-NAME partially reversed this effect (P < 0.01). Immunofluorescence technique showed that GPER was expressed in renal interlobular artery smooth muscle and endothelial cells. After IR injury, the GPER protein expression increased, and the eNOS protein expression decreased significantly (P < 0.01). Western blot showed that after IR injury, the GPER protein expression increased, and the eNOS protein expression decreased significantly. After G1 intervention, the GPER content did not change, and the eNOS content increased significantly (P < 0.01). After ischemia and reperfusion, the serum NO content decreased significantly, but it increased after G1 intervention. G15 and L-NAME reversed the effects of G1 to varying degrees (both at P < 0.01). CONCLUSION: GPER may improve the renal interlobular artery vascular function by increasing the NO content, thereby protecting against renal IR injury.


Assuntos
Rim/metabolismo , Receptores Estrogênicos/metabolismo , Artéria Renal/metabolismo , Traumatismo por Reperfusão/metabolismo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Animais , Feminino , Rim/irrigação sanguínea , Rim/patologia , Ovariectomia/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle
16.
Cir Cir ; 87(2): 196-204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30768074

RESUMO

Introduction: Primary hyperparathyroidism (PHPT) is the leading cause of outpatient hypercalcemia associated with increased cardiovascular risk. The flow-mediated vasodilation (FMV) has been proposed as a non-invasive method for assessing endothelial function. Objective: To compare the endothelial dysfunction measured by FMV and diastolic dysfunction in patients with PHPT before and after parathyroidectomy. Method: We performed a quasi-experimental (before-after) study to evaluate diastolic function and FMV in patients with PHPT before and six months after parathyroidectomy. Results: Fifteen patients completed study: 12 women and 3 men; 73% presented lithiasis, 27% osteoporosis and 53% metabolic syndrome; 73% presented diastolic dysfunction before the surgery and 60% after the surgery (p = 0.09). Post-isquemia brachial diameter improved from 41 mm (before surgery) to 46 mm (after surgery; p = 0.020). After surgery, we also observed an increase in the brachial diameter pre vs. post-ischemia from 41 to 46 mm (p = 0.005). Before surgery, the change in the delta of brachial diameter pre and post-ischemia was 1 mm and up to 4 mm after surgery (p = 0.03). Conclusions: There is a minor endothelial dysfunction measured by FMV in patients who underwent surgery for PHPT at 6 months after surgery, as well as a trend towards improvement in diastolic dysfunction. Echocardiography can be useful in the preoperative evaluation in patients with asymptomatic PHPT.


Assuntos
Endotélio Vascular/fisiopatologia , Hiperparatireoidismo Primário/fisiopatologia , Hiperparatireoidismo Primário/cirurgia , Síndrome Metabólica/fisiopatologia , Paratireoidectomia , Vasodilatação/fisiologia , Idoso , Diástole/fisiologia , Ecocardiografia , Feminino , Humanos , Hiperparatireoidismo Primário/complicações , Masculino , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
18.
Diabetes Res Clin Pract ; 148: 160-168, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30641171

RESUMO

AIMS: Omentin is an adipokine that has protective effects against cardiovascular damage. Previous studies showed an inverse relationship between omentin and obesity, diabetes, and cardiovascular disease. This study aimed to investigate the association between omentin and vascular endothelial function in patients with type 2 diabetes (T2D). METHODS: The subjects were 425 patients with T2D and 223 non-diabetic controls. Fasting plasma omentin levels were measured by enzyme-linked immunosorbent assay, and the endothelium-dependent, flow-mediated dilatation (FMD) was measured by ultrasonography. RESULTS: Plasma omentin levels were higher, while FMD was lower in participants with T2D than in non-diabetic controls. No significant correlation was found between plasma omentin levels and FMD in either non-diabetic controls or participants with T2D on multivariate analysis. However, stratified analysis in T2D patients revealed that plasma omentin levels were independently and positively associated with FMD in high cardiovascular risk subgroups according to age (≥65 years), estimated glomerular filtration rate (<60 mL/min/1.73 m2), or preexisting cardiovascular diseases but not in low-risk subgroups. CONCLUSIONS: Plasma omentin levels are independently associated with endothelial function in subgroups of patients with T2D at elevated cardiovascular risk. This study suggests a protective role of omentin against endothelial dysfunction, particularly in high-risk patients.


Assuntos
Doenças Cardiovasculares/sangue , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Endotélio Vascular/fisiopatologia , Lectinas/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vasodilatação/fisiologia
19.
Diabetologia ; 62(3): 485-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30607464

RESUMO

AIMS/HYPOTHESIS: Plasma ATP is a potent vasodilator and is thought to play a role in the local regulation of blood flow. Type 2 diabetes is associated with reduced tissue perfusion. We aimed to examine whether individuals with type 2 diabetes have reduced plasma ATP concentrations compared with healthy control participants (case-control design). METHODS: We measured femoral arterial and venous plasma ATP levels with the intravascular microdialysis technique during normoxia, hypoxia and one-legged knee-extensor exercise (10 W and 30 W) in nine participants with type 2 diabetes and eight control participants. In addition, we infused acetylcholine (ACh), sodium nitroprusside (SNP) and ATP into the femoral artery to assess vascular function and ATP signalling. RESULTS: Individuals with type 2 diabetes had a lower leg blood flow (LBF; 2.9 ± 0.1 l/min) compared with the control participants (3.2 ± 0.1 l/min) during exercise (p < 0.05), in parallel with lower venous plasma ATP concentration (205 ± 35 vs 431 ± 72 nmol/l; p < 0.05). During systemic hypoxia, LBF increased from 0.35 ± 0.04 to 0.54 ± 0.06 l/min in control individuals, whereas it did not increase (0.25 ± 0.04 vs 0.31 ± 0.03 l/min) in the those with type 2 diabetes and was lower than in the control individuals (p < 0.05). Hypoxia increased venous plasma ATP levels in both groups (p < 0.05), but the increase was higher in control individuals (90 ± 26 nmol/l) compared to those with type 2 diabetes (18 ± 5 nmol/l). LBF and vascular conductance were lower during ATP (0.15 and 0.4 µmol min-1 [kg leg mass]-1) and ACh (100 µg min-1 [kg leg mass]-1) infusion in individuals with type 2 diabetes compared with the control participants (p < 0.05), whereas there was no difference during SNP infusion. CONCLUSIONS/INTERPRETATION: These findings demonstrate that individuals with type 2 diabetes have lower plasma ATP concentrations during exercise and hypoxia compared with control individuals, and this occurs in parallel with lower blood flow. Moreover, individuals with type 2 diabetes have a reduced vasodilatory response to infused ATP. These impairments in the ATP system are both likely to contribute to the reduced tissue perfusion associated with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02001766.


Assuntos
Trifosfato de Adenosina/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício/fisiologia , Hipóxia/fisiopatologia , Músculo Esquelético/fisiopatologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia
20.
Physiol Res ; 68(2): 219-231, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30628831

RESUMO

The endothelium contributes to the maintenance of vasodilator tone by releasing endothelium-derived relaxing factors, including nitric oxide (NO). In hypertension, endothelial nitric oxide synthase (eNOS) produces less NO and could be one of the contributing factors to the increased peripheral vascular resistance. Agonist-induced Ca(2+) entry is essential for the activation of eNOS. The transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca(2+)-permeant cation channel, is expressed in the endothelial cells and involved in the regulation of vascular tone. The present study aimed to investigate the role of TRPV4 channel in endothelium-dependent NO-mediated relaxation of the resistance artery in hypertensive rats. Using a wire myograph, relaxation response to the TRPV4 activator, 4alpha-phorbol-12,13-didecanoate (4alphaPDD) was assessed in mesenteric arteries obtained from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). Compared to WKY, SHR demonstrated a significantly attenuated 4alphaPDD-induced endothelium-dependent NO-mediated relaxation. Immunohistochemical analysis revealed positive staining for TRPV4 in the endothelium of mesenteric artery sections in both WKY and SHR. Furthermore, TRPV4 mRNA and protein expressions in SHR were significantly lower than their expression levels in WKY rats. We conclude that 4alphaPDD-induced endothelium-dependent NO-mediated vasorelaxation is reduced in SHR and downregulation of TRPV4 could be one of the contributing mechanisms.


Assuntos
Endotélio Vascular/metabolismo , Hipertensão/metabolismo , Artérias Mesentéricas/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Canais de Cátion TRPV/metabolismo , Vasodilatação/fisiologia , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Endotélio Vascular/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Técnicas de Cultura de Órgãos , Forbóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Canais de Cátion TRPV/agonistas , Vasodilatação/efeitos dos fármacos
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