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1.
FASEB J ; 35(3): e21419, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33566370

RESUMO

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/farmacologia , /metabolismo , Losartan/farmacologia , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Furina/genética , Furina/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Vasoconstritores/farmacologia
2.
Am J Physiol Heart Circ Physiol ; 320(3): H1080-H1088, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416458

RESUMO

Insufficient sleep is associated with endothelial vasomotor dysfunction and increased cardiovascular risk. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn, reducing cardiovascular risk. We tested the hypotheses that regular aerobic exercise would 1) improve endothelial vasodilation and 2) decrease endothelin (ET)-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep <7 h/night. Thirty-six healthy, middle-aged adults were studied: 16 with normal sleep duration (age: 57 ± 2 yr; sleep duration: 7.4 ± 0.1 h/night) and 20 with short sleep duration (age: 56 ± 1 yr; sleep duration: 6.2 ± 0.1 h/night). The 20 short sleepers completed a 3-mo aerobic exercise training intervention. Forearm blood flow was determined (via plethysmography) in response to intra-arterial acetylcholine (ACh), BQ-123 (ETA receptor antagonist), ACh + BQ-123, and sodium nitroprusside. Forearm blood flow responses to ACh were lower (∼20%; P < 0.05) in the short (from 4.2 ± 0.2 to 10.5 ± 0.6 mL/100 mL tissue/min) versus normal (4.2 ± 0.2 to 12.7 ± 0.6 mL/100 mL tissue/min) sleepers. In response to BQ-123, the short-sleep group had a significantly greater increase in resting forearm blood flow than the normal-sleep group (∼25% vs. ∼8%). ACh + BQ-123 resulted in a significant (∼25%) increase in the ACh-mediated vasodilation in the short-sleep group only. After exercise training, although nightly sleep duration was unchanged (6.4 ± 0.1 h/night), ACh-mediated vasodilation was significantly higher (∼20%), ET-1-mediated vasoconstriction was significantly lower (∼80%), and the vasodilator response to ACh was not increased with ETA receptor blockade. Regular aerobic exercise, independent of changes in nightly sleep duration, can counteract insufficient sleep-related endothelial vasomotor dysfunction.NEW & NOTEWORTHY Habitual insufficient nightly sleep (<7 h/night) is associated with increased risk of cardiovascular disease and events. Endothelial dysfunction, specifically reduced endothelium-dependent vasodilation and increased endothelin (ET)-1-mediated vasoconstriction, is considered to be a major contributing mechanism underlying increased vascular risk with insufficient sleep. In contrast to insufficient sleep, regular aerobic exercise enhances endothelial vasomotor function, reducing the risk of cardiovascular disease and associated events. In the present study, we determined the effects of aerobic exercise training on endothelium-dependent vasodilation and ET-1 vasoconstriction in adults who habitually sleep <7 h/night. After exercise training, although nightly sleep duration was unchanged, endothelium-dependent vasodilation was significantly enhanced and ET-1-mediated vasoconstrictor tone was significantly reduced in adults who sleep <7 h/night. Regular aerobic exercise training can mitigate insufficient sleep-related endothelial vasomotor dysfunction and, in turn, potentially reduce the cardiovascular risk associated with habitual insufficient nightly sleep.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Endotélio Vascular/fisiopatologia , Exercício Físico , Hemodinâmica , Privação do Sono/terapia , Sono , Sistema Vasomotor/fisiopatologia , Acetilcolina/farmacologia , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Endotelinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Estilo de Vida Saudável , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento de Redução do Risco , Privação do Sono/diagnóstico , Privação do Sono/fisiopatologia , Fatores de Tempo , Vasoconstrição , Vasoconstritores/farmacologia , Vasodilatação , Vasodilatadores/farmacologia , Sistema Vasomotor/efeitos dos fármacos
3.
Int Heart J ; 62(1): 162-170, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33455985

RESUMO

High-mobility group box 1 (HMGB1) is increased in the myocardium under pressure overload (PO) and is involved in PO-induced cardiac remodeling. The mechanisms of the upregulation of cardiac HMGB1 expression have not been fully elucidated. In the present study, a mouse transverse aortic constriction (TAC) model was used, and an angiotensin II (Ang II) type 1 (AT1) receptor inhibitor (losartan) or Ang II type 2 (AT2) receptor inhibitor (PD123319) was administrated to mice for 14 days. Cardiac myocytes were cultured and treated with Ang II for 5 minutes to 48 hours conditionally with the blockage of the AT1 or AT2 receptor. TAC-induced cardiac hypertrophy was observed at 14 days after the operation, which was partially reversed by losartan, but not by PD123319. Similarly, the upregulated HMGB1 expression levels observed in both the serum and myocardium induced by TAC were reduced by losartan. Elevated cardiac HMGB1 protein levels, but not mRNA or serum levels, were significantly decreased by PD123319. Furthermore, HMGB1 expression levels in culture media and cardiac myocytes were increased following Ang II treatment in vitro, positively associated with the duration of treatment. Similarly, Ang II-induced upregulation of HMGB1 in vitro was inhibited by both losartan and PD123319. These results suggest that upregulation of HMGB1 in serum and myocardium under PO, which are partially derived from cardiac myocytes, may be induced by Ang II via the AT1 and AT2 receptors. Additionally, amelioration of PO-induced cardiac hypertrophy following losartan treatment may be associated with the reduction of HMGB1 expression through the AT1 receptor.


Assuntos
Angiotensina II/farmacologia , Proteína HMGB1/efeitos dos fármacos , Losartan/farmacologia , Miocárdio/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/patologia , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Estudos de Casos e Controles , Constrição , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Piridinas/administração & dosagem , Piridinas/farmacologia , Regulação para Cima , Vasoconstritores/farmacologia
4.
Clin Sci (Lond) ; 134(18): 2489-2501, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32990314

RESUMO

Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin-angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Angiotensina II/efeitos dos fármacos , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vasoconstritores/farmacologia
5.
Am J Physiol Heart Circ Physiol ; 319(4): H787-H792, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32857604

RESUMO

Fluctuations in diastolic pressure modulate muscle sympathetic nerve activity (MSNA) through the arterial baroreflex. A higher sympathetic baroreflex sensitivity (sBRS) to pressure falls compared with rises has been reported; however, the underlying mechanisms are unclear. We assessed whether beat-to-beat falling and rising diastolic pressures operate on two distinct baroreflex response curves. Twenty-two men (32 ± 8 yr) underwent sequential bolus injections of nitroprusside and phenylephrine (modified Oxford test) with continuous recording of heart rate, blood pressure, and MSNA. The weighted negative linear regression slope between falling or rising diastolic pressure and MSNA burst incidence quantified sBRSfall and sBRSrise, respectively. The diastolic pressure evoking a MSNA burst incidence of 50 (T50) was calculated. sBRSfall was greater than sBRSrise (-6.24 ± 2.80 vs. -4.34 ± 2.16 bursts·100 heartbeats-1·mmHg-1, P = 0.01) and had a narrower operating range (14 ± 8 vs. 20 ± 10 mmHg, P = 0.01) that was shifted rightward (T50, 75 ± 9 and 70 ± 11 mmHg, P < 0.001). At diastolic pressures below baseline, sBRSfall was less than sBRSrise (-1.81 ± 1.31 vs. -3.59 ± 1.70 bursts·100 heartbeats-1·mmHg-1, P = 0.003) as low absolute pressures operated closer to the saturation plateau on the falling, compared with the rising pressure curve. At pressures above baseline, sBRSfall was greater than sBRSrise (-5.23 ± 1.94 and -3.79 ± 1.67 bursts·100 heartbeats-1·mmHg-1, P = 0.03). These findings demonstrate that the sympathetic arterial baroreflex possesses two response curves for processing beat-to-beat diastolic pressure falls and rises. The falling pressure curve is rightward shifted, which reduces sensitivity to falling pressure at low absolute pressures. This demonstrates that the direction of the hysteresis is influenced by the prevailing pressure level relative to each baroreflex response curve.NEW & NOTEWORTHY The findings show that the arterial baroreflex processes diastolic pressure dependent on the direction of pressure change from the previous beat, yielding two distinct baroreflex response curves to falling and rising pressure. Overall, the falling pressure curve is rightward shifted and more sensitive. The rightward shift caused a hysteresis reversal at hypotensive pressures as the falling pressure saturation plateau of the sigmoid response curve occurred at higher pressures than the rising pressure curve.


Assuntos
Pressão Arterial , Barorreflexo , Frequência Cardíaca , Músculo Esquelético/inervação , Nervo Fibular/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Pressão Arterial/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Fatores de Tempo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
6.
Life Sci ; 256: 117986, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585245

RESUMO

AIMS: HSP70, a molecular chaperone, helps to maintain proteostasis. In muscle biology, however, evidence suggests HSP70 to have a more versatile range of functions, as genetic deletion of its inducible genes impairs Ca2+ handling, and consequently, cardiac and skeletal muscle contractility. Still, it is unknown whether HSP70 is involved in vascular reactivity, an intrinsic physiological mechanism of blood vessels. Therefore, we designed this study to test the hypothesis that proper vascular reactivity requires the assistance of HSP70. MAIN METHODS: We performed functional studies in a wire-myograph using thoracic aorta isolated from male Sprague Dawley rats. Experiments were conducted with and without an HSP70 inhibitor as well as in heat-stressed vessels. The expression levels of HSP70 were evaluated with Western blotting. NO and ROS levels were assessed with fluorescence microscopy. KEY FINDINGS: We report that blockade of HSP70 weakens contraction in response to phenylephrine (dose-response) in the aorta. Additionally, we demonstrated that inhibition of HSP70 affects the amplitude of the fast and of the slow components of the time-force curve. Corroborating these findings, we found that inhibition of HSP70, in vessels over-expressing this protein, partly rescues the contractile phenotype of aortic rings. Furthermore, we show that blockade of HSP70 facilitates relaxation in response to acetylcholine and clonidine without affecting the basal levels of NO and ROS. SIGNIFICANCE: Our work introduces an additional physiological role for HSP70, the assistance of vascular reactivity, which highlights this protein as a new player in vascular physiology, and therefore, uncovers a promising research avenue for vascular diseases.


Assuntos
Aorta Torácica/fisiologia , Endotélio Vascular/fisiologia , Proteínas de Choque Térmico HSP70/fisiologia , Músculo Liso Vascular/fisiologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/agonistas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fenilefrina/farmacologia , Nucleosídeos de Purina/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
8.
Anesthesiology ; 133(2): 304-317, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32482999

RESUMO

BACKGROUND: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine. METHODS: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation. RESULTS: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 µmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] µmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 µmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] µmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups. CONCLUSIONS: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.


Assuntos
Anestesia/tendências , Neoplasias Encefálicas/tratamento farmacológico , Circulação Cerebrovascular/efeitos dos fármacos , Efedrina/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Fenilefrina/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Circulação Cerebrovascular/fisiologia , Método Duplo-Cego , Efedrina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Fenilefrina/farmacologia , Estudos Prospectivos , Resultado do Tratamento , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico
9.
Prostate ; 80(11): 831-849, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449814

RESUMO

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.


Assuntos
Integrina alfa2beta1/antagonistas & inibidores , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Dipeptídeos/farmacologia , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Piperazinas/farmacologia , Próstata/metabolismo , Próstata/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Tromboxano A2/metabolismo , Vasoconstritores/farmacologia
10.
Am J Physiol Heart Circ Physiol ; 319(1): H42-H50, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32412783

RESUMO

Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly. While TrpC6 has been suggested to contribute to PIC signaling, direct supporting evidence is contradictory. Therefore, the aim of this study was to determine the importance of TrpC6 in PIC signaling using a mouse model lacking TrpC6. To address this aim, we evaluated graded pressure (20-90 mmHg), depolarization (4-80 mM KCl)-, and adrenergic receptor (phenylephrine; PE 10-7-10-4 M)-mediated constriction of isolated middle cerebral artery (MCA) segments from 9-wk-old male wild-type (TrpC6+/+, n = 7) and homozygous null (TrpC6-/-, n = 9) TrpC6 mice (Jackson Laboratories). Isolated MCA segments were cannulated and pressurized with physiological salt solution using pressure myography (Living Systems). Vasoconstrictor responses to KCl and PE were identical in TrpC6-/- and TrpC6+/+ mice. In contrast, PIC responses were totally abolished in TrpC6-/- mice. At 90 mmHg, the calculated myogenic tone was -0.8 ± 0.5 vs. 10.7 ± 1.7%, P = 0.0002 in TrpC6-/- and TrpC6+/+ mice, respectively. Additionally, there were no changes in mechanical properties of circumferential wall strain and stress or morphological properties of wall thickness and wall-to-lumen ratio at 50 mmHg between TrpPC6-/- and TrpC6+/+ mice. Although these results demonstrate that TrpC6 is critical for the integrated PIC response, they do not identify whether TrpC6 acts as a mechanosensor or a downstream signaling component.NEW & NOTEWORTHY Pressure-induced, but not agonist-induced, vasoconstriction is abolished in the middle cerebral artery (MCA) of TrpC6 null mice. TrpC6 localization in dissociated cerebral vascular smooth muscle cells is primarily cytoplasmic and not associated with the surface membrane where a mechanoelectrical coupler might be expected. These findings suggest that TrpC6 is required for transduction of pressure-induced constriction in the MCA; however, its role as a mechanoelectrical coupler or downstream signal amplifier remains unresolved.


Assuntos
Artéria Cerebral Média/metabolismo , Pressão , Canal de Cátion TRPC6/metabolismo , Vasoconstrição , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiologia , Tono Muscular , Fenilefrina/farmacologia , Potássio/farmacologia , Canal de Cátion TRPC6/genética , Vasoconstritores/farmacologia
11.
Am J Physiol Heart Circ Physiol ; 319(1): H123-H132, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469638

RESUMO

Cold exposure causes cutaneous vasoconstriction via a reflex increase in sympathetic activity and a local effect to augment adrenergic constriction. Local cooling also initiates cutaneous dilatation, which may function to restrain cold-induced constriction. However, the underlying mechanisms and physiological role of cold-induced dilatation have not been defined. Experiments were performed to assess the role of endothelial-derived mediators in this response. In isolated pressurized cutaneous mouse tail arteries, cooling (28°C) did not affect the magnitude of dilatation to acetylcholine in preconstricted arteries. However, inhibition of nitric oxide (NO) [NG-nitro-l-arginine methyl ester (l-NAME)] and prostacyclin (PGI2) (indomethacin) reduced acetylcholine-induced dilatation at 37°C but not at 28°C, suggesting that cooling increased NO/PGI2-independent dilatation. This NO/PGI2-independent dilatation was reduced by inhibition of endothelial SK (UCL1684) and IK (TRAM34) Ca2+-activated K+-channels (KCa), consistent with endothelium-derived hyperpolarization (EDH). Cooling also increased dilatation to direct activation of KCa channels (SKA31, CyPPA) but did not affect dilatation to exogenous NO (DEA-NONOate). This cooling-induced increase in EDH-type dilatations was associated with divergent effects on potential downstream EDH mechanisms: cooling reduced dilatation to K+, which mimics an intercellular K+ cloud, but increased direct communication between endothelial and smooth muscle cells (myoendothelial coupling), assessed by cellular transfer of biocytin. Indeed, inhibition of gap junctions (carbenoxolone) abolished the EDH-type component of dilatation to acetylcholine during cooling but did affect NO-dominated dilatation at 37°C. Cooling also inhibited U46619 constriction that was prevented by inhibition of IK and SK KCa channels or inhibition of gap junctions. The results suggest that cooling dilates cutaneous arteries by increasing myoendothelial communication and amplifying EDH-type dilatation.NEW & NOTEWORTHY Cold causes cutaneous vasoconstriction to restrict heat loss. Although cold also initiates cutaneous dilatation, the mechanisms and role of this dilatation have not been clearly defined. This study demonstrates that cooling increases myoendothelial coupling between smooth muscle and endothelial cells in cutaneous arteries, which is associated with increased endothelium-derived hyperpolarization (EDH)-type dilatation. Dysfunction in this process may contribute to excessive cold-induced constriction and tissue injury.


Assuntos
Artérias/fisiologia , Temperatura Baixa , Endotélio Vascular/fisiologia , Músculo Liso Vascular/fisiologia , Pele/irrigação sanguínea , Vasodilatação , Acetilcolina/farmacologia , Alcanos/farmacologia , Animais , Artérias/efeitos dos fármacos , Carbenoxolona/farmacologia , Endotélio Vascular/metabolismo , Epoprostenol/farmacologia , Indometacina/farmacologia , Masculino , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Canais de Potássio Cálcio-Ativados/metabolismo , Pirazóis/farmacologia , Compostos de Quinolínio/farmacologia , Vasoconstrição , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
13.
Cell Physiol Biochem ; 54(3): 371-383, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32298554

RESUMO

BACKGROUND/AIMS: This study aimed to establish a precise and well-defined working model, assessing pharmaceutical effects on vascular smooth muscle cell monolayer in-vitro. It describes various analysis techniques to determine the most suitable to measure the biomechanical impact of vasoactive agents by using CellDrum technology. METHODS: The so-called CellDrum technology was applied to analyse the biomechanical properties of confluent human aorta muscle cells (haSMC) in monolayer. The cell generated tensions deviations in the range of a few N/m² are evaluated by the CellDrum technology. This study focuses on the dilative and contractive effects of L-type Ca2+ channel agonists and antagonists, respectively. We analyzed the effects of Bay K8644, nifedipine and verapamil. Three different measurement modes were developed and applied to determine the most appropriate analysis technique for the study purpose. These three operation modes are called, particular time mode" (PTM), "long term mode" (LTM) and "real-time mode" (RTM). RESULTS: It was possible to quantify the biomechanical response of haSMCs to the addition of vasoactive agents using CellDrum technology. Due to the supplementation of 100nM Bay K8644, the tension increased approximately 10.6% from initial tension maximum, whereas, the treatment with nifedipine and verapamil caused a significant decrease in cellular tension: 10nM nifedipine decreased the biomechanical stress around 6,5% and 50nM verapamil by 2,8%, compared to the initial tension maximum. Additionally, all tested measurement modes provide similar results while focusing on different analysis parameters. CONCLUSION: The CellDrum technology allows highly sensitive biomechanical stress measurements of cultured haSMC monolayers. The mechanical stress responses evoked by the application of vasoactive calcium channel modulators were quantified functionally (N/m²). All tested operation modes resulted in equal findings, whereas each mode features operation-related data analysis.


Assuntos
Biofísica/métodos , Músculo Liso Vascular/efeitos dos fármacos , Vasoconstritores/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Aorta/efeitos dos fármacos , Fenômenos Biomecânicos , Biofísica/instrumentação , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Nifedipino/farmacologia , Estresse Mecânico , Vasoconstrição , Verapamil/farmacologia
14.
Am J Respir Crit Care Med ; 202(1): 91-99, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272020

RESUMO

Rationale: Guidelines for vasopressor titration suggest a universal target-mean arterial pressure (MAP) >65 mm Hg. The implications for patients with premorbid low/high blood pressure are unknown.Objectives: To investigate the relationship between premorbid blood pressure and vasopressor duration for patients with shock.Methods: We performed a retrospective cohort study of adults admitted with shock to Calgary ICUs (June 2012-December 2018). The primary exposure was premorbid blood pressure: low (systolic <100); normal (systolic 100-139 and diastolic <90); and high (systolic ≥140 or diastolic ≥90). The primary outcome was vasopressor duration; secondary outcomes included ICU/hospital length of stay and ICU/hospital mortality. We examined associations of premorbid blood pressure with vasopressor duration and length of stay using multivariable competing risk models and mortality using multivariable mixed-effects logistic regression.Measurements and Main Results: Of 3,542 admissions with shock, 177 (5.0%) had premorbid low, 2,887 (81.5%) normal, and 478 (13.5%) high blood pressure. Premorbid low admissions had lower MAPs (vs. normal or high premorbid admissions) over the duration of vasopressor use (P = 0.003) and were maintained nearest premorbid MAPs while receiving vasopressors (P < 0.001). After adjustment, premorbid low admissions had longer vasopressor use (median, 1.35 d vs. 1.04 d for normal; hazard ratio for discontinuation vs. normal, 0.78 [0.73-0.85]; P < 0.001) and premorbid high admissions had shorter use (median, 0.84 d; hazard ratio, 1.22 [1.12-1.33]; P < 0.001). Premorbid low admissions had longer adjusted length of stay and higher adjusted mortality than premorbid normal admissions.Conclusions: Premorbid blood pressure was inversely associated with vasopressor duration.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/complicações , Hipotensão/complicações , Padrões de Prática Médica/estatística & dados numéricos , Choque/tratamento farmacológico , Vasoconstritores/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta , Feminino , Humanos , Hipertensão/fisiopatologia , Hipotensão/fisiopatologia , Tempo de Internação/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Choque/complicações , Choque/mortalidade , Choque/fisiopatologia , Resultado do Tratamento , Vasoconstritores/farmacologia , Vasoconstritores/uso terapêutico , Adulto Jovem
15.
Am J Physiol Heart Circ Physiol ; 318(5): H1041-H1048, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32196361

RESUMO

Discrete calcium signals within the vascular endothelium decrease with age and contribute to impaired endothelial-dependent vasodilation. Calreticulin (Calr), a multifunctional calcium binding protein and endoplasmic reticulum (ER) chaperone, can mediate calcium signals and vascular function within the endothelial cells (ECs) of small resistance arteries. We found Calr protein expression significantly decreases with age in mesenteric arteries and examined the functional role of EC Calr in vasodilation and calcium mobilization in the context of aging. Third-order mesenteric arteries from mice with or without EC Calr knockdown were examined for calcium signals and constriction to phenylephrine (PE) or vasodilation to carbachol (CCh) after 75 wk of age. PE constriction in aged mice with or without EC Calr was unchanged. However, calcium signals and vasodilation to endothelial-dependent agonist carbachol were significantly impaired in aged EC Calr knockdown mice. Ex vivo incubation of arteries with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) significantly improved vasodilation in mice lacking EC Calr. Our data suggests diminished vascular Calr expression with age can contribute to the detrimental effects of aging on endothelial calcium regulation and vasodilation.NEW & NOTEWORTHY Calreticulin (Calr) is responsible for key physiological processes in endoplasmic reticulum, especially in aging tissue. In particular, endothelial Calr is crucial to vascular function. In this study, we deleted Calr from the endothelium and aged the mice up to 75 wk to examine changes in vascular function. We found two key differences: 1) calcium events in endothelium were severely diminished after muscarinic stimulation, which 2) corresponded with a dramatic decrease in muscarinic vasodilation. Remarkably, we were able to rescue the effect of Calr deletion on endothelial-dependent vasodilatory function using tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum stress that is currently in clinical trials.


Assuntos
Envelhecimento/metabolismo , Calreticulina/metabolismo , Endotélio Vascular/metabolismo , Envelhecimento/fisiologia , Animais , Sinalização do Cálcio , Calreticulina/genética , Carbacol/farmacologia , Endotélio Vascular/fisiologia , Deleção de Genes , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fenilefrina/farmacologia , Ácido Tauroquenodesoxicólico/farmacologia , Vasoconstritores/farmacologia , Vasodilatação
16.
Arq Bras Cardiol ; 114(2): 295-303, 2020 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215501

RESUMO

BACKGROUND: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. OBJECTIVE: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. METHOD: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. RESULTS: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. CONCLUSIONS: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.


Assuntos
Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Epinefrina/farmacologia , Felipressina/farmacologia , Poluição por Fumaça de Tabaco/efeitos adversos , Vasoconstritores/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipotensão , Masculino , Ratos Wistar , Fatores de Tempo , Vasodilatação/efeitos dos fármacos
17.
Life Sci ; 250: 117586, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222464

RESUMO

AIM: The inward rectifier K+ (Kir) channels and prostanoids are important factors in regulating vascular tone, but the relationship between them has not been well studied. We aimed to study the involvement of prostanoids in regulating Kir activity in the rat intrarenal arteries (RIRAs). MAIN METHODS: The vascular tone of isolated RIRAs was recorded with a wire myograph. The intracellular Ca2+ concentrations ([Ca2+]i) and Kir currents were measured with a Ca2+-sensitive fluorescence probe and patch clamp, respectively, in the arterial smooth muscle cell (ASMC) freshly isolated from RIRAs. Kir2.1 expression in RIRAs was assayed by Western blotting. KEY FINDINGS: At 0.03-1.0 mM, BaCl2 (a specific Kir blocker) concentration-dependently contracted RIRAs and elevated [Ca2+]i levels. Mild stimulations with various vasoconstrictors at low concentrations significantly potentiated RIRA contraction induced by Kir closure with BaCl2. In both the quiescent and the stimulated RIRAs, cyclooxygenase inhibition and thromboxane-prostanoid receptor (TPR) antagonism depressed BaCl2-induced RIRA contraction, while nitric oxide (NO) synthetase inhibition and endothelium-denudation enhanced the contraction. Kir2.1 expression was significantly more abundant in smaller RIRAs. Ba2+-sensitive Kir currents were depressed by TPR agonist U46619 while increased by NO donor sodium nitroprusside. SIGNIFICANCE: The present results reveal that vasoconstrictor stimulation augments RIRA contraction induced by Kir closure with Ba+ and indicate that prostanoid synthesis followed by TPR activation is involved in the modulation of the myocyte Kir activity. This study suggests that prostanoid synthesis and TPR may be potential targets for dysfunctions in renal blood circulation.


Assuntos
Miócitos de Músculo Liso/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Prostaglandinas/metabolismo , Artéria Renal/citologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Artérias/metabolismo , Cálcio/metabolismo , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Rim/irrigação sanguínea , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina/metabolismo , Tromboxanos/metabolismo , Vasoconstritores/farmacologia
18.
Biochem Biophys Res Commun ; 524(4): 853-860, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32046856

RESUMO

Telmisartan, an angiotensin II type 1 receptor blocker (ARB), is widely used to treat hypertension. Dysfunction of vascular smooth muscle cells (VSMCs) is well-established to contribute to the pathogenesis of various vascular diseases. A growing body of evidence indicates that increased VSMC contractility plays a primary role in the development of pathological artery spasms. Nevertheless, effect of telmisartan on VSMC contractility, and its mechanism of action remain unknown. Here, we investigated the mechanism by which telmisartan inhibits VSMC contractility and vessel contraction in rat VSMCs and endothelium-deprived aortas. Telmisartan inhibited phenylephrine-induced vessel contraction in endothelium-deprived aortas, and decreased myosin light chain kinase (MLCK) levels (without altering corresponding mRNA levels) and myosin light chain (MLC) phosphorylation at Ser19 (p-MLC-Ser19) in VSMCs. MG-132 but not doxycycline significantly restored telmisartan-inhibited MLCK expression and p-MLC-Ser19. Telmisartan induced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 (p-AMPK-Thr172), and compound C or ectopic expression of the dominant negative (dn)-AMPKα1 gene significantly reversed telmisartan-inhibited MLCK expression and p-MLC-Ser19. Of the ARBs tested (including losartan and fimasartan), only telmisartan increased p-AMPK-Thr172, and inhibited MLCK expression and p-MLC-Ser19. GW9662 had no effects on telmisartan-induced changes. Similar to the in vitro results, telmisartan enhanced p-AMPK-Thr172, and inhibited MLCK expression and p-MLC-Ser19 in endothelium-deprived aortas. Furthermore, the telmisartan-inhibited vessel contraction in the aortas was significantly reversed by MG-132 or compound C. In conclusion, we demonstrated that telmisartan inhibits VSMC contractility and vessel contraction by activating AMPK/proteasome/MLCK degradation signaling axis. These results suggest that telmisartan can be used to treat pathological vasospasms.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Anti-Hipertensivos/farmacologia , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Quinase de Cadeia Leve de Miosina/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Telmisartan/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Doxiciclina/farmacologia , Regulação da Expressão Gênica , Leupeptinas/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologia
19.
PLoS One ; 15(2): e0228274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053637

RESUMO

OBJECTIVE: Fluid overload is common among critically ill patients and is associated with worse outcomes. We aimed to assess the effect of diuretics on urine output, vasopressor dose, acute kidney injury (AKI) incidence, and need for renal replacement therapies (RRT) among patients who receive vasopressors. PATIENTS AND METHODS: This is a single-center retrospective study of all adult patients admitted to the intensive care unit between January 2006 and December 2016 and received >6 hours of vasopressor therapy and at least one concomitant dose of diuretic. We excluded patients from cardiac care units. Hourly urine output and vasopressor dose for 6 hours before and after the first dose of diuretic therapy was compared. Rates of AKI development and RRT initiation were assessed with a propensity-matched cohort of patients who received vasopressors but did not receive diuretics. RESULTS: There was an increasing trend of prescribing diuretics in patients receiving vasopressors over the course of the study. We included 939 patients with median (IQR) age of 68(57, 78) years old and 400 (43%) female. The average hourly urine output during the first six hours following time zero in comparison with average hourly urine output during the six hours prior to time zero was significantly higher in diuretic group in comparison with patients who did not receive diuretics [81 (95% CI 73-89) ml/h vs. 42 (95% CI 39-45) ml/h, respectively; p<0.001]. After propensity matching, the rate of AKI within 7 days of exposure and the need for RRT were similar between the study and matched control patients (66 (15.6%) vs. 83 (19.6%), p = 0.11, and 34 (8.0%) vs. 37 (8.7%), p = 0.69, respectively). Mortality, however, was higher in the group that received diuretics. Ninety-day mortality was 191 (45.2%) in the exposed group VS 156 (36.9%) p = .009. CONCLUSIONS: While the use of diuretic therapy in critically ill patients receiving vasopressor infusions augmented urine output, it was not associated with higher vasopressor requirements, AKI incidence, and need for renal replacement therapy.


Assuntos
Diuréticos/farmacologia , Choque/tratamento farmacológico , Vasoconstritores/farmacologia , Lesão Renal Aguda/complicações , Idoso , Estudos de Coortes , Estado Terminal , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal , Estudos Retrospectivos , Choque/complicações , Choque/fisiopatologia , Choque/urina , Resultado do Tratamento , Vasoconstritores/uso terapêutico
20.
Clin Sci (Lond) ; 134(5): 513-527, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32104886

RESUMO

An important link exists between hypertension and inflammation. Hypertensive patients present elevated circulating levels of proinflammatory cytokines, including interleukin-17A (IL-17A). This cytokine participates in host defense, autoimmune and chronic inflammatory pathologies, and cardiovascular diseases, mainly through the regulation of proinflammatory factors. Emerging evidence also suggests that IL-17A could play a role in regulating blood pressure and end-organ damage. Here, our preclinical studies in a murine model of systemic IL-17A administration showed that increased levels of circulating IL-17A raised blood pressure induced inward remodeling of small mesenteric arteries (SMAs) and arterial stiffness. In IL-17A-infused mice, treatment with hydralazine and hydrochlorothiazide diminished blood pressure elevation, without modifying mechanical and structural properties of SMA, suggesting a direct vascular effect of IL-17A. The mechanisms of IL-17A seem to involve an induction of vascular smooth muscle cell (VSMC) hypertrophy and phenotype changes, in the absence of extracellular matrix (ECM) proteins accumulation. Accordingly, treatment with an IL-17A neutralizing antibody diminished SMA remodeling in a model of angiotensin II (Ang II) infusion. Moreover, in vitro studies in VSMCs reported here, provide further evidence of the direct effects of IL-17A on cell growth responses. Our experimental data suggest that IL-17A is a key mediator of vascular remodeling of the small arteries, which might contribute, at least in part, to blood pressure elevation.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Interleucina-17/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Animais , Forma Celular/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Interleucina-17/administração & dosagem , Masculino , Artérias Mesentéricas/fisiologia , Camundongos Endogâmicos C57BL , Músculo Liso Vascular , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologia
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