Effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/PPARγ pathway in arrhythmic rats / 中国中药杂志

This paper aimed to investigate the effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/peroxisome proliferator-activated receptor γ(PPARγ) pathway in arrhythmic rats. SD rats were randomly divided into a control group, a model group, a low-dose(20 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a medium-dose(40 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a high-dose(80 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a propranolol hydrochloride(2 mg·kg~(-1)) group, with 12 rats in each group. Except the control group, rats in other groups were prepared as models of arrhythmia by sublingual injection of 1 mL·kg~(-1) of 0.002% aconitine. After grouping and intervention with drugs, the arrhythmia, myocardial cells apoptosis, myocardial tissue glutathione peroxidase(GSH-Px), catalase(CAT), malondialdehyde(MDA), serum interleukin-6(IL-6), prostaglandin E2(PGE2) levels, myocardial tissue apoptosis, and Wnt/β-catenin/PPARγ pathway-related protein expression of rats in each group were measured. As compared with the control group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA levels in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels increased significantly in the model group, whereas the GSH-Px and CAT levels, and Bcl-2 and PPARγ protein expression levels in myocardial tissues reduced significantly. As compared with the model group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA leve in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels reduced in the drug intervention groups, whereas the GSH-Px and CAT levels and Bcl-2 and PPARγ protein expression levels in myocardial tissues increased. The groups of total flavonoids of buckwheat flower and leaf were in a dose-dependent manner. There was no significant difference in the levels of each index in rats between the propranolol hydrochloride group and the high-dose group of total flavonoids of buckwheat flower and leaf. The total flavonoids of buckwheat flower and leaf inhibit the activation of Wnt/β-catenin pathway, up-regulate the expression of PPARγ, reduce oxidative stress and inflammatory damage in myocardial tissues of arrhythmic rats, reduce myocardial cell apoptosis, and improve the symptoms of arrhythmia in rats.

Effectiveness of fixed doses of propranolol in the treatment of hemangiomas regardless of child's weight gain: a case report / Efetividade do tratamento de hemangiomas utilizando doses fixas de propranolol em comprimido independentemente do ganho de peso da criança: relato de caso

ABSTRACT Objective: To present the outcomes of fixed doses of propranolol tablets for the treatment of hemangiomas. Case description: Two illustrative cases of hemangioma in infant patients younger than six months old are described. Treatments were started in 2010 and 2011 and were monitored until August 2017. Patients were treated with fixed doses, initially calculated based on the upper limit of 3 mg/kg/day and administrated in two daily doses rounded down to the nearest multiple of five milligrams. Dosage was not adjusted to patients' weight gain. The tablets were crushed and then diluted in a maximum amount of 3 mL of water. This procedure was necessary because propranolol was not available in oral solution in 2009, when dosages available in the Brazilian market were 10, 40 and 80 mg. Both patients presented significative improvement in the first 60 days and were in complete remission by the end of the treatment. Comments: It is possible to treat patients with Propranolol 10 mg tablets, even though the dosage is not as precise as when calculated according to patients' weight. The maintenance of a fixed dose, ignoring the patient's progressive weight gains, helps avoiding the rebound effect and decreases complications.

RESUMO Objetivo: Apresentar a experiência com a utilização de propranolol em doses fixas, em forma de comprimido, para o tratamento de hemangiomas. Descrição do caso: Dois casos ilustrativos de portadores de hemangiomas com menos de seis meses de idade são descritos. O início de tratamento ocorreu nos anos de 2010 e 2011 com seguimento até agosto de 2017. Os pacientes foram tratados com doses fixas iniciais calculadas com limite máximo de 3 mg/kg/dia, divididas em duas doses diárias, sempre com quantidades múltiplas de 5 mg. Os comprimidos de 10 mg ou a sua metade eram macerados e diluídos em 3 mL de água. As doses não foram mais alteradas. Esse uso foi decorrente da ausência da forma líquida de propranolol em 2009, quando começamos a utilizar esse tratamento, sendo então apenas disponíveis comprimidos de 10, 40 e 80 mg. Os pacientes obtiveram melhora acentuada nos primeiros 60 dias e remissão completa posteriormente. Comentários: É possível o uso de comprimidos de 10 mg, apesar de resultar numa dose não exata, como a calculada por kg/peso. A manutenção da mesma dose, mesmo com aumento progressivo de peso, pode evitar o efeito rebote e diminuir o índice de complicações.

Drug interactions in maternal intensive care: prevalence, risk factors, and potential risk medications / Interações medicamentosas em terapia intensiva materna: prevalência, fatores e medicamentos de risco

ABSTRACT Objective: To characterize severe potential drug interactions in maternal intensive care, and to determine their frequency, risk factors and potential risk medications. Methods: An observational and longitudinal study conducted between December 2014 and December 2015 in a maternal intensive care unit. Clinical data were collected and severe potential drug interactions were identified on pregnant inpatients. The drug interactions were classified by type, prevalence and exposure rate. A multivariate logistic regression model was used to identify the severe potential drug interactions and the related drugs (p<0.05). Results: A total of 95.1% of patients were exposed to, at least, one potential drug interaction; in that, 91.7% 33.9% were related to, respectively, moderate and severe potential drug interactions. The patients were exposed, on average, on 69.2% of days they were in the intensive care unit. The main drugs involved in more severe drug interactions were magnesium sulfate, metoclopramide, propranolol and diazepam. Conclusion: The severe potential drug interactions were observed in almost all patients of the study, and, approximately one third of those interactions were related to greater severity and resulted in exposure during long hospital stay. The higher number of prescribed drugs and its previous use of medications at home increase the occurrence of severe potential drug interactions.

RESUMO Objetivo: Caracterizar as interações medicamentosas potenciais graves em terapia intensiva materna, e determinar sua frequência, os fatores e os medicamentos de risco associados à ocorrência dessas interações. Métodos: Estudo observacional e longitudinal executado entre dezembro de 2014 a dezembro de 2015, conduzido em uma unidade de terapia intensiva materna. Foram coletados dados clínicos e identificadas interações medicamentosas potenciais graves de gestantes admitidas. As interações medicamentosas foram caracterizadas quanto ao tipo, à prevalência e à taxa de exposição. Um modelo multivariado de regressão logística foi utilizado para identificação de fatores associados à ocorrência de interações medicamentosas potenciais graves e os medicamentos implicados (p<0,05). Resultados: Um total de 95,1% das pacientes foi exposto a, no mínimo, uma interação medicamentosa potencial, com 91,7% delas envolvidas com interações medicamentosas potenciais moderadas e 33,9% com as interações graves. As pacientes ficaram expostas, em média, em 69,2% dos dias que estiveram sob terapia intensiva. Os principais medicamentos implicados em interações medicamentosas de maior gravidade foram sulfato de magnésio, metoclopramida, propranolol e diazepam. Conclusão: As interações medicamentosas potenciais graves ocorreram na maioria das pacientes avaliadas. Aproximadamente um terço das interações foram graves e levaram à maior exposição por um longo período de internação. Maior número de fármacos prescritos e uso prévio domiciliar de medicamentos elevam a ocorrência de interações medicamentosas potenciais graves.

Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.

Efecto inotrópico y cronotrópico del propranolol sobre aurículas extraídas de ratas con insulina-resistencia inducida por fructosa / Inotropic and chronotropic effects of propranolol in isolated atrium of rats with fructose-induced insulin-resistance

La insulina-resistencia (IR) es una deficiencia metabólica asociada princi palmente con diabetes tipo 2 y comúnmente relacionada a la etiopatogenia de enfermedades cardiovasculares, siendo el factor determinante del síndrome metabólico. La investigación pretende conocer los efectos cronotrópico e inotrópico del propranolol sobre aurículas de ratas IR. Para ello, 16 ejemplares Sprague-Dawley, fueron divididos en Grupo control, alimentado ad libitum con alimento para perros Perrarina® y Grupo experimental, alimentado con Perrarina®-manteca vegetal, y suministro de agua con fructosa (20%)-sacarosa (20%) durante ocho meses. Al finalizar este periodo, se verificó la insulina-resistencia y las aurículas extraídas se mantuvieron en solución Krebs (37ºC, pH 7,4; 95% O2 - 5% CO2), en baño de órganos aislados marca Letica®, conectado a un polígrafo Grass®, registrándose la frecuencia de los latidos y evaluando las diferencias a través de la prueba t de Student (grado de significancia p<0,05). Se establecieron curvas dosis-respuesta acumulativas con isoproterenol y previa incubación de 15 minutos con propranolol (1x10 -6 M), registrándose un efecto cronotrópico negativo en el grupo control mas no así en las ratas IR, estableciéndose diferencias significativas entre el porcentaje de incremento de los latidos/seg en ambos grupos (Control 58,81±4,08; IR 68,84±4,16; p<0,001). La máxima fuerza de contracción auricular alcanzada por el grupo IR con propranolol (278,47±11,22), generó diferencias significativas (p<0,001), en comparación con el grupo control (42,60±3,13), evidenciándose que el propranolol no generó bloqueo sobre los receptores beta-adrenérgicos auriculares de las ratas insulina-resistentes.

Insulin resistance (IR) is a metabolic deficiency associated with type 2 diabe tes and commonly related to the pathogenesis of cardiovascular diseases, being the determining factor of the metabolic syndrome. This research aims to understand the chronotropic and inotropic effects of Propranolol in isolated atrium of rats with fructose-induced insulin-resistance. For this reason, 16 male Sprague-Dawley rats were assigned to two groups and given ad libitum access to one of the following diets: Perrarina® dog chow or Perrarina® dog chow supplemen ted with vegetable shortening and with fructose (20%) and sucrose (20%) added to the water supply. Both groups were maintained on their respective dietary regimens for eight months. At the end of this period insulin resistance was verified by routine blood test. The rat hearts were rapidly removed, and the atria were dissected and kept in Krebs solutions (37ºC, pH 7.4; 95% O2 - 5% CO2) in an isolated organ bath Letica®, connected to a polygraph Grass®, registering atria frequency. The Student ́s t-test was used to evaluate statistical differences between the two groups (p<0.05). Cumulative dose-response curves with isoproterenol were established in basal condition, and after fifteen minutes of pre-incubation with propranolol (1x10 -6 M). A significant positive chronotropic effect was observed in IR rats (8.84±4.16 vs 58.81±4.08 beats/sec of control; p<0.001). The maximum force of atrial contraction after pre-incubation with propranolol was significantly higher in the IR group (278.47±11.22 atrial contraction percentage; p<0.001). These findings suggest that a blunted response of atrial β-adrenoceptor to propranolol exists in rats with fructose-induced insulin-resistance.

Efeitos combinados do ácido zoledrônico e do propranolol sobre a densidade óssea e marcadores bioquímicos de remodelação óssea em ratas osteopênicas submetidas à ovariectomia / Additive effects of zoledronic acid and propranolol on bone density and biochemical markers of bone turnover in osteopenic ovariectomized rats

Objetivos: Este estudo foi desenvolvido para investigar a eficácia e a segurança do ácidozoledrônico (ZOL) e do propranolol (PRO) como monoterapia e terapia combinada em ummodelo de rato com osteoporose pós-menopáusica. Métodos: Ratas Wistar fêmeas foram ovariectomizadas (OVX) ou submetidas à cirurgia simulada (placebo) aos três meses de idade. Doze semanas depois da cirurgia, as ratas foram divididas em seis grupos: (1) placebo + veículo; (2) OVX + veículo; (3) OVX + ZOL (100 µg/kg, dose única intravenosa); (4) OVX + ZOL (50 µg/kg, dose única intravenosa); (5) OVX + PRO (0,1 mg/kg, via subcutânea, cinco dias por semana); (6) OVX + ZOL (50 µg/kg, dose única intravenosa) + PRO (0,1 mg/kg, via subcutânea, cinco dias por semana) durante 12 semanas. Depois do tratamento, testou-se a densidade óssea, a porosidade e a microarquitetura tra-becular dos fêmures. Também foram avaliados marcadores bioquímicos séricos e urinários. Resultados: A terapia combinada com ZOL mais PRO foi mais eficaz em corrigir a diminuição do cálcio sérico e o aumento do nível sérico de fosfatase alcalina e fosfatase ácida resistenteao tartarato do que a monoterapia com ZOL ou PRO. Além disso, a terapia combinada comZOL mais PRO foi mais eficaz em corrigir o aumento dos níveis urinários de cálcio, fósforo ecreatinina do que a monoterapia com ZOL ou PRO. A terapia combinada com ZOL mais PRO também preservou a microarquitetura trabecular e a porosidade do osso cortical. Conclusão: Os resultados sugerem que a terapia combinada com ZOL mais PRO pode ser aabordagem mais eficaz para o tratamento da osteoporose grave em humanos. .

Objectives: The present study was designed to investigate further the efficacy and safety of zoledronic acid (ZOL) and propranolol (PRO) as monotherapy and combination therapy in a rat model of postmenopausal osteoporosis. Methods: Female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months ofage. Twelve weeks post-surgery, rats were randomized into six groups: (1) sham + vehicle; (2) OVX + vehicle; (3) OVX + ZOL (100 뀅g/kg, i.v. single dose); (4) OVX + ZOL (50 뀅g/kg, i.v. single dose); (5) OVX + PRO (0.1 mg/kg, s.c. 5 days per week); (6) OVX + ZOL (50 뀅g/kg, i.v. single dose) + PRO (0.1 mg/kg, s.c. 5 days per week) for 12 weeks. After treatment, femurs were tested for bone density, porosity and trabecular micro-architecture. Biochemical markers in serum and urine were also determined. Results: Combined treatment with ZOL plus PRO corrected the decrease in serum calcium and increase in serum alkaline phosphatase and tartarate resistant acid phosphatase level better than single-drug therapy using ZOL or PRO. Moreover, combined treatment with ZOL plus PRO corrected the increase in urine calcium, phosphorous and creatinine level better than single-drug therapy using ZOL or PRO. Combination therapy using ZOL plus PRO also preserved the trabecular micro-architecture and cortical bone porosity. Conclusion: These data suggest that combined treatment with ZOL plus PRO could be a more effective approach for treating severe osteoporosis in humans. .

Effect of propranolol on capsular reaction around silicone implants in guinea pigs

PURPOSE: To evaluate the effect of propranolol on capsular architecture around silicone implants by measuring the inflammation, capsular thickness, and collagen fiber density, using a guinea pig experimental model. METHODS: Thirty six adult male guinea pigs randomly divided into two groups (n=18) were used. Each one received a silicone implant with textured-surface. The capsular tissue around implants from untreated or treated animals with the beta-adrenoceptor antagonist propranolol (10 mg/kg, dissolved in daily water) were analyzed for inflammation by histological scoring, capsular thickness by computerized histometry, and collagen fibers type I and Type III density by picrosirius polarization at different time points (7, 14 or 21 days after silicone implantation). RESULTS: Propranolol treatment reduced inflammation and impaired capsular thickness and delayed collagen maturation around the textured implant. CONCLUSION: Propranolol reduces the risk of developing capsular contracture around silicone implants with textured surface. .

Differences in Regional Glucose Metabolism of the Brain Measured with F-18-FDG-PET in Patients with Essential Tremor According to Their Response to Beta-Blockers

OBJECTIVE: In this study, there was an investigation as to whether there is a functional difference in essential tremor (ET), according to responses to beta-blockers, by evaluating regional changes in cerebral glucose metabolism. MATERIALS AND METHODS: Seventeen male patients with ET were recruited and categorized into two groups: 8 that responded to medical therapy (group A); and 9 that did not respond to medical therapy (group B). Eleven age-sex matched healthy control male subjects were also included in this study. All subjects underwent F-18 fluorodeoxyglucose (FDG)-PET, and evaluated for their severity of tremor symptoms, which were measured as a score on the Fahn-Tolosa-Marin tremor rating scale (FTM). The FDG-PET images were analyzed using a statistical parametric mapping program. RESULTS: The mean FTM score 6 months after the initiation of propranolol therapy was significantly lower in group A (18.13 > 8.13), compared with group B (14.67 = 14.67). The glucose metabolism in group A in the left basal ganglia was seen to be decreased, compared with group B. The ET showed a more significantly decreased glucose metabolism in both the fronto-temporo-occipital lobes, precuneus of right parietal lobe, and both cerebellums compared with the healthy controls. CONCLUSION: Essential tremor is caused by electrophysiological disturbances within the cortical-cerebellar networks and degenerative process of the cerebellum. Furthermore, ET may have different pathophysiologies in terms of the origin of disease according to the response to first-line therapy.

Modulatory effects of taurine on jejunal contractility

Taurine (2-aminoethanesulfonic acid) is widely distributed in animal tissues and has diverse pharmacological effects. However, the role of taurine in modulating smooth muscle contractility is still controversial. We propose that taurine (5-80 mM) can exert bidirectional modulation on the contractility of isolated rat jejunal segments. Different low and high contractile states were induced in isolated jejunal segments of rats to observe the effects of taurine and the associated mechanisms. Taurine induced stimulatory effects on the contractility of isolated rat jejunal segments at 3 different low contractile states, and inhibitory effects at 3 different high contractile states. Bidirectional modulation was not observed in the presence of verapamil or tetrodotoxin, suggesting that taurine-induced bidirectional modulation is Ca2+ dependent and requires the presence of the enteric nervous system. The stimulatory effects of taurine on the contractility of isolated jejunal segments was blocked by atropine but not by diphenhydramine or by cimetidine, suggesting that muscarinic-linked activation was involved in the stimulatory effects when isolated jejunal segments were in a low contractile state. The inhibitory effects of taurine on the contractility of isolated jejunal segments were blocked by propranolol and L-NG-nitroarginine but not by phentolamine, suggesting that adrenergic β receptors and a nitric oxide relaxing mechanism were involved when isolated jejunal segments were in high contractile states. No bidirectional effects of taurine on myosin phosphorylation were observed. The contractile states of jejunal segments determine taurine-induced stimulatory or inhibitory effects, which are associated with muscarinic receptors and adrenergic β receptors, and a nitric oxide associated relaxing mechanism.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

effects of isoproterenol and propranolol on cytokine profile secretion by cultured tumor-infiltrating lymphocytes derived from colorectal cancer patients

Anti-tumor immunity and cytokine profiles have important roles in the development of cancer. Norepinephrine [NE] release due to sympathetic activation leads to a Th2 deviation via the beta-2 adrenergic receptor [beta -2AR] and could increase cancer progression. This study intends to determine the effects of isoproterenol [ISO; betaagonist] and propranolol [PRO; beta-antagonist] on the production of IFN-gamma, IL-4, and IL-17. Cytokine levels have been examined in tumor-infiltrating lymphocytes [TILs] and peripheral blood mononuclear cells [PBMCs] of patients with colorectal cancer [CRC]. The beta-2AR expression on lymphocyte subsets was also assessed. In this experimental study, TILs were isolated from fresh CRC tissue and patient PBMCs were obtained just prior to surgery. The cells were cultured in medium for 72 hours. Concomitantly, cells were stimulated with 10 micro g/ ml phytohemagglutinin [PHA] alone or in the presence of either 1 micro mol/L of PRO or 1 micro mol/L ISO. The concentration of cytokines in the supernatants was measured by ELISA. Three-color flow cytometry was used to determine the expression of beta-2AR on the lymphocyte subsets. Statistical analyses were performed via paired or independent t-test. Levels of IFN-gamma, IL-4 and IL-17 were elevated after PHA-stimulation of PBMCs and TILs. However, the elevation of IFN-gamma and IL-17 production by TILs in response to PHA was significantly lower than PBMCs. In the presence of ISO, the IFN-gamma/IL-4 ratio reduced in all groups, but this reduction was very low in TILs. Interestingly, the effects of PRO on cytokine production were, at least partially, comparable to those of ISO. Depressed levels of beta-2AR expression were demonstrated on CD4+IFN-gamma+ and CD4+IL-17+ lymphocytes in patients' PBMCs and TILs. This study has demonstrated the effects of ISO and PRO on cytokine production by TILs and determined beta-2AR expression on these cells. ISO failed to induce a shift toward the expected Th2 cytokine profile in CRC patients' TILs, which might be due to the downregulation of beta-2AR expression on TILs. Additionally, in this study, PRO induced a shift to a Th2 profile in PBMCs

Noninvasive method for electrocardiogram recording in conscious rats: feasibility for heart rate variability analysis

Heart rate variability (HRV) analysis consists in a well-established tool for the assessment of cardiac autonomic control, both in humans and in animal models. Conventional methods for HRV analysis in rats rely on conscious state electrocardiogram (ECG) recording based on prior invasive surgical procedures for electrodes/transmitters implants. The aim of the present study was to test a noninvasive and inexpensive method for ECG recording in conscious rats, assessing its feasibility for HRV analysis. A custom-made elastic cotton jacket was developed to fit the rat's mean thoracic circumference, with two pieces of platinum electrodes attached on its inner surface, allowing ECG to be recorded noninvasively in conscious, restrained rats (n=6). Time- and frequency-domain HRV analyses were conducted, under basal and autonomic blockade conditions. High-quality ECG signals were obtained, being feasible for HRV analysis. As expected, mean RR interval was significantly decreased in the presence of atropine (p <0.05) and increased in the presence of propranolol (p<0.001). Also, reinforcing the reliability of the method, low- and high-frequency HRV spectral powers were significantly decreased in the presence of propranolol (p <0.05) and atropine (p< 0.001), respectively. In summary, the present work describes a novel, inexpensive and noninvasive method for surface ECG recording in conscious rats.

A análise da variabilidade da freqüência cardíaca (VFC) consiste em uma metodologia bem estabelecida para o estudo do controle autonômico cardíaco, tanto em humanos como em modelos animais. As metodologias convencionais para o estudo da VFC em ratos utilizam-se de procedimentos cirúrgicos para o implante de eletródios ou transmissores, o que possibilita a posterior aquisição do eletrocardiograma (ECG) no estado consciente. O objetivo do presente trabalho foi o de desenvolver e aplicar um método não-invasivo para o registro do ECG em ratos conscientes, verificando sua validade para a análise da VFC. Uma vestimenta de tecido elástico em algodão foi desenvolvida de acordo com as dimensões médias da circunferência torácica dos animais, e dois pequenos eletródios retangulares de platina foram aderidos à superfície interna da vestimenta, permitindo o registro do ECG de forma não-invasiva em ratos conscientes (n=6), sob contenção. Foram conduzidas análises de VFC nos domínios do tempo e da freqüência, tanto para a condição basal, como para as condições de bloqueio autonômico. Foram obtidos sinais de ECG de alta qualidade, viáveis para a análise de VFC. Conforme esperado, o intervalo RR médio foi significativamente reduzido na presença de atropina (p<0.05), e aumentado na presença de propranolol (p<0.001). Reforçando a validade do método, as potências espectrais de baixa e alta freqüência da VFC sofreram reduções significativas, respectivamente, na presença de propranolol (p<0.05) e atropina (p<0.05). Em resumo, o presente trabalho descreve um novo método, de baixo custo e natureza não-invasiva, para a realização do ECG de superfície em ratos conscientes.

Glucocorticoids, master modulators of the thymic catecholaminergic system?

There is evidence that the major mediators of stress, i.e., catecholamines and glucocorticoids, play an important role in modulating thymopoiesis and consequently immune responses. Furthermore, there are data suggesting that glucocorticoids influence catecholamine action. Therefore, to assess the putative relevance of glucocorticoid-catecholamine interplay in the modulation of thymopoiesis we analyzed thymocyte differentiation/maturation in non-adrenalectomized and andrenalectomized rats subjected to treatment with propranolol (0.4 mg·100 g body weight-1·day-1) for 4 days. The effects of β-adrenoceptor blockade on thymopoiesis in non-adrenalectomized rats differed not only quantitatively but also qualitatively from those in adrenalectomized rats. In adrenalectomized rats, besides a more efficient thymopoiesis [judged by a more pronounced increase in the relative proportion of the most mature single-positive TCRαβhigh thymocytes as revealed by two-way ANOVA; for CD4+CD8- F (1,20) = 10.92, P < 0.01; for CD4-CD8+ F (1,20) = 7.47, P < 0.05], a skewed thymocyte maturation towards the CD4-CD8+ phenotype, and consequently a diminished CD4+CD8-/CD4-CD8+ mature TCRαβhigh thymocyte ratio (3.41 ± 0.21 in non-adrenalectomized rats vs 2.90 ± 0.31 in adrenalectomized rats, P < 0.05) were found. Therefore, we assumed that catecholaminergic modulation of thymopoiesis exhibits a substantial degree of glucocorticoid-dependent plasticity. Given that glucocorticoids, apart from catecholamine synthesis, influence adrenoceptor expression, we also hypothesized that the lack of adrenal glucocorticoids affected not only β-adrenoceptor- but also α-adrenoceptor-mediated modulation of thymopoiesis.

The period between beta-blocker use and physical activity changes training heart rate behavior / O período entre o uso de beta-bloqueador e atividade física mudanças de formação do comportamento da freqüência cardíaca

The Brazilian Society of Cardiology (SBC) proposes that hypertensive subjects who use beta-blockers and practice physical exercises must have their training heart rate (HR) corrected due to the negative chronotropic effect of this drug. Nevertheless, if the physical activity is performed outside of plasmatic half-life, correction may not be necessary. This study investigated the exercise chronotropic response both inside and outside the beta-blocker plasmatic half-life. Nine subjects in use of atenolol or propranolol, and six controls, carried out three walking sessions in three days according to different schedules: EX2 (two hours after drug administration, at the plasmatic peak); EX11 (eleven hours after drug administration, at the end of plasmatic half-life); and EX23 (twenty-three hours after drug administration, outside the plasmatic half-life. The walking sessions were performed on an ergometric treadmill and HR was monitored by a heart rate monitor. During the exercises, mean HRs were 97.2, 108.4 and 109 for EX2, EX11 and EX23, respectively, with the value for EX2 statistically lower than the others (p<0.05). There were no statistical differences in the control group (p>0.05). The study concludes that the attenuation of the positive chronotropic response which occurs during exercise in subjects using beta-blockers, is less evident when the exercise is performed outside the plasmatic half-life of the drug.

A Sociedade Brasileira de Cardiologia (SBC) propõe que os hipertensos que utilizam beta-bloqueadores e praticam exercícios físicos devem ter sua frequência cardíaca de treinamento (HR) corrigida devido ao efeito cronotrópico negativo desse fármaco. Contudo, se a atividade física é realizada fora da meia-vida plasmática do fármaco, a correção pode não ser necessária. Este estudo investigou a resposta cronotrópica ao exercício dentro e fora da meia-vida plasmática do beta-bloqueador. Nove indivíduos que usavam atenolol ou propranolol e seis controles, efetuaram três sessões de caminhada em três dias, de acordo com diferentes esquemas: EX2 (duas horas após a administração do fármaco, no pico plasmático); EX11 (11 horas após a administração do fármaco, no fim da meia-vida plasmática) e EX23 (23 horas após a administração do fármaco, fora da meia-vida plasmática). As caminhadas foram realizadas em esteira ergométrica e a HR foi monitorada por monitor de freqüência cardíaca. Durante os exercícios, as HR médias foram de 97,2, 108,4 e 109, para EX2, EX11 e EX23, respectivamente, com valor de EX2 estatisticamente mais baixo do que os outros (p<0,05). Não houve diferenças estatísticas no grupo controle (p>0,05). O estudo conclui que a atenuação da resposta cronotrópica positiva, que ocorre durante o exercício em indivíduos que utilizam beta-bloqueadores, é menos evidente quando o exercício é realizado fora da meia-vida plasmática do fármaco.

Efeitos da administração de beta-bloqueador na remodelação ventricular induzida pelo tabagismo em ratos / Efectos de la administración de betabloqueante en la remodelación ventricular inducida por el tabaquismo en ratas / Effects of the administration of beta-blockers on ventricular remodeling induced by cigarette smoking in rats

FUNDAMENTO: O papel do sistema adrenérgico na remodelação induzida pelo tabagismo é desconhecido. OBJETIVO: Investigar a influência do propranolol na remodelação induzida pela exposição à fumaça de cigarro. MÉTODOS: Ratos foram alocados em três grupos: 1) C, n=10 - animais controle; 2) F, n=10 - animais expostos à fumaça de cigarro; 3) BB, n=10 - animais expostos à fumaça de cigarro e que receberam propranolol (40 mg/kg/dia). Após dois meses, os animais foram submetidos a estudo ecocardiográfico e morfométrico. Utilizou-se análise de variância (ANOVA) de uma via (média ± desvio padrão) ou Kruskal-Wallis (mediana e intervalo interquartil). RESULTADOS: O Grupo BB apresentou menor frequência cardíaca que o Grupo F (C = 358 ± 74 btm, F = 374 ± 53 bpm, BB = 297 ± 30; P = 0,02). O Grupo F apresentou maiores diâmetros diastólicos (C = 18,6 ± 3,4 mm/kg, F = 22,8 ± 1,8 mm/kg, BB = 21,7 ± 1,8 mm/kg; P = 0,003) e sistólicos (C = 8,6 ± 2,1 mmkg, F = 11,3 ± 1,3 mm/kg, BB = 9,9 ± 1,2 mm/kg; P = 0,004) do ventrículo esquerdo (VE), ajustado ao peso corporal (PC) e tendência de menor fração de ejeção (C = 0,90 ± 0,03, F = 0,87 ± 0,03, BB =0,90 ± 0,02; P = 0,07) que o Grupo C. O Grupo BB apresentou tendência de menor relação VE/PC que o Grupo F (C = 1,94 (1,87 - 1,97), F = 2,03 (1,9-2,1) mg/g, BB = 1,89 (1,86-1,94); P = 0,09). CONCLUSÃO: A administração de propranolol atenuou algumas variáveis da remodelação ventricular induzida pela exposição à fumaça do cigarro em ratos.

BACKGROUND: The role of the adrenergic system on ventricular remodeling induced by cigarette smoking is unknown. OBJECTIVES: To investigate the influence of propranolol on ventricular remodeling induced by exposure to tobacco smoke. METHODS: Rats were divided into three groups: 1) C, n=10 - control group; 2) F, n=10 - animals exposed to tobacco smoke; 3) BB, n=10 - animals receiving propranolol and exposed to tobacco smoke (40 mg/kg/day). After 2 months, the animals underwent echocardiographic and morphometric analyses. One-way ANOVA (mean ± standard deviation) or the Kruskal-Wallis test (median and interquartile interval) was used. RESULTS: Group BB showed a lower heart rate than group F (C = 358 ± 74 bpm, F = 374 ± 53 bpm, BB = 297 ± 30; P = 0.02). Group F showed greater end-diastolic diameters (C = 18.6 ± 3.4 mm/kg, F = 22.8 ± 1.8 mm/kg, BB = 21.7 ± 1.8 mm/kg; P = 0.003) and left ventricular (LV) end-systolic diameters (C = 8.6 ± 2.1 mm/kg, F = 11.3 ± 1.3 mm/kg, BB = 9.9 ± 1.2 mm/kg; P = 0.004), adjusted for body weight (BW) and a tendency towards a lower ejection fraction (C = 0.90 ± 0.03, F = 0.87 ± 0.03, BB =0.90 ± 0.02; P = 0.07) than group C. Group BB showed a tendency towards a lower LV/BW ratio than group F (C = 1.94 (1.87 - 1.97), F = 2.03 (1.9-2.1) mg/g, BB = 1.89 (1.86-1.94); P = 0.09). CONCLUSION: Administration of propranolol attenuated some of the variables of ventricular remodeling induced by the exposure to tobacco smoke in rats.

FUNDAMENTO: Aún se desconoce el rol del sistema adrenérgico en la remodelación inducida por el tabaquismo. OBJETIVO: Investigar la influencia del propranolol en la remodelación inducida por la exposición al humo del cigarrillo. MÉTODOS: Se dividieron las ratas en tres grupos: 1) C, n=10 - animales control; 2) F, n=10 - animales expuestos al humo de cigarrillo; 3) BB, n=10 - animales expuestos al humo de cigarrillo y que recibieron propranolol (40 mg/kg/día). Tras dos meses, los animales fueron sometidos a estudio ecocardiográfico y morfométrico. Se empleó el análisis de varianza (ANOVA) de una vía (promedio ± desviación estándar) o Kruskal-Wallis (mediana e intervalo intercuartil). RESULTADOS: El Grupo BB presentó menor frecuencia cardiaca que el Grupo F (C = 358 ± 74 lpm, F = 374 ± 53 lpm, BB = 297 ± 30; P = 0,02). El Grupo F presentó mayores diámetros diastólicos (C = 18,6 ± 3,4 mm/kg, F = 22,8 ± 1,8 mm/kg, BB = 21,7 ± 1,8 mm/kg; P = 0,003) y sistólicos (C = 8,6 ± 2,1 mm/kg, F = 11,3 ± 1,3 mm/kg, BB = 9,9 ± 1,2 mm/kg; P = 0,004) del ventrículo izquierdo (VI), ajustado al peso corporal (PC) y tendencia de menor fracción de eyección (C = 0,90 ± 0,03, F = 0,87 ± 0,03, BB =0,90 ± 0,02; P = 0,07) que el Grupo C. El Grupo BB presentó tendencia de menor relación VI/PC que el Grupo F (C = 1,94 (1,87 - 1,97), F = 2,03 (1,9-2,1) mg/g, BB = 1,89 (1,86-1,94); P = 0,09). CONCLUSIÓN: La administración de propranolol atenuó algunas variables de la remodelación ventricular inducida por la exposición al humo del cigarrillo en ratas.

O exercício físico atenua o déficit autonômico cardíaco induzido pelo bloqueio da síntese do óxido nítrico / El ejercicio físico atenúa el déficit autonómico cardiaco inducido por el bloqueo de la síntesis de óxido nítrico / Physical exercise attenuates the cardiac autonomic deficit induced by nitric oxide synthesis blockade

FUNDAMENTO: O bloqueio da síntese do óxido nítrico (NO) é caracterizado pelo aumento da atividade simpática cardíaca, e o treinamento físico promove a redução da atividade simpática. OBJETIVO: Investigamos o efeito do bloqueio da síntese do NO sobre o controle autonômico cardiovascular em ratos submetidos ao exercício aeróbio durante dez semanas. MÉTODOS: Ratos wistar foram divididos em quatro grupos: controle tratados com ração e água ad libitum durante dez semanas (RC); controle tratados com N G-nitro-L-arginine methyl ester (L-NAME) na última semana (RCL); treinados durante dez semanas em esteira motorizada (RT); treinados por dez semanas e tratados com L-NAME na última semana (RTL). O controle autonômico cardiovascular foi investigado em todos os grupos com a utilização de duplo bloqueio com metilatropina e propranolol, e análise da variabilidade. RESULTADOS: Os grupos RCL e RTL apresentaram hipertensão. O grupo RCL apresentou taquicardia e predomínio do tônus simpático na determinação da FC após o bloqueio autonômico farmacológico. O grupo RT apresentou bradicardia e menor freqüência cardíaca (FC) intrínseca em relação aos demais. A avaliação da variabilidade da FC mostrou menores valores absolutos e normalizados na banda de baixa freqüência (BF) no grupo RCL. Por sua vez, o grupo RTL apresentou elevação na banda de BF em valores absolutos. A análise da variabilidade da PAS mostrou que os grupos RCL e RTL apresentaram maiores valores na banda de BF. CONCLUSÃO: O exercício físico prévio impediu o déficit no controle autonômico cardíaco induzido pelo tratamento com L-NAME, no entanto não impediu o aumento na variabilidade da PAS.

BACKGROUND: The nitric oxide (NO) synthesis blockade is characterized by an increase in the cardiac sympathetic activity and the physical training promotes the decrease in the sympathetic activity. OBJECTIVE: We investigated the effect of the NO synthesis blockade on the autonomic cardiovascular control in rats submitted to aerobic exercises during a 10-week period. METHODS: Male Wistar rats were divided in four groups: control rats, treated with chow food and water ad libitum for 10 weeks (CR); control rats, treated with N G-nitro-L-arginine methyl ester (L-NAME) during the last week (CRL); rats trained during 10 weeks on an electrical treadmill (TR); rats trained for 10 weeks and treated with L-NAME during the last week (TRL). The autonomic cardiovascular control was investigated in all groups with the use of a double blockade with methylatropine and propranolol and analysis of variability. RESULTS: The CRL and TRL groups presented hypertension. The CRL group presented tachycardia and predominance of the sympathetic tonus in heat rate (HR) measurement after the pharmacological autonomic blockade. The TR group presented bradycardia and lower intrinsic HR when compared to the others. The evaluation of the HR variability showed lower absolute and normalized values in the low frequency (LF) band in the CRL group. On the other hand, the TRL presented an increase in the LF band in absolute values. The analysis of variability of the systemic arterial pressure (SAP) showed that the CRL and TRL groups presented higher values in the LF band. CONCLUSION: The previous physical exercise prevented the deficit in the autonomic cardiac control induced by the treatment with L-NAME, but did not prevent the increase in the SAP variability.

FUNDAMENTO: El bloqueo de la síntesis de óxido nítrico (NO) se caracteriza por el incremento de la actividad simpática cardiaca, y el entrenamiento físico promueve la reducción de la actividad simpática. OBJETIVO: Investigamos el efecto del bloqueo de la síntesis del NO sobre el control autonómico cardiovascular en ratones sometidos al ejercicio aerobio durante diez semanas. MÉTODOS: Se dividieron ratones wistar en cuatro grupos: control tratados con ración y agua ad libitum durante diez semanas (RC); control tratados con NG-nitro-L-arginina metil éster (L-NAME) en la última semana (RCL); entrenados durante diez semanas en cinta motorizada (RT); entrenados por diez semanas y tratados con L-NAME en la última semana (RTL). Se investigó el control autonómico cardiovascular en todos los grupos con la utilización de doble bloqueo con metilatropina y propranolol, y análisis de la variabilidad. RESULTADOS: Los grupos RCL y RTL presentaron hipertensión. El grupo RCL presentó taquicardia y predominio del tono simpático en la determinación de la FC tras el bloqueo autonómico farmacológico. El grupo RT presentó bradicardia y menor frecuencia cardiaca (FC) intrínseca en relación a los demás. La evaluación de la variabilidad de la FC mostró menores valores absolutos y normalizados en la banda de baja frecuencia (BF) en el grupo RCL. El grupo RTL presentó elevación en la banda de BF en valores absolutos. El análisis de la variabilidad de la PAS mostró que los grupos RCL y RTL presentaron mayores valores en la banda de BF. CONCLUSIÓN: El ejercicio físico previo impidió el déficit en el control autonómico cardiaco inducido por el tratamiento con L-NAME, pero no impidió el aumento en la variabilidad de la PAS.

STAT3 is involved in phosphatidic acid-induced Bcl-2 expression in HeLa cells

Phosphatidic acid (PA), the product of a PLD-mediated reaction, is a lipid second messenger that participates in various intracellular signaling events and is known to regulate a growing list of signaling proteins. We found that Bcl-2 was upregulated by PA treatment in HeLa cells. However, how PA upregulates Bcl-2 expression has not yet been studied. In this study, we tried to discover the mechanisms of Bcl-2 up-regulation by PA treatment in HeLa cells. Treatment with PA resulted in significantly increased expression of Bcl-2 in HeLa cells. Moreover, PA-induced Bcl-2 expression was blocked by mepacrine, an inhibitor of PLA2, but not by propranolol, an inhibitor of PA phospholyhydrolase (PAP). Treatment of 1,2-dipalmitoryl-sn-glycero-3-phosphate (DPPA) also increased Bcl-2 expression. These results indicate that Bcl-2 expression is mediated by lysophosphatidic acid (LPA), not by arachidonic acid (AA). Thereafter, we used MEK1/2 inhibitor, PD98059 to investigate the relationship between ERK1/2 MAPK and PA-induced Bcl-2 expression. PA-induced Bcl-2 expression was decreased when ERK1/2 was inhibited by PD98059. The transcription factor such as STAT3 which is controlled by ERK1/2 MAPK was increased along with Bcl-2 expression when the cells were treated with PA. Furthermore, STAT3 siRNA treatments inhibited PA-induced Bcl-2 expression, suggesting that STAT3 (Ser727) is involved in PA-induced Bcl-2 expression. Taken together, these findings indicate that PA acts as an important mediator for increasing Bcl-2 expression through STAT3 (Ser727) activation via the ERK1/2 MAPK pathway.

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats.

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.

Positive inotropic effect of Murraya koenigii (Linn.) Spreng extract on an isolated perfused frog heart.

Ethanolic extract of fresh leaves of M. koenigii (MKEE) showed a dose dependent positive inotropic effect on isolated frog heart. The responses to MKEE (62.5-1000 microg) were not affected in either way by theophylline, imidazole, propranolol and sildenafil. The change in potassium and sodium concentration did not alter MKEE-induced positive inotropic effect. Lignocaine did not alter the responses to MKEE significantly. Responses to MKEE were significantly inhibited when calcium concentration was reduced to half (from 1.58 to 0.79 mM) and were significantly potentiated when calcium concentration was doubled (from 1.58 to 3.16 mM). Verapamil was found to inhibit the responses significantly. The results suggest that M. koenigii induced positive inotropic effect possibly by increasing availability of calcium from extra cellular sites.