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1.
Theranostics ; 11(16): 7813-7828, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335966

RESUMO

Non-invasive monitoring of hemodynamic tumor responses to chemotherapy could provide unique insights into the development of therapeutic resistance and inform therapeutic decision-making in the clinic. Methods: Here, we examined the longitudinal and dynamic effects of the common chemotherapeutic drug Taxotere on breast tumor (KPL-4) blood volume and oxygen saturation using eigenspectra multispectral optoacoustic tomography (eMSOT) imaging over a period of 41 days. Tumor vascular function was assessed by dynamic oxygen-enhanced eMSOT (OE-eMSOT). The obtained in vivo optoacoustic data were thoroughly validated by ex vivo cryoimaging and immunohistochemical staining against markers of vascularity and hypoxia. Results: We provide the first preclinical evidence that prolonged treatment with Taxotere causes a significant drop in mean whole tumor oxygenation. Furthermore, application of OE-eMSOT showed a diminished vascular response in Taxotere-treated tumors and revealed the presence of static blood pools, indicating increased vascular permeability. Conclusion: Our work has important translational implications and supports the feasibility of eMSOT imaging for non-invasive assessment of tumor microenvironmental responses to chemotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Hemodinâmica/fisiologia , Tomografia Óptica/métodos , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Docetaxel/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipóxia/metabolismo , Camundongos , Camundongos SCID , Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Tomografia/métodos , Tomografia Computadorizada por Raios X/métodos , Microambiente Tumoral/fisiologia
2.
Medicine (Baltimore) ; 100(34): e27045, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449490

RESUMO

BACKGROUND: Laryngeal microsurgery (LMS) causes hemodynamic instability and postoperative agitation, cough, pain, nausea, and vomiting. Moreover, because of a short operation time, it is associated with challenging anesthetic management. The aim of this study was to compare the usefulness of continuous administration of dexmedetomidine and remifentanil in inducing general anesthesia in patients undergoing LMS. METHODS: This is a prospective randomized control design. Continuous intravenous infusion of dexmedetomidine (group D) or remifentanil (group R) was administered from 10 minutes before the induction of anesthesia to the end of surgery. In both groups, 1.5 mg/kg propofol and 0.5 mg/kg rocuronium were administered for the induction of anesthesia, and desflurane were titrated during the measurement of the bispectral index. We recorded hemodynamic data, recovery time, grade of cough, pain score, and analgesic requirements during the perioperative period. RESULTS: 61 patients were finally analyzed (30 for group D, 31 for group R). The incidence of moderate to severe postoperative sore throat was higher in group R than in group D (42% vs 10%, P = .008), and the quantity of rescue fentanyl used in post-anesthesia care unit was significantly higher in group R than in group D (23.2 ±â€Š24.7 mg vs 3.3 ±â€Š8.6 mg; P < .001); however, the time required for eye opening was significantly longer in group D than in group R (599.4 ±â€Š177.9 seconds vs 493.5 ±â€Š103.6 seconds; P = .006). The proportion of patients with no cough or single cough during extubation was comparable between the 2 groups (group D vs group R: 73% vs 70%) as was the incidence of hemodynamic instability. CONCLUSION: Although there was a transient delay in emergence time, dexmedetomidine reduced postoperative opioid use and the incidence of sore throat. Dexmedetomidine may be used as an alternative agent to opioids in patients undergoing LMS.


Assuntos
Dexmedetomidina/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipnóticos e Sedativos/uso terapêutico , Laringe/cirurgia , Remifentanil/uso terapêutico , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Período de Recuperação da Anestesia , Tosse/etiologia , Feminino , Humanos , Masculino , Microcirurgia , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/prevenção & controle , Período Perioperatório , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
3.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207775

RESUMO

Arterial hypercapnia reduces renal perfusion. Beetroot juice (BRJ) increases nitric oxide bioavailability and may improve renal blood flow. We tested the hypothesis that acute consumption of BRJ attenuates both decreases in blood velocity and increases in vascular resistance in the renal and segmental arteries during acute hypercapnia. In fourteen healthy young adults, blood velocity and vascular resistance were measured with Doppler ultrasound in the renal and segmental arteries during five minutes of breathing a carbon dioxide gas mixture (CO2) before and three hours after consuming 500 mL of BRJ. There was no difference between pre- and post-BRJ consumption in the increase in the partial pressure of end-tidal CO2 during CO2 breathing (pre: +4 ± 1 mmHg; post: +4 ± 2 mmHg, p = 0.4281). Segmental artery blood velocity decreased during CO2 breathing in both pre- (by -1.8 ± 1.9 cm/s, p = 0.0193) and post-BRJ (by -2.1 ± 1.9 cm/s, p = 0.0079), but there were no differences between pre- and post-consumption (p = 0.7633). Segmental artery vascular resistance increased from room air baseline during CO2 at pre-BRJ consumption (by 0.4 ± 0.4 mmHg/cm/s, p = 0.0153) but not post-BRJ (p = 0.1336), with no differences between pre- and post-consumption (p = 0.7407). These findings indicate that BRJ consumption does not attenuate reductions in renal perfusion during acute mild hypercapnia in healthy young adults.


Assuntos
Beta vulgaris , Sucos de Frutas e Vegetais , Hemodinâmica/efeitos dos fármacos , Hipercapnia/fisiopatologia , Rim/irrigação sanguínea , Raízes de Plantas , Adulto , Pressão Arterial , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Dióxido de Carbono , Ingestão de Líquidos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Artéria Renal/fisiopatologia , Respiração/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Ultrassonografia Doppler , Resistência Vascular/efeitos dos fármacos
5.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199303

RESUMO

The main purpose of new stent technologies is to overcome unfavorable material-related incompatibilities by producing bio- and hemo-compatible polymers with anti-inflammatory and anti-thrombogenic properties. In this context, wettability is an important surface property, which has a major impact on the biological response of blood cells. However, the influence of local hemodynamic changes also influences blood cell activation. Therefore, we investigated biodegradable polymers with different wettability to identify possible aspects for a better prediction of blood compatibility. We applied shear rates of 100 s-1 and 1500 s-1 and assessed platelet and monocyte activation as well as the formation of CD62P+ monocyte-bound platelets via flow cytometry. Aggregation of circulating platelets induced by collagen was assessed by light transmission aggregometry. Via live cell imaging, leukocytes were tracked on biomaterial surfaces to assess their average velocity. Monocyte adhesion on biomaterials was determined by fluorescence microscopy. In response to low shear rates of 100 s-1, activation of circulating platelets and monocytes as well as the formation of CD62P+ monocyte-bound platelets corresponded to the wettability of the underlying material with the most favorable conditions on more hydrophilic surfaces. Under high shear rates, however, blood compatibility cannot only be predicted by the concept of wettability. We assume that the mechanisms of blood cell-polymer interactions do not allow for a rule-of-thumb prediction of the blood compatibility of a material, which makes extensive in vitro testing mandatory.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Poliésteres/farmacologia , Plaquetas/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Água , Molhabilidade
6.
Medicine (Baltimore) ; 100(22): e26211, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087896

RESUMO

BACKGROUND: Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH. METHODS: Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test. RESULTS: Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed. CONCLUSIONS: We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.


Assuntos
Ativadores de Enzimas/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Doença Crônica , Gerenciamento de Dados , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Hipertensão Arterial Pulmonar/complicações , Embolia Pulmonar/complicações , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Guanilil Ciclase Solúvel/efeitos dos fármacos , Resultado do Tratamento
8.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
9.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066865

RESUMO

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-ß and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Cardiotônicos/uso terapêutico , Hipertensão Maligna/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Feminino , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Maligna/enzimologia , Hipertensão Maligna/patologia , Hipertensão Maligna/fisiopatologia , Inflamação/complicações , Inflamação/tratamento farmacológico , Miocárdio/patologia , NG-Nitroarginina Metil Éster/química , NG-Nitroarginina Metil Éster/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Ratos Endogâmicos SHR , Resveratrol/química , Resveratrol/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Proteína X Associada a bcl-2/metabolismo
10.
Am J Physiol Heart Circ Physiol ; 321(1): H175-H184, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34018850

RESUMO

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.


Assuntos
Contração Miocárdica/efeitos dos fármacos , Nitrito de Sódio/administração & dosagem , Sístole/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/efeitos dos fármacos
11.
J Trauma Nurs ; 28(3): 149-158, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33949348

RESUMO

BACKGROUND: Propofol and dexmedetomidine may cause hemodynamic adverse effects (AEs) and more data are needed in a trauma and surgical population. OBJECTIVE: The objective of this study was to evaluate the rate of hemodynamic AEs requiring an intervention between dexmedetomidine and propofol in a critically ill trauma and surgical population. METHODS: This was a retrospective cohort study at a Level 1 trauma center. Intensive care unit patients admitted from October 1, 2017, through October 31, 2018, were divided into two groups: dexmedetomidine or propofol. The primary end point was the proportion of patients who required a therapeutic intervention for a hemodynamic AE within the first 24 hr of initiation of dexmedetomidine or propofol. RESULTS: A total of 800 charts were reviewed and 85 patients (dexmedetomidine [n = 35] and propofol [n = 50]) were included. The study population consisted of Caucasian (86%) males (61%) with a median age of 61 [interquartile range-IQR 48, 72], and 18% and 24% required antihypertensive and vasopressor agents, respectively. No difference in the primary outcome was observed (17 [49%] vs. 27 [54%], p = .624). There was no difference in the overall incidence of hemodynamic AE (18 [51%] vs. 30 [60%], p = .433). Dexmedetomidine patients had a greater decrease in median heart rate (HR) compared with the propofol (23 [IQR 16, 41] vs. 14 [IQR 5, 24] beats/min, p = .002). CONCLUSIONS: The rate of hemodynamic AEs requiring therapeutic interventions was similar between dexmedetomidine and propofol in a critically ill trauma and surgical population; however, dexmedetomidine may be associated with a larger decrease in HR.


Assuntos
Hemodinâmica , Idoso , Estado Terminal , Dexmedetomidina/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Pessoa de Meia-Idade , Propofol/farmacologia , Estudos Retrospectivos
12.
Best Pract Res Clin Anaesthesiol ; 35(2): 231-240, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34030807

RESUMO

In patients undergoing craniotomy, general anesthesia should be addressed to warrant good hypnosis, immobility, and analgesia, to ensure systemic and cerebral physiological status and provide the best possible surgical field. Regarding craniotomies, it is unclear if there are substantial differences in providing general anesthesia using total intravenous anesthesia (TIVA) or balanced anesthesia (BA) accomplished using the third generation halogenates. New evidence highlighted that the last generation of halogenated agents has possible advantages compared with intravenous drugs: rapid induction, minimal absorption and metabolization, reproducible pharmacokinetic, faster recovery, cardioprotective effect, and opioid spare analgesia. This review aims to report evidence related to the use of the latest halogenated agents in patients undergoing craniotomy and to present available clinical evidence on their effects: cerebral and systemic hemodynamic, neurophysiological monitoring, and timing and quality of recovery after anesthesia.


Assuntos
Período de Recuperação da Anestesia , Anestesia Geral/métodos , Anestesia por Inalação/métodos , Procedimentos Neurocirúrgicos/métodos , Anestesia Geral/efeitos adversos , Anestesia por Inalação/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Desflurano/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos
13.
Biomed Res Int ; 2021: 5598351, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33969119

RESUMO

Hypertensive-induced renal damage (HRD) is an important public health and socioeconomic problem worldwide. The herb pair Radix Astragali- (RA-) Radix Salviae Miltiorrhizae (RS) is a common prescribed herbal formula for the treatment of HRD. However, the underlying mechanisms are unclear. The purpose of our study is to explore the mechanism of combination of Radix Astragali (RA) and Radix Salviae Miltiorrhizae (RS) ameliorating HRD by regulation of the renal sympathetic nerve. Thirty 24-week-old spontaneously hypertensive rats (SHRs) as the experimental group were randomly divided into the RA group, the RS group, the RA+RS group, the valsartan group, and the SHR group and six age-matched Wistar Kyoto rats (WKY) as the control group. After 4 weeks of corresponding drug administration, venipuncture was done to collect blood and prepare serum for analysis. A color Doppler ultrasound diagnostic instrument was used to observe renal hemodynamics. Enzyme-linked immunosorbent assay was used to detect norepinephrine (NE), epinephrine (E), angiotensin II (Ang II), and B-type brain natriuretic peptide (BNP). Simultaneously, the kidneys were removed immediately and observed under a transmission electron microscope to observe the ultrastructural changes. And the concentration of transforming growth factor-ß1 (TGF-ß1), angiotensin type 1 receptor (AT1), and nitric oxide (NO) was detected by immunohistochemistry. Our results showed that renal ultrasonography of rats showed no significant difference in renal size among groups. The RA+RS group had obviously decreased vascular resistance index. The levels of NE, E, BNP, Ang II, AT1, and TGF-ß1 were decreased (P < 0.05), and the density of NO was increased. Pathological damage of the kidney was alleviated. In conclusion, the results of the present study suggested sympathetic overexpression in the pathogenesis of HRD. The combination of RA and RS may inhibit the hyperexcitability of sympathetic nerves and maintain the normal physiological structure and function of kidney tissue and has a protective effect on the cardiovascular system.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hipertensão/tratamento farmacológico , Rim/patologia , Salvia miltiorrhiza/química , Animais , Biomarcadores/sangue , Medicamentos de Ervas Chinesas/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/fisiopatologia , Rim/diagnóstico por imagem , Rim/fisiopatologia , Rim/ultraestrutura , Masculino , Modelos Biológicos , Óxido Nítrico/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Resistência Vascular/efeitos dos fármacos
14.
Am J Physiol Heart Circ Physiol ; 320(6): H2305-H2312, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861146

RESUMO

Adults with metabolic syndrome (MetS) have increased fasting arterial stiffness and altered central hemodynamics that contribute, partly, to increased cardiovascular disease (CVD) risk. Although insulin affects aortic wave reflections in healthy adults, the effects in individuals with MetS are unclear. We hypothesized that insulin stimulation would reduce measures of pressure waveforms and hemodynamics in people with MetS. Thirty-five adults with obesity (27 women; 54.2 ± 6.0 yr; 37.1 ± 4.8 kg/m2) were selected for MetS (ATP III criteria) following an overnight fast. Pulse wave analysis was assessed using applanation tonometry before and after a 2-h euglycemic-hyperinsulinemic clamp (90 mg/dL, 40 mU/m2/min). Deconvolution analysis was used to decompose the aortic waveform [augmentation index corrected to heart rate of 75 beats/min (AIx@75); augmentation pressure (AP)] into backward and forward pressure components. Aerobic fitness (V̇o2max), body composition (DXA), and blood biochemistries were also assessed. Insulin significantly reduced augmentation index (AIx@75, 28.0 ± 9.6 vs. 23.0 ± 9.9%, P < 0.01), augmentation pressure (14.8 ± 6.4 vs. 12.0 ± 5.7 mmHg, P < 0.01), pulse pressure amplification (1.26 ± 0.01 vs. 0.03 ± 0.01, P = 0.01), and inflammation [high-sensitivity C-reactive protein (hsCRP): P = 0.02; matrix metallopeptidase 7 (MMP-7): P = 0.03] compared to fasting. In subgroup analyses to understand HTN influence, there were no insulin stimulation differences on any outcome. V̇o2max, visceral fat, and blood potassium correlated with fasting AIx@75 (r = -0.39, P = 0.02; r = 0.41, P = 0.03; r = -0.53, P = 0.002). Potassium levels were also associated with insulin-mediated reductions in AP (r = 0.52, P = 0.002). Our results suggest insulin stimulation improves indices of aortic reflection in adults with MetS.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on central and peripheral hemodynamics in adults with metabolic syndrome. We provide evidence that insulin infusion reduces aortic wave reflection, potentially through a reduction in inflammation and/or via a potassium-mediated vascular response.


Assuntos
Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Insulina/farmacologia , Síndrome Metabólica/fisiopatologia , Análise de Onda de Pulso , Rigidez Vascular/efeitos dos fármacos , Aorta/fisiopatologia , Composição Corporal , Aptidão Cardiorrespiratória , Feminino , Técnica Clamp de Glucose , Hemodinâmica/efeitos dos fármacos , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Consumo de Oxigênio , Rigidez Vascular/fisiologia
15.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806919

RESUMO

Argon inhalation attenuates multiorgan failure (MOF) after experimental ischemic injury. We hypothesized that this protection could involve decreased High Mobility Group Box 1 (HMGB1) systemic release. We investigated this issue in an animal model of MOF induced by aortic cross-clamping. Anesthetized rabbits were submitted to supra-coeliac aortic cross-clamping for 30 min, followed by 300 min of reperfusion. They were randomly divided into three groups (n = 7/group). The Control group inhaled nitrogen (70%) and oxygen (30%). The Argon group was exposed to a mixture of argon (70%) and oxygen (30%). The last group inhaled nitrogen/oxygen (70/30%) with an administration of the HMGB1 inhibitor glycyrrhizin (4 mg/kg i.v.) 5 min before aortic unclamping. At the end of follow-up, cardiac output was significantly higher in Argon and Glycyrrhizin vs. Control (60 ± 4 and 49 ± 4 vs. 33 ± 8 mL/kg/min, respectively). Metabolic acidosis was attenuated in Argon and Glycyrrhizin vs. Control, along with reduced amount of norepinephrine to reverse arterial hypotension. This was associated with reduced interleukin-6 and HMGB1 plasma concentration in Argon and Glycyrrhizin vs. Control. End-organ damages were also attenuated in the liver and kidney in Argon and Glycyrrhizin vs. Control, respectively. Argon inhalation reduced HMGB1 blood level after experimental aortic cross-clamping and provided similar benefits to direct HMGB1 inhibition.


Assuntos
Argônio/farmacologia , Proteína HMGB1/antagonistas & inibidores , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/metabolismo , Animais , Biópsia , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Testes de Função Cardíaca , Hemodinâmica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Coelhos
17.
Toxicol Appl Pharmacol ; 421: 115533, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33848515

RESUMO

Decreased activity of AMP-activated protein kinase (AMPK) is implicated in the pathogenesis of diabetic cardiomyopathy (DCM). Recent evidence suggests a crosstalk between cinacalcet and AMPK activation. This study investigated the effects of cinacalcet on cardiac remodeling and dysfunction in type 2 diabetic rats (T2DM). High fat diet for 4 weeks combined with single intraperitoneal injection of streptozotocin (30 mg/kg) was used to induce type 2 diabetes in rats. Diabetic rats were either orally treated with vehicle, 5 or 10 mg/kg cinacalcet for 4 weeks. Control rats were fed standard chow diet and intraperitoneally injected with citrate buffer. T2DM rats showed lower body weight (BW), hyperglycemia and dyslipidemia, along with increased heart weight (HW) and HW/BW ratio. Masson's trichrome stained cardiac sections revealed massive fibrosis in T2DM rats. There were increased TGF-ß1 and hydroxyproline levels, coupled with up-regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in hearts of T2DM rats. These alterations were associated with redox imbalance and impaired cardiac functions. Decreased phosphorylation of AMPK at threonine172 residue was found in T2DM hearts. Cinacalcet for 4 weeks significantly activated AMPK and alleviated cardiac remodeling and dysfunction in a dose-dependent manner, without affecting blood glucose, serum calcium and phosphorus levels. Cinacalcet increased the mitochondrial DNA content, and expressions of PGC-1α, UCP-3, beclin-1 and LC3-II/LC3-I ratio. Cinacalcet decreased the pro-apoptotic Bax, while increased the anti-apoptotic Bcl-2 in cardiac tissue of T2DM rats. These findings might highlight cinacalcet as an alternative therapy to combat the development and progression of DCM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Cinacalcete/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/enzimologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Fibrose , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Estreptozocina
18.
Eur J Pharmacol ; 901: 174077, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798601

RESUMO

This study investigated the hemodynamic effect of Bay 60-7550, a phosphodiesterase type 2 (PDE2) inhibitor, in healthy rat hearts both in vivo and ex vivo and its underlying mechanisms. In vivo rat left ventricular pressure-volume loop, Langendorff isolated rat heart, Ca2+ transient of left ventricular myocyte and Western blot experiments were used in this study. The results demonstrated that Bay 60-7550 (1.5 mg/kg, i. p.) increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-diastolic volume, heart rate, and ejection fraction. The simultaneous aortic pressure recording indicated that the systolic blood pressure was increased and diastolic blood pressure was decreased by Bay 60-7550. Also, the arterial elastance which is proportional to the peripheral vessel resistance was significantly decreased. Bay 60-7550 (0.001, 0.01, 0.1, 1 µmol/l) also enhanced the left ventricular development pressure in non-paced and paced modes with a decrease of heart rate in non-paced model. Bay 60-7550 (1 µmol/l) increased SERCA2a activity and SR Ca2+ content and reduced SR Ca2+ leak rate. Furthermore, Bay 60-7550 (0.1 µmol/l) increased the phosphorylation of phospholamban at 16-serine without significantly changing the phosphorylation levels of phospholamban at 17-threonine and RyR2. Bay 60-7550 increased the rat heart contractility and reduced peripheral arterial resistance may be mediated by increasing the phosphorylation of phospholamban and dilating peripheral vessels. PDE2 inhibitors which result in a positive inotropic effect and a decrease in peripheral resistance might serve as a target for developing agents for the treatment of heart failure in clinical settings.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cardiotônicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Imidazóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Triazinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resistência Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
19.
Eur J Pharmacol ; 901: 174096, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33848542

RESUMO

Depression after myocardial infarction (MI) and chronic heart failure (CHF) is a common condition that is resistant to anti-depressive drugs. Ghrelin (a peptide hormone) shows dual protective effects on heart and brain. Whether ghrelin treatment attenuated depression after MI was investigated. Coronary artery occlusion was performed to induce MI and subsequent CHF in rats. Ghrelin (100 µg/kg in 0.5 ml of saline) or vehicle (0.5 ml of saline) was injected subcutaneously twice a day for 4 weeks. At week 5, all the animals underwent behavioral assessments including sucrose preference test (SPT), elevated plus maze test (EPM), and open field test (OFT). After cardiac function analysis, brain tissues were processed to determine inflammatory cytokines and microglial activations in hippocampus. Results showed that ghrelin substantially improved cardiac dysfunction, infarction size, and cardiac remodeling and modulated the release of inflammatory cytokines and the increase of Iba-1 positive microglia and glial fibrillary acidic protein-positive astrocytes in the CA1 area of hippocampus. Behavioral tests revealed that this treatment remarkably increased sucrose preference and mobile times and numbers. These findings provided evidence that peripheral ghrelin administration inhibits depression-like behavior and neuroinflammation and thus could be a new approach for the treatment of CHF-associated depression.


Assuntos
Depressão/tratamento farmacológico , Depressão/etiologia , Grelina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Neurite (Inflamação)/tratamento farmacológico , Animais , Ansiedade/prevenção & controle , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Hemodinâmica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Eur J Pharmacol ; 901: 174095, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862063

RESUMO

Previous clinical studies have shown that anisodamine could improve no-reflow phenomenon and prevent reperfusion arrhythmias, but whether this protective effect is related to the antagonism of the M-type cholinergic receptor or other potential mechanisms is uncertain. The aim of the present study was to investigate the role of the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) in cardioprotective effect of anisodamine against ischemia/reperfusion injury. Anisodamine and 5- hydroxydecanoic acid were used to explore the relationship between anisodamine and mitoK ATP . Using a Langendorff isolated heart ischemia/reperfusion injury model, hemodynamic parameters and reperfusion ventricular arrhythmia were evaluated; in addition, changes in myocardial infarct size, cTnI from coronary effluent and myocardial ultrastructure, as well as ATP, MDA and SOD in myocardial tissues, were detected. In the hypoxia/reoxygenation injury model of neonatal rat cardiomyocyte, cTnI release in the culture medium and levels of ATP, MDA and SOD in cardiomyocytes and mitochondrial membrane potential, were analyzed. Overall, anisodamine could significantly improve the hemodynamic indexes of isolated rat heart injured by ischemia/reperfusion, reduce the occurrence of ventricular reperfusion arrhythmia and myocardial infarction area, and improve the ultrastructural damage of myocardium and mitochondria. The in vitro results demonstrated that anisodamine could improve mitochondrial energy metabolism, reduce oxidative stress and stabilize mitochondrial membrane potential. The cardioprotective effects were significantly inhibited by 5-hydroxydecanoic acid. In conclusion, this study suggests that the opening of mitoK ATP could play an important role in the protective effect of anisodamine against myocardial ischemia/reperfusion injury.


Assuntos
Cardiotônicos/uso terapêutico , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Canais de Potássio/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Alcaloides de Solanáceas/uso terapêutico , Trifosfato de Adenosina/metabolismo , Animais , Arritmias Cardíacas/prevenção & controle , Ácidos Decanoicos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hidroxiácidos/farmacologia , Técnicas In Vitro , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Sprague-Dawley , Alcaloides de Solanáceas/antagonistas & inibidores , Superóxido Dismutase/metabolismo
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