Mestrado em Ciências Fisiológicas
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- ItemO ácido elágico melhora o padrão funcional hemodinâmico e previne o remodelamento cardíaco após infarto agudo do miocárdio em ratas ovariectomizadas(Universidade Federal do Espírito Santo, 2024-03-27) Gonçalves, Laís Lopes; Simões, Simone Alves de Almeida; https://orcid.org/0000-0002-9905-509X; http://lattes.cnpq.br/4036865618615755; Abreu, Glaucia Rodrigues de; https://orcid.org/0009-0008-8772-8470; http://lattes.cnpq.br/0229590907405570; https://orcid.org/0000-0002-8603-8354; http://lattes.cnpq.br/0964569425731887; Gouvea, Sônia Alves; https://orcid.org/0000-0001-5180-471X; http://lattes.cnpq.br/7268228122543743; Lemos, Virgínia Soares; https://orcid.org/0000-0003-1234-9325; http://lattes.cnpq.br/6575569264319071Postmenopausal women have a higher incidence of acute myocardial infarction (MI) and a worse prognosis. The main cause of fibrosis and heart failure is MI. We previously demonstrated that Ellagic acid (EA) attenuates diastolic dysfunction by reducing cardiac oxidative stress. Here, we examined the effect of the administration of EA on cardiac fibrosis and other pathological effects induced by MI in female rats that have been exposed to estrogen deprivation. Ovariectomized Wistar rats were subjected to coronary artery ligation to induce MI. The EA (30 mg/kg) was administered by oral gavage daily for four weeks. Hemodynamic parameters were measured through cannulation of the carotid artery. Picrosirius red staining was used to evaluate collagen deposition and to determine the size of the infarction. MMP-8 expression was measured by immunofluorescence. Nitric oxide (NO) and reactive oxygen species (ROS) production were quantified by the DAF-2 and DHE probes, respectively. ELISA was used for the quantification of inflammatory cytokines. MI promoted ventricular dysfunction and cardiac fibrosis. Oral administration of EA reduced the size of the myocardial lesion, improved hemodynamic parameters, decreased the deposition of total collagen, and type I collagen, and increased the deposition of type III collagen. MMP-8 expression and IL-6 production were increased in the heart after MI and EA decreased them. Finally, the administration of EA increased the production of in situ NO and decreased the production of ROS. These data highlight that oral treatment with EA may be a potential natural therapeutic for menopausal women under cardiac stress.
- ItemPreditores de mortalidade e recuperação funcional após traumatismo cranioencefálico grave: um estudo observacional prospectivo do tipo coorte(Universidade Federal do Espírito Santo, 2023-10-06) Goncalves, Jéssica Vaz; Arêas, Fernando Zanela da Silva; https://orcid.org/0000-0002-2068-2606; http://lattes.cnpq.br/2219697069216192; https://orcid.org/0000000157960043; http://lattes.cnpq.br/9396185941965261; Nascimento, Lucas Rodrigues; https://orcid.org/0000-0002-6792-0819; http://lattes.cnpq.br/4634873197928322Severe Traumatic Brain Injury (TBI) is a significant global public health issue, considered the leading cause of mortality and disability in young adults. Some clinical, neurosurgical, and sociodemographic factors have already been described as predictors of higher risks of in-hospital mortality and lower levels of functional recovery after the traumatic event. Identifying these predictive factors is crucial for guiding treatment and prognosis strategies, as well as shaping public health policies for this population. The aim of this study was to identify predictors of mortality and functional recovery from hospital admission up to 12 months after severe TBI. This was a prospective observational cohort study conducted at a trauma referral hospital in the state of Espírito Santo, Brazil. All individuals diagnosed with severe TBI over the age of 18 admitted within a one-year period were included. The analyzed outcomes were in-hospital mortality and functional recovery assessed using the Extended Glasgow Outcome Scale (GOSE) at the time of hospital discharge, 3, 6, and 12 months after TBI. After applying the inclusion criteria, 383 patients were included, of which 211 (55%) died, and 172 (45%) survived hospitalization. Among these, 145 completed the one-year follow-up. The mean age was 49 years, 80% were male, and falls (46.5%) were the main cause of injury. In the final binomial logistic regression model, age over 65 years, days on mechanical ventilation, and low educational level were strong predictors of unfavorable functional recovery over the 12 months following the trauma. Pupillary changes, such as anisocoria and mydriasis, high respiratory rate, decreased body temperature, ISS scores >25, and the performance of decompressive craniectomy were associated with a higher risk of in-hospital mortality. This study was the first to investigate predictors of mortality and functional recovery one year after severe Traumatic Brain Injury in the Brazilian population. The higher mortality rate in TBI patients compared to both high-income countries (HICs) and low- and middleincome countries (LMICs) underscores the importance of considering regional disparities when developing and implementing TBI management strategies worldwide.
- ItemA PRIVAÇÃO ANDROGÊNICA DE LONGO PRAZO MODULA A REATIVIDADE VASCULAR POR VIAS DEPENDENTES DE ALDOSTERONA E ANGIOTENSINA II(Universidade Federal do Espírito Santo, 2022-08-31) Costa, Anna Karolina Nascimento; Stefanon, Ivanita; https://orcid.org/0000-0003-2638-5183; http://lattes.cnpq.br/8456612999765726; https://orcid.org/; http://lattes.cnpq.br/0575590472541198; Bissoli, Nazare Souza; https://orcid.org/; http://lattes.cnpq.br/8865368585732583; Davel, Ana Paula Couto; https://orcid.org/; http://lattes.cnpq.br/Testosterone is a vasoactive hormone, which acts by genomic and non-genomic mechanisms. Acutely, it may have endothelium-dependent vasodilatory actions. However, the long-term modulation of testosterone on the regulation of vascular tone remains unclear. The hypothesis of this study is that, in the long term, testosterone participates in the vascular reactivity regulation, dependent on the renin-angiotensin- aldosterone system. Wistar rats (N=128), at 12 weeks of age, were divided into male Control (SHAM) and orchiectomy surgery (OQT), treated for 3 months with losartan, an angiotensin II receptor blocker (SHAM+LOS and OQT+ LOS), 15 mg/kg, s.c); spironolactone (SHAM+SPI and OQT+SPI, 80 mg/kg, gavage), mineralocorticoid receptor antagonist and apocynin, NADPH oxidase inhibitor (SHAM+APO and OQT+APO, 30 mg/kg, drinking water), Vascular reactivity was analysed in isolated aortic rings, as the percentage of response to KCl (75 mM), superfused with modified Krebs pH 7.4, 36.5oC. The presence of vascular presence was observed in vitro as curves-response to phenylephrine (10-11 to 10-3 M) and absence of: L-NAME, 100 μM; indomethacin (INDO, 10 μM) and endothelium-denuded rings (E-). Plasma lipid peroxidation was measured using the TBARS technique. (CEUA-UFES 017/2020). Results were expressed as mean ± SEM and using Student's t test, analysis of variance (ANOVA), one way. The OQT groups, untreated and OQT treated with APO and LOS, had lower body weight at the end of the 3 months (SHAM 231 ± 11g; OQT= 158,4 ± 13,0g*; OQT+APO 208,3 ± 15,4g; OQT+LOS 156,0 ± 23,0g *p<0,05). The Rmax for phenylephrine was the same between the SHAM and OQT groups. Treatments for 3 months with LOS and APO did not change Rmax to phenylephrine. However, LOS treatment reduced the pD2 of the OQT group (log EC50: OQT= -6.240 ± 0.15 vs OQT+LOS= -7.218 ± 0.23 *p<0.01). Inhibition of MR receptors with spironolactone determined a lower maximal contraction to phenylephrine in the OQT group than in the SHAM, suggesting that this pathway could be testosterone dependent. (SHAM+SPI =120.4 ± 7.56% n=10 vs OQT+SPI= 93.3 ± 10.2% n=10; *p<0.05). Phenylephrine reactivity increased in the presence of L-NAME and in the absence of E, similarly between the groups. Inhibition of the COX pathway with indomethacin determined a reduction in Rmax in both groups (Rmax SHAM= 118.3 ± 8.04 vs SHAM+INDO = 56.27 ± 6.61, p <0.01 and OQT= 119.8 ± 8.41 vs OQT+INDO= 72.64 ± 9.34, p<0.01). There was no difference in reactivity between the groups incubated with indomethacin (SHAM+INDO and OQT+INDO). There was a reduction in RMax, in the presence of indomethacin, only in the OQT+SPI group. This result suggests the participation of aldosterone in the COX activation pathway, possibly of a vasoconstrictor, since in the SHAM+SPI group, indomethacin reduced the maximum contraction (Rmax: SHAM+SPI = 120.4 ± 7.56; OQT+ SPI= 93.28 ± 10.18; SHAM+SPI+INDO = 89.99 ± 8.45; OQT+SPI+INDO = 74.15 ± 7.92, * p <0.05). Endothelial NO bioavaliability seems to have been modified in the group treated with losartan, especially in the OQT+LOS- LN group, suggesting the importance of the testosterone pathway in the production of NO mediated by angiotensin II receptors. These data suggest that testosterone participates in the production of NO mediated by angio II, because when we remove the production of NO, through the LN, in the OQT group, there was a reduction in Rmax in relation to its control. Is suggests the importance of testosterone in the contractile response. mediated by the AT1 angiotensin receptor (Rmax: SHAM+LOS = 127.5 ± 5.63; OQT+LOS = 135.6 ± 4.74; SHAM+LOS LN = 183.4 ± 10.50; OQT+LOS LN = 151.8 ± 8.311; * p<0.05). The effects of treatment with the angiotensin II inhibitor, losartan, on rings without endothelium, showed that the endothelium injury caused an increase in the response to phenylephrine in the SHAM group. However, there was no difference between the OQT+LOS E- and OQT+LOS CT groups, suggesting a vasoconstrictor positive modulation that depends on the presence of angiotensin II. These data suggest that testosterone participates in the production of NO mediated by angio II, because when we remove the production of NO, through the LN, in the castrated group there is a reduction in Rmax in relation to its control, suggesting the importance of testosterone in the contractile response. mediated by the AT1 angiotensin receptor (Rmax: SHAM+LOS = 127.5 ± 5.63; OQT+LOS = 135.6 ± 4.74; SHAM+LOS LN = 183.4 ± 10.50; OQT+LOS LN = 151.8 ± 8.311; * p<0.05). The effects of treatment with the angiotensin II inhibitor, losartan, on rings without endothelium, showed that the endothelium injury caused an increase in the response to phenylephrine in the SHAM group. However, there was no difference between the OQT+LOS E- and OQT+LOS CT groups, suggesting a vasoconstrictor positive modulation that depends on the presence of angiotensin II. Orchidectomy modified the endothelium-dependent response during treatment with losartam (Rmax: SHAM+LOS = 127.5 ± 5.63; OQT+LOS = 135.6 ± 4.74; SHAM+LOS E- = 217.3 ± 217.3 ± 26.77; OQT+LOS E- = 145.3 ± 7.90. * p<0.05). In conclusion, the set of these results suggest the long term participation of testosterone and aldosterone in the modulation of vascular contraction induced by phenylephrine.
- ItemEfeitos agudos da exposição “in vitro” ao ferro (ii) sobre a função endotelial de aorta de ratos(Universidade Federal do Espírito Santo, 2023-04-06) Carnelli, Anderson Ramiro Rangel; Santos, Leonardo dos; https://orcid.org/0000-0002-4340-6364; http://lattes.cnpq.br/4132087001362623; https://orcid.org/; http://lattes.cnpq.br/6170108738039122; Padilha, Alessandra Simão; https://orcid.org/0000-0002-9585-1347; http://lattes.cnpq.br/7658998034219799; Marques, Vinicius Bermond; https://orcid.org/0000-0002-3522-3867; http://lattes.cnpq.br/4197044018432036INTRODUCTION: Although iron is an essential mineral for homeostasis, excessive iron accumulation in our body can lead to intoxication or overload, since there are not regulated processes for its excretion. Oral intoxication, mainly by children due to accidental ingestion, or parenteral administration, due to high-dose infusions, exhibit high morbidity and mortality rates. In excess, free iron can damage organs and systems, especially the cardiovascular system. It is currently well known that not only chronic iron overload, but also acute incubation of rat myocardial tissue with ferrous ion (Fe2+) result in contractile dysfunction of the cardiac muscle. In addition, several studies also suggest significant vasculopathy in rats chronically overloaded with iron, related to intense oxidative stress. However, the “in vitro” effects of this metal on the vasculature have not been identified. Thus, due to the vasculopathy already described in chronic exposure "in vivo" models, and its oxidative potential, the hypothesis is that "in vitro" exposure of aortic segments to Fe2+ is capable of altering the endothelial structure and function, in its modulatory role on vascular tone. OBJECTIVE: To evaluate whether “in vitro” exposure to high concentrations of Fe2+ induce morphofunctional changes in the vascular endothelium of rat aortic segments. MATERIAL AND METHODS: Aortic rings isolated from male Wistar rats (250-350g) were used to evaluate the vascular reactivity to phenylephrine after incubation with a standard nutrient solution added with ferrous sulfate (FeSO4 10, 25, 100, 250, and 1000 µM) for 30 minutes. the vasodilatory responses to acetylcholine or a nitric oxide donor, sodium nitroprusside, were evaluated in rings previously pre-contracted with phenylephrine. In addition, the role of the endothelium in the effects of Fe2+ 100 and 1000 µM on vascular reactivity was analyzed by mechanical injury of the intimal layer. Furthermore, some segments with intact endothelium were pre-incubated with an inhibitor of nitric oxide synthase, a cyclooxygenase inhibitor, a hydroxyl radical scavenger, and a hydrogen peroxide inactivator (L-NAME, indomethacin, DMSO and catalase, respectively). Finally, samples of aortic segments were analyzed by scanning electron microscopy and energydispersive spectroscopy for evaluation of the morphology and elemental mapping of the endothelial surface; in addition to the extraction of vascular tissue for analysis of advanced protein oxidation products and the main product of lipid peroxidation, malondialdehyde. RESULTS: “In vitro” exposure to Fe2+ increased vascular reactivity to phenylephrine after 30 minutes, from 25 µM, with more significant effects observed after exposure to concentrations of 100, 250, and 1000 µM. In the acetylcholine curves, aortic rings exposed to high Fe2+ had a lower vasodilatory response, while the response sodium nitroprusside was preserved, suggesting an impairment in endothelial function. Removal of the endothelium and incubation with L-NAME increased vasoconstrictive response in all rings. However, the magnitude of this increase was lower in those arterial segments exposed to Fe2+ , indicating a reduction in endothelial modulation and participation of nitric oxide, which was confirmed with DAF fluorescence that evidenced reduced NO bioavailability in samples incubated with Fe2+ . In the presence of indomethacin, vasoconstriction of aortic rings exposed to Fe2+ 1000 µM decreased, suggesting a role of the AA-COX pathway in hypercontractility at higher concentration of Fe2+ . After incubation with catalase and DMSO, there was a decrease in the contractile response of segments exposed to Fe2+, indicating a role of reactive oxygen species (ROS) in this effect. Despite this, there was no significant difference in AOPP or MDA in the rings incubated with Fe2+, suggesting that, despite the effect on vascular reactivity, the increase in ROS at 30 minutes should occur at levels still undetectable by the techniques used and do not cause sufficient damage. Qualitative microanalysis spectroscopy showed significant variations in iron concentration among the studied groups. The control group had low or no presence of iron, while the Fe-incubated groups showed a considerable and even greater increase.. CONCLUSION: “In vitro” incubation with high concentrations of Fe2+ is sufficient to damage to endothelial cells, resulting in impaired endothelial modulation. The mechanisms appear to be related to the exacerbation of contractile pathways derived from COX and a decrease in the bioavailability of NO in association with the production of ROS.
- ItemRegulação da reatividade vascular, dependente do estresse oxidativo e da via da PKD1, em ratos espontaneamente hipertensos(Universidade Federal do Espírito Santo, 2023-04-14) Hortelan, Michelle Rossana Martins; Stefanon, Ivanita; https://orcid.org/0000-0003-2638-5183 ; http://lattes.cnpq.br/8456612999765726; http://lattes.cnpq.br/5146590072402292; Bissoli, Nazaré Souza; https://orcid.org/0000-0003-2638-5183; http://lattes.cnpq.br/8865368585732583; Batista, Priscila Rossi de; https://orcid.org/0000-0001-5850-0989; http://lattes.cnpq.br/9629149780640340High blood pressure is one of the main causes of cardiovascular diseases. In the hypertension animal model, SHR, vascular dysfunction has been described as dependent on oxidative inactivation of nitric oxide (NO) due to higher vascular production of reactive oxygen species (ROS) dependent on NADPH oxidase (NOX). NOX's redox signaling pathways involve regulatory mechanisms, depending on second-mediated pathways messengers and intra- and extracellular signalers. Recently, importance has been given to the signaling pathway dependent on PKD1, an enzyme that belongs to the protein-kinase-dependent Ca2+-calmodulin superfamily. PKD1 has been related to vascular smooth muscle contraction and thus to the modulation of vascular reactivity. The hypothesis of this study is that the PKD1 pathway is involved in the regulation of vascular tone, in the SHR model, via NOXdependent oxidative stress. We used isolated aortic rings from Wistar and SHR rats to evaluate vascular reactivity mediated by α1 receptors and for angiotensin II (ATII). We performed concentration-response curves to phenylephrine (10−10 to 10−4 M) and angiotensin II (10−10 to 10−5 M) cumulatively, in the presence and absence of CID 3,2 μM, a selective inhibitor of PKD1, and Apokinin 30 μM, a NOX inhibitor. Vascular oxidative stress was analyzed by the thiobarbituric acid reactive species (TBARS) measurement technique, which allows us to evaluate lipid peroxidation and oxidative fluorescence of DHE in situ. Systolic blood pressure (SBP, mmHg) was measured by tail plethysmography 48 hours before the experiments. The results are described as mean ± SEM and were analyzed using: Student's t-test, one- or two-way ANOVA and Tukey's post-hoc test. The SHR group had lower body mass (Wistar (n=10) 313 ± 5.5 g vs SHR (n=10), 260 ± 8.5*g, *p<0.01) and higher SBP (Wistar: 130.0 ± 1.7 vs SHR: (n=10), 197.3 ± 2.5* mmHg, *p<0.01). There was no difference in HR values between the groups. The results collected so far demonstrated that the inhibition of PKD1, with ICD, did not modify the reactivity to phenylephrine in the Wistar group (Wistar Rmax: 114.4 ± 7.54 x Wistar-CID= 96.11 ± 13.7 % KCl). However, the incubation of aortic rings with CID reduced aortic reactivity to phenylephrine in the SHR group (SHR Rmax: 129.9 ± 8.28 x SHR-CID= 83.74 ± 9.3* % KCl, *p<0.01). The vasoconstrictor response to Angiotensin II was reduced in the presence of CID only in the Wistar group (Wistar Rmax: 52.5 ± 3.7 x Wistar-CID= 38.8 ± 6.4 % KCl, *p<0.01). There was no difference in Rmax responses between the CID and CID-Apokinin groups in the Wistar and SHR Documento assinado digitalmente conforme descrito no(s) Protocolo(s) de Assinatura constante(s) neste arquivo, de onde é possível verificar a groups. The vascular oxidative stress was not different between the groups, in the presence and absence of CID after incubation with Angiotensin II. However, the coincubation of CID and Apokinin, reduced the production of MDA in the SHR group. Based on the results found, we can accept our hypothesis that the PKD1 pathway participates in the regulation of aortic ring reactivity in the SHR and Wistar groups. We conclude that, while the PKD1 pathway seems to play a key role in the contraction of the aortic rings of the SHR group mediated by phenylephrine, the same pathway seems to be involved only in the response to angiotensin II in the Wistar group. Our hypothesis of the participation of oxidative stress in CID-mediated responses was rejected, since co-perfusation with Apokinin did not modify the CID-mediated response. This information is relevant to the understanding of the mechanisms involved in the regulation of blood pressure and may have important implications for the development of targeted therapies for the treatment of arterial hypertension.