RESUMO
ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17ß-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.
Assuntos
Infarto da Artéria Cerebral Média/fisiopatologia , Artéria Cerebral Média/fisiopatologia , Ovariectomia , Ovário/fisiopatologia , Vasoconstrição , Animais , Modelos Animais de Doenças , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/metabolismo , Técnicas de Cultura de Órgãos , Ovário/metabolismo , Progesterona/farmacologia , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Electronic cigarettes (E-cigs) have been promoted as harm-free or less risky than smoking, even for women during pregnancy. These claims are made largely on E-cig aerosol having fewer number of toxic chemicals compared with cigarette smoke. Given that even low levels of smoking are found to produce adverse birth outcomes, we sought to test the hypothesis that vaping during pregnancy (with or without nicotine) would not be harm-free and would result in vascular dysfunction that would be evident in offspring during adolescent and/or adult life. Pregnant female Sprague Dawley rats were exposed to E-cig aerosol (1 h/day, 5 days/wk, starting on gestational day 2 until pups were weaned) using e-liquid with 0 mg/mL (E-cig0) or 18 mg/mL nicotine (E-cig18) and compared with ambient air-exposed controls. Body mass at birth and at weaning were not different between groups. Assessment of middle cerebral artery (MCA) reactivity revealed a 51%-56% reduction in endothelial-dependent dilation response to acetylcholine (ACh) for both E-cig0 and E-cig18 in 1-mo, 3-mo (adolescent), and 7-mo-old (adult) offspring (P < 0.05 compared with air, all time points). MCA responses to sodium nitroprusside (SNP) and myogenic tone were not different across groups, suggesting that endothelial-independent responses were not altered. The MCA vasoconstrictor response (5-hydroxytryptamine, 5-HT) was also not different across treatment and age groups. These data demonstrate that maternal vaping during pregnancy is not harm-free and confers significant cerebrovascular health risk/dysfunction to offspring that persists into adult life. NEW & NOTEWORTHY These data established that vaping electronic cigarettes during pregnancy, with or without nicotine, is not safe and confers significant risk potential to the cerebrovascular health of offspring in early and adult life. A key finding is that vaping without nicotine does not protect offspring from cerebrovascular dysfunction and results in the same level of cerebrovascular dysfunction (compared with maternal vaping with nicotine), indicating that the physical and/or chemical properties from the base solution (other than nicotine) are responsible for the cerebrovascular dysfunction that we observed. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/maternal-vaping-impairs-vascular-function-in-theoffspring/.
Assuntos
Vapor do Cigarro Eletrônico/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Vaping , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Aerossóis , Animais , Sistemas Eletrônicos de Liberação de Nicotina , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Artéria Cerebral Média/fisiopatologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Nitroprussiato/farmacologia , Gravidez , Ratos , Serotonina/farmacologia , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: In this study, we examined the effect of acute hyponatremia associated with vasopressin (AVP) on the responses of the isolated rat's MCAs and PAs to acidosis, nitric oxide donor (SNAP) and to endothelium-dependent vasodilator ATP. METHODS: The studies were performed on isolated, perfused and pressurized MCAs and PAs in control conditions and during AVP-associated hyponatremia. Hyponatremia was induced in vitro by lowering Na+ concentration from 144 to 121 mmol/L in intra- and extravascular fluid in the presence of AVP. RESULTS: Parenchymal arterioles showed greater response to an increase in H+ and K+ ions concentration and to ATP in comparison with MCAs in control normonatremic conditions. Both PAs and MCAs constricted in response to acute hyponatremia associated with AVP. Interestingly, disordered regulation of vascular tone was observed in PAs but not in MCAs. The abnormalities in the regulation comprised a significant reduction of PA response to acidosis and the absence of the response to the administration of SNAP or ATP. CONCLUSIONS: Arginine vasopressin-associated hyponatremia leads to constriction and dysregulation of PAs which may impair neurovascular coupling.
Assuntos
Arteríolas/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Hiponatremia/fisiopatologia , Acidose/fisiopatologia , Doença Aguda , Trifosfato de Adenosina/farmacologia , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/fisiologia , Arteríolas/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hiponatremia/etiologia , Técnicas In Vitro , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiopatologia , Doadores de Óxido Nítrico/farmacologia , Ratos , Ratos Wistar , S-Nitroso-N-Acetilpenicilamina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Previous studies have demonstrated that nicotine can induce relaxation of the middle cerebral artery (MCA). However, whether this relaxation is associated with the activity of sensory calcitonin gene-related peptide (CGRP) nerves and whether this is modulated by hydrogen protons (H), facilitating the release of CGRP from sensory CGRPergic nerve terminals in the MCA, remains unclear. In this study, we examined the role of H in the modulation of neurogenic vasomotor responses in the rat-isolated endothelium-denuded MCA. Wire myography was used to measure vasoreactivity and indicated that nicotine-induced relaxation was sensitive to tetrodotoxin and lidocaine and drastically reduced levels of guanethidine (an adrenergic neuronal blocker), N-nitro-L-arginine (L-NNA), CGRP8-37, vasoactive intestinal polypeptide (VIP)6-28, capsaicin, capsazepine (a transient receptor potential vanilloid-1 inhibitor), and tetraethylammonium. However, this nicotine-induced relaxation was not sensitive to propranolol. Lowering the pH of the buffer solution with HCl caused pH-dependent vasorelaxation and deceased intracellular pH in the MCA rings, which was sensitive to L-NNA, CGRP8-37, VIP6-28, capsazepine, 4-aminopyridine (a voltage-gated potassium channel antagonist), and paxilline (a large conductance Ca-activated K channel antagonist). However, HCl-induced relaxation was not inhibited by glibenclamide (an ATP-sensitive K channel blocker). These results suggested that electrical and chemical activation of cerebral perivascular adrenergic nerves led to the release of H, which then facilitated the release of NO, VIP, and CGRP, resulting in vasorelaxation. Lowering the pH of the buffer solution caused potassium channels of vascular smooth muscle cells and perivascular nerves to open. In conclusion, our results demonstrated that H may act as a modulator on MCA perivascular nerves and/or smooth muscles.
Assuntos
Neurônios Adrenérgicos/metabolismo , Axônios/metabolismo , Hidrogênio/metabolismo , Artéria Cerebral Média/inervação , Músculo Liso Vascular/inervação , Vasodilatação , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Concentração de Íons de Hidrogênio , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Nicotina/farmacologia , Óxido Nítrico/metabolismo , Ratos Endogâmicos WKY , Peptídeo Intestinal Vasoativo/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: ATP-sensitive potassium (KATP ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown. OBJECTIVE: To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache. METHODS: In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning. RESULTS: The MMA circumference was significantly larger after levcromakalim compared with placebo (P < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo. CONCLUSION: Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of KATP channels can activate and sensitize the perivascular nociceptors.
Assuntos
Cromakalim/efeitos adversos , Cefaleia/induzido quimicamente , Artérias Meníngeas/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Adulto , Cromakalim/farmacologia , Método Duplo-Cego , Feminino , Cefaleia/diagnóstico por imagem , Cefaleia/tratamento farmacológico , Cefaleia/fisiopatologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Artérias Meníngeas/diagnóstico por imagem , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/efeitos dos fármacos , Especificidade de Órgãos , Canais de Potássio/fisiologia , Sumatriptana/uso terapêutico , Vasoconstritores/uso terapêutico , Vasodilatadores/farmacologia , Adulto JovemRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an important signaling peptide in migraine pathogenesis. Recently, we have shown that the less-abundant PACAP isoform, PACAP27, induced migraine and headache in patients equipotently to PACAP38. The present study examined the effect of PACAP27 on cerebral hemodynamics in healthy volunteers using high resolution magnetic resonance angiography (MRA). Eighteen healthy volunteers received infusion of PACAP27 (10â¯pmol/kg/min) or placebo over 20â¯min and were scanned repeatedly in fixed intervals for 5â¯h in a double-blind, randomized, placebo-controlled study. The circumference of extra-intracerebral arteries was measured and compared with PACAP38 data. We found significant dilation of middle meningeal artery (MMA) (pâ¯=â¯0.019), superficial temporal artery (pâ¯=â¯0.001) and external carotid artery (pâ¯=â¯0.039) after PACAP27 infusion compared to placebo. Whereas the middle cerebral artery (MCA) (pâ¯=â¯0.011) and internal carotid artery (ICA) (pICAcervicalâ¯=â¯0.015, pICAcerebralâ¯=â¯0.019) were constricted. No effects on basilar artery (pâ¯=â¯0.708) and cavernous portion of ICA were found. Post hoc analyses revealed significant larger area under the curve for MMA after PACAP38 compared to PACAP27 (pâ¯=â¯0.033). We also found that PACAP27 induced headache in nine out of twelve (75%) volunteers and one (17%) after placebo. In conclusion, PACAP27 induced headache and dilated extracerebral arteries (>5â¯h) and slightly constricted MCA in healthy volunteers. Post hoc analysis of PACAP38 data compared with PACAP27 showed that PACAP isoforms dilates MMA with significantly different magnitude.
Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Cefaleia/fisiopatologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/efeitos adversos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adolescente , Adulto , Área Sob a Curva , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiologia , Circulação Cerebrovascular/fisiologia , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Cefaleia/diagnóstico por imagem , Voluntários Saudáveis , Humanos , Angiografia por Ressonância Magnética , Masculino , Artérias Meníngeas/diagnóstico por imagem , Artérias Meníngeas/efeitos dos fármacos , Artérias Meníngeas/fisiologia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Artérias Temporais/diagnóstico por imagem , Artérias Temporais/efeitos dos fármacos , Artérias Temporais/fisiologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
The counter-regulatory axis, Angiotensin Converting Enzyme 2, Angiotensin-(1-7), Mas receptor (ACE2/Ang-1-7/MasR), of the renin angiotensin system (RAS) is a potential therapeutic target in stroke, with Ang-(1-7) reported to have neuroprotective effects in pre-clinical stroke models. Here, an extensive investigation of the functional and mechanistic effects of Ang-(1-7) was performed in a rodent model of stroke. Using longitudinal magnetic resonance imaging (MRI) it was observed that central administration of Ang-(1-7) following transient middle cerebral artery occlusion (MCAO) increased the amount of tissue salvage compared to reperfusion alone. This protective effect was not due to early changes in blood brain barrier (BBB) permeability, microglia activation or inflammatory gene expression. However, increases in NADPH oxidase 1 (Nox1) mRNA expression were observed in the treatment group compared to control. In order to determine whether Ang-(1-7) has direct cerebrovascular effects, laser speckle contrast imaging (LSCI) was performed to measure dynamic changes in cortical perfusion following reperfusion. Delivery of Ang-(1-7) did not have any effect on cortical perfusion following reperfusion however; it showed an indication to prevent the 'steal phenomenon' within the contralateral hemisphere. The comprehensive series of studies have demonstrated a moderate protective effect of Ang-(1-7) when given alongside reperfusion to increase tissue salvage.
Assuntos
Angiotensina I/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , NADPH Oxidase 1/genética , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Acidente Vascular Cerebral/tratamento farmacológico , Enzima de Conversão de Angiotensina 2 , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Meios de Contraste/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Imageamento por Ressonância Magnética , Microglia/efeitos dos fármacos , Microglia/patologia , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/efeitos dos fármacos , Fármacos Neuroprotetores , Proto-Oncogene Mas , RNA Mensageiro/genética , Ratos , Sistema Renina-Angiotensina/genética , Reperfusão/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologiaRESUMO
OBJECTIVES: Exposure to airborne particle (PM2.5 ) is a risk factor for intracranial atherosclerosis (ICA). Because of the established role of systemic inflammation and oxidative stress by PM2.5 , we determined whether these processes account for PM2.5 -mediated ICA, and also whether omega-3 fatty acid (O3FA) dietary supplementation could attenuate them. METHODS: Adult Sprague-Dawley rats were exposed to filtered air (FA) or PM2.5 and fed either a normal chow diet (NCD) or a high-cholesterol diet (HCD), administered with or without O3FA (5 mg/kg/day by gavage) for 12 weeks. The lumen and thickness of the middle cerebral artery (MCA) were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß (IL-1ß), and interferon gamma (IFN-γ) were detected by ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity, mRNA levels of Nrf2, HO-1, NQO-1, and protein level of NOX subunit gp91 were quantified to determine the oxidative profile of brain vessels. RESULTS: PM2.5 increased (P < .05) ICA, especially in the HCD group; elevated serum TNF-α, IL-6, IL-1ß, and IFN-γ; increased cerebrovascular ROS, MDA, NOX activity, and gp91 protein levels; and decreased cerebrovascular SOD activity. Nrf2, HO-1, and NQO-1 mRNA levels were upregulated (P < .05) by PM2.5 exposure, especially in the HCD group. O3FA attenuated (P < .05) PM2.5 -induced systemic inflammation, vascular oxidative injury, and ICA. CONCLUSIONS: PM2.5 exposure induced systemic inflammation, cerebrovascular oxidative injury, and ICA in rats with HCD. O3FA prevented ICA development, and may therefore exert a protective effect against the atherogenic potential of PM2.5 .
Assuntos
Poluentes Atmosféricos/toxicidade , Arteriosclerose Intracraniana/induzido quimicamente , Artéria Cerebral Média/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Modelos Animais de Doenças , Inflamação , Arteriosclerose Intracraniana/imunologia , Arteriosclerose Intracraniana/patologia , Masculino , Artéria Cerebral Média/imunologia , Artéria Cerebral Média/patologia , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
The goal of the present study was to examine the effect of 1 wk of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries of male Sprague-Dawley rats ( n = 15-16 rats/group). Reduced FID in the HS group was restored by intake of the superoxide scavenger tempol (HS + tempol in vivo group). The nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and selective inhibitor of microsomal cytochrome P-450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide significantly reduced FID in the low salt diet-fed group, whereas FID in the HS group was mediated by NO only. Cyclooxygenase-2 mRNA (but not protein) expression was decreased in the HS and HS + tempol in vivo groups. Hypoxia-inducible factor-1α and VEGF protein levels were increased in the HS group but decreased in the HS + tempol in vivo group. Assessment by direct fluorescence of middle cerebral arteries under flow revealed significantly reduced vascular NO levels and increased superoxide/reactive oxygen species levels in the HS group. These results suggest that HS intake impairs FID and changes FID mechanisms to entirely NO dependent, in contrast to the low-salt diet-fed group, where FID is NO, prostanoid, and epoxyeicosatrienoic acid dependent. These changes were accompanied by increased lipid peroxidation products in the plasma of HS diet-fed rats, increased vascular superoxide/reactive oxygen species levels, and decreased NO levels, together with increased expression of hypoxia-inducible factor-1α and VEGF. NEW & NOTEWORTHY High-salt (HS) diet changes the mechanisms of flow-induced dilation in rat middle cerebral arteries from a combination of nitric oxide-, prostanoid-, and epoxyeicosatrienoic acid-dependent mechanisms to, albeit reduced, a solely nitric oxide-dependent dilation. In vivo reactive oxygen species scavenging restores flow-induced dilation in HS diet-fed rats and ameliorates HS-induced increases in the transcription factor hypoxia-inducible factor-1α and expression of its downstream target genes.
Assuntos
Circulação Cerebrovascular , Artéria Cerebral Média/efeitos dos fármacos , Sódio na Dieta/farmacologia , Vasodilatação , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Indometacina/farmacologia , Masculino , Artéria Cerebral Média/metabolismo , Artéria Cerebral Média/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The age-related decrease in cerebral blood flow velocity increases the risk of cerebrovascular disease. Milk protein-derived bioactive peptides, e.g., lactotripeptide (LTP), have been shown to inhibit angiotensin converting enzyme activities and increase vasodilator production. We hypothesized that LTP ingestion increases cerebral blood flow velocity in middle-aged and older adults. In a randomized, placebo-controlled, double-blind design, 15 healthy middle-aged and older adults were assigned to either a LTP group or a placebo group. The subjects ingested LTP or placebo orally for 8â¯weeks. Before and after intervention, middle cerebral blood flow velocity was measured using transcranial Doppler ultrasonography. The baseline middle cerebral blood flow velocity and most other key dependent variables did not differ between the groups. LTP ingestion significantly increased middle cerebral blood flow velocity, but there was no such improvement in the placebo groups. We concluded that 8â¯weeks of LTP ingestion increased middle cerebral blood flow velocity in middle-aged and older adults.
Assuntos
Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Proteínas do Leite/química , Peptídeos/farmacologia , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiologia , Peptídeos/uso terapêutico , Ultrassonografia Doppler TranscranianaRESUMO
Objetivo: Investigar os efeitos da administração da corticoterapia antenatal sobre a hemodinâmica fetal, utilizando uma análise longitudinal e quantitativa das curvas de velocidade de fluxo do Doppler das artérias umbilical e cerebral média. Metodologia: Este estudo utilizou revisão de prontuários e incluiu 30 fetos que estavam sob o risco de parto prematuro. Vinte e oito gestantes foram tratadas com betametasona, visando o amadurecimento pulmonar fetal. Os exames Dopplervelocimétricos das artérias umbilical e cerebral média foram realizados uma vez antes da corticoterapia e depois da administração do medicamento, totalizando três ou oito observações ao longo do tempo. Optamos pelo emprego do modelo linear hierárquico sob abordagem Bayesiana. Resultados: Na análise da artéria umbilical, observamos diminuição significativa do índice de pulsatilidade após uso da corticoterapia. Porém, não foi observada mudança significativa no índice de pulsatilidade da artéria cerebral média, independente da idade gestacional e do diagnóstico de pré-eclâmpsia. Concluímos que o corticoide antenatal induz mudanças na hemodinâmica fetal, sendo observada a redução significativa no índice de pulsatilidade da artéria umbilical, sem alterar a vascularização cerebral. Apesar do resultado, não é possível afirmar se este achado causado pela administração da betametasona antenatal tem efeito benéfico para o prognóstico fetal.
Assuntos
Humanos , Feminino , Gravidez , Betametasona/administração & dosagem , Corticosteroides/uso terapêutico , Artéria Cerebral Média/efeitos dos fármacos , Artéria Umbilical Única/tratamento farmacológico , Hemodinâmica , Trabalho de Parto Prematuro , PrognósticoRESUMO
BACKGROUND/AIMS: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke. METHODS: We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models. RESULTS: A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAO rats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide's protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95. CONCLUSION: The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for stroke patients.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/análise , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Iridoides/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/análise , Receptores de N-Metil-D-Aspartato/análise , Animais , Morte Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos Sprague-DawleyRESUMO
Abstract Purpose: To evaluate the effects of enoxaparin and unfractionated heparin (UFH) administered in prophylactic and therapeutic doses on fetal vessels in healthy pregnant Wistar rats, according to Doppler velocimetry measurements. Methods: Fifty animals were assigned to one of five groups: controls (saline), prophylactic and therapeutic enoxaparin (1 and 2 mg/kg/day, respectively), and prophylactic and therapeutic UFH (72 and 400 UI/kg/day, respectively). Uterine horns were examined by ultrasound for identification of live fetuses. A sample of these fetuses underwent Doppler velocimetry. Spectral curves, peak systolic velocity (PSV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery, ductus venosus, and umbilical artery were investigated. Differences were considered statistically significant when p<0.05. Results: No significant differences in PSV, PI, or RI values were observed among the groups. Conclusion: Doppler velocimetry measurements revealed no significant effects of enoxaparin or unfractionated heparin on fetal vessels in pregnant Wistar rats.
Assuntos
Animais , Feminino , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Heparina/farmacologia , Enoxaparina/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Feto/irrigação sanguínea , Anticoagulantes/farmacologia , Artérias Umbilicais/fisiopatologia , Gravidez , Aumento de Peso/efeitos dos fármacos , Ultrassonografia Pré-Natal/métodos , Ratos Wistar , Ecocardiografia Doppler de Pulso/métodos , Artéria Cerebral Média/fisiopatologia , Modelos Animais , Artéria Uterina/fisiopatologiaRESUMO
OBJECTIVE: Accumulating data have recently underlined argon´s neuroprotective potential. However, to the best of our knowledge, no data are available on the cerebrovascular effects of argon (Ar) in humans. We hypothesized that argon inhalation does not affect mean blood flow velocity of the middle cerebral artery (Vmca), cerebral flow index (FI), zero flow pressure (ZFP), effective cerebral perfusion pressure (CPPe), resistance area product (RAP) and the arterio-jugular venous content differences of oxygen (AJVDO2), glucose (AJVDG), and lactate (AJVDL) in anesthetized patients. MATERIALS AND METHODS: In a secondary analysis of an earlier controlled cross-over trial we compared parameters of the cerebral circulation under 15 minutes exposure to 70%Ar/30%O2 versus 70%N2/30%O2 in 29 male patients under fentanyl-midazolam anaesthesia before coronary surgery. Vmca was measured by transcranial Doppler sonography. ZFP and RAP were estimated by linear regression analysis of pressure-flow velocity relationships of the middle cerebral artery. CPPe was calculated as the difference between mean arterial pressure and ZFP. AJVDO2, AJVDG and AJVDL were calculated as the differences in contents between arterial and jugular-venous blood of oxygen, glucose, and lactate. Statistical analysis was done by t-tests and ANOVA. RESULTS: Mechanical ventilation with 70% Ar did not cause any significant changes in mean arterial pressure, Vmca, FI, ZFP, CPPe, RAP, AJVDO2, AJVDG, and AJVDL. DISCUSSION: Short-term inhalation of 70% Ar does not affect global cerebral circulation or metabolism in male humans under general anaesthesia.
Assuntos
Argônio/farmacologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Glucose/metabolismo , Ácido Láctico/metabolismo , Artéria Cerebral Média/efeitos dos fármacos , Adulto , Idoso , Anestesia Geral , Circulação Cerebrovascular/efeitos dos fármacos , Estudos Cross-Over , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Estudos ProspectivosRESUMO
OBJECTIVE: Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). APPROACH AND RESULTS: This study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). CONCLUSIONS: These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.
Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Artéria Cerebral Média/metabolismo , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Vasodilatação , Angiotensina I/farmacologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/inervação , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/inervação , Neovascularização Fisiológica/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/agonistas , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vasodilatação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
PURPOSE:: To develop a model for studying cerebrovascular disease prevention in elderly women. METHODS:: Sixty 18-month-old Sprague Dawley (SD) rats were randomly divided into an estrogen administration group (EA, n=30) and a non-administration group (NA, n=30); thirty 4-month-old SD rats were allocated to a control group. The EA group received estradiol benzoate starting on the 5th day of a 34-day breeding period, and the serum levels of estradiol (E2), estrogen receptor (ER), and malondialdehyde (MDA) were measured. The MCA of each group was then sampled for viscoelastic experiments. RESULTS:: The serum levels of E2 and MDA in the EA group showed significant differences compared to those in the control group (p<0.05), while the difference in ER between the EA and control groups was not significant (p>0.05). The decrease in MCA stress at 7,200 s and the increase in strain at 7,200 s in the EA group showed no significant differences compared to the control group (p>0.05). CONCLUSION:: Estradiol administration inhibited the formation of lipid peroxidation products and restored middle cerebral arterial viscoelasticity in aged female rats.
Assuntos
Estradiol/análogos & derivados , Estrogênios/farmacologia , Artéria Cerebral Média/efeitos dos fármacos , Animais , Elasticidade/efeitos dos fármacos , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/farmacologia , Estrogênios/administração & dosagem , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/sangue , Artéria Cerebral Média/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Receptores de Estradiol/sangue , Valores de Referência , Fatores de Tempo , Viscosidade/efeitos dos fármacosRESUMO
BACKGROUND/AIM: H2S is a novel vasoactivator. To verify the hypothesis that H2S may act as an endothelium-derived hyperpolarizing factor (EDHF) in the rat cerebrovasculature, the role of H2S in endothelium-derived relaxing factor (EDRF)-mediated responses was investigated. METHODS: Cystathionine-γ-lyase (CSE) was knocked down with an siRNA technique. Artery diameter, hyperpolarization and Ca2+-activated K+ (KCa) current were measured. RESULTS: CSE knockdown was indicated by a decrease in protein and mRNA expression in the rat middle cerebral artery (MCA) and cerebral basilar artery (CBA). Acetylcholine (ACh) induced significant hyperpolarization and vasodilation in endothelium-intact MCA and CBA. Removal of the endothelium abolished these responses. The nitric oxide (NO) synthase inhibitor L-NAME, but not the PGI2 production inhibitor indomethacin, significantly inhibited ACh-induced hyperpolarization and vasodilation in the CBA. In the presence of L-NAME and indomethacin, ACh-induced hyperpolarization and vasodilation in the MCA and CBA were attenuated. The non-NO/PGI2-mediated responses were abolished by the KCa channel blockers charybdotoxin and apamin. In the cerebral arteries from the CSE knockdown rat, non-NO/PGI2-mediated responses were significantly attenuated, and the remaining responses were abolished by charybdotoxin and apamin or the CSE inhibitor propargylglycine. CSE knockdown did not affect L-NAME-sensitive responses in the CBA. Sodium hydrosulfide (NaHS) augmented the KCa current in CBA vascular smooth muscle cells. CONCLUSION: EDHF-mediated responses in rat cerebral arteries were due to H2S activating the KCa channel.
Assuntos
Artéria Basilar/metabolismo , Fatores Biológicos/metabolismo , Sulfeto de Hidrogênio/metabolismo , Artéria Cerebral Média/metabolismo , Vasodilatação , Animais , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/enzimologia , Inibidores de Ciclo-Oxigenase/farmacologia , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Relação Dose-Resposta a Droga , Epoprostenol/metabolismo , Masculino , Potenciais da Membrana , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Ratos Sprague-Dawley , Transdução de Sinais , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
ABSTRACT PURPOSE: To develop a model for studying cerebrovascular disease prevention in elderly women. METHODS: Sixty 18-month-old Sprague Dawley (SD) rats were randomly divided into an estrogen administration group (EA, n=30) and a non-administration group (NA, n=30); thirty 4-month-old SD rats were allocated to a control group. The EA group received estradiol benzoate starting on the 5th day of a 34-day breeding period, and the serum levels of estradiol (E2), estrogen receptor (ER), and malondialdehyde (MDA) were measured. The MCA of each group was then sampled for viscoelastic experiments. RESULTS: The serum levels of E2 and MDA in the EA group showed significant differences compared to those in the control group (p<0.05), while the difference in ER between the EA and control groups was not significant (p>0.05). The decrease in MCA stress at 7,200 s and the increase in strain at 7,200 s in the EA group showed no significant differences compared to the control group (p>0.05). CONCLUSION: Estradiol administration inhibited the formation of lipid peroxidation products and restored middle cerebral arterial viscoelasticity in aged female rats.
Assuntos
Animais , Feminino , Artéria Cerebral Média/efeitos dos fármacos , Estradiol/análogos & derivados , Estrogênios/farmacologia , Valores de Referência , Fatores de Tempo , Viscosidade/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Distribuição Aleatória , Receptores de Estradiol/sangue , Ratos Sprague-Dawley , Artéria Cerebral Média/fisiologia , Elasticidade/efeitos dos fármacos , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/farmacologia , Estrogênios/administração & dosagem , Malondialdeído/sangueRESUMO
BACKGROUND: Supraglottic airway devices (SGDs) are of current use in anesthesia practice and in emergency conditions. It has been suggested that cerebral blood flow (CBF) can decrease after SGD insertion or cuff inflation; however, it is uncertain if this reduction is caused by the SGD or the anesthetic drugs utilized for the anesthetic procedure. During minor surgery we separated CBF measurements by an adequate time interval in order to measure the distinctive changes in cerebral hemodynamics associated with anesthesia induction, SGD insertion and cuff inflation. METHODS: Patients scheduled for minor surgery requiring general anesthesia and SGD placement were included. Middle cerebral artery mean flow velocity (FVm-mca) and the Pulsatility Index (PI) were measured through use of trans-cranial Doppler (TCD) at baseline, after anesthesia induction, SGD insertion and cuff inflation, once a steady cardio-circulatory state was reached and end tidal CO2 (etCO2) was within normal range. RESULTS: A total of 21 patients were included. Following anesthesia induction, in concomitance to a reduction in mean arterial pressure (MAP), there was a mean decrease in FVm-mca by 16.60 cm/s, P<0.005 and a mean increase in PI by 0.24, P<0.0015. MAP, FVm-mca and PI did not change significantly, neither after SGD placement (P>0.05), nor after SGD cuffing (P>0.05). CONCLUSIONS: SGD insertion and cuff inflation did not influence cerebral hemodynamics in anesthetized patients undergoing minor surgery. At normal etCO2 range, the CBF reduction with transient increase in PI was associated with anesthesia induction and not SGD insertion itself.
Assuntos
Anestésicos/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Intubação Intratraqueal/instrumentação , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiologia , Anestesia Geral , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Velocidade do Fluxo Sanguíneo , Hemodinâmica , Humanos , Procedimentos Cirúrgicos Menores , Ultrassonografia Doppler TranscranianaRESUMO
Stroke is a major health issue in women. Our previous studies in male rats showed decreased myogenic tone in middle cerebral arteries (MCAs) after ischemia and reperfusion (I/R), while tone in parenchymal arterioles (PAs) was increased. This vascular response may aggravate stroke damage in males by limiting reperfusion; however, the effect in females is not known. The current study investigated the effect of I/R and tissue plasminogen activator (tPA) on myogenic tone and reactivity of MCAs and PAs in female rats. Nitrosative stress by peroxynitrite and recruitment of inflammatory neutrophils to the microvasculature were also studied. Female rats were subjected to 2-h MCA filament occlusion (n = 16) or sham surgery (n = 17) and given tPA (1 mg/kg, i.v) or vehicle followed by 30-min reperfusion. Myogenic tone and reactivity were measured in isolated and pressurized MCAs and PAs from the same animals. Cerebrovascular F-actin, 3-nitrotyrosine (3-NT, peroxynitrite marker), and intravascular neutrophils were quantified. Myogenic tone and constriction to the nitric oxide synthase inhibitor Nω-nitro-L-arginine were decreased in MCAs but unchanged in PAs after I/R with no effect of tPA. F-actin and 3-NT expression were unaffected by I/R or tPA. Our study showed that MCAs from females, similar to what has been seen in males, are dilated after I/R and have decreased myogenic tone while tone in PAs was unchanged. Increased small vessel resistance may contribute to decreased reperfusion and worse outcome after stroke.