Serca2a and Na(+)/Ca(2+) exchanger are involved in left ventricular function following cardiac remodelling of female rats treated with anabolic androgenic steroid.

UNLABELLED: Anabolic-androgenic steroids are misused, including by women, but little is known about the cardiovascular effects of these drugs on women. AIM: To evaluated the effects of nandrolone decanoate (ND) and resistive physical exercise on cardiac contractility in young female rats. MAIN METHODS: Female Wistar rats were separated into 4 groups: C (untrained animals); E (animals were submitted to resistance exercise by jumping in water 5 times per week); ND (animals were treated with ND, 20mg/kg/week for 4weeks); and NDE (trained and treated). The haemodynamic parameters (+dP/dtmax, -dP/dtmin and Tau) were assessed in the left ventricle. The heart was collected for histological analyses and collagen deposition. The gastrocnemius muscle was weighed, and hypertrophy was assessed by the ratio of their weights to gastrocnemius/tibia length. The expression of calcium handling proteins was measured by western blot analysis. RESULTS: ND treatment and physical exercise increased cardiac contractility and relaxation. In addition, ND promoted increases in phospholamban phosphorylated (p-PLB) and isoforms of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, while resistance exercise increased the phosphorylation of PLB and expression of Na(+)/Ca(2+) exchangers (NCX). Cardiac hypertrophy and collagen deposition were observed after ND treatment. CONCLUSION: Regulatory components of cytosolic calcium, such as SERCA2a and p-PLB, play important roles in modulating the contractility and relaxation effects of ND in females.

Relationship between male hormonal status, Bezold-Jarisch reflex function, and ACE activity (cardiac and plasmatic).

The negative relationship between androgens and the Bezold-Jarisch reflex (BJR) has been demonstrated, but no studies evaluated the physiological influence of testosterone on this reflex. We evaluated the influence of male rat castration on the BJR, cardiac morphometric parameters, and the plasmatic and the cardiac angiotensin converting enzyme (ACE) activity. After castration (CAS), the rats were divided into 24 and 72 h (CAS24H, CAS72H), and 7 and 21 days (CAS7D, CAS21D) groups. The BJR was studied by administering increasing doses of phenylbiguanide (PBG; 1.5-24 µg/kg) at different times after castration. Castration results in the following: (i) reduction in testosterone levels (SHAM: 238.7 ± 15.1; CAS24H: 9.0 ± 0.5; CAS72H: 6.7 ± 0.4; CAS7D: 5.2 ± 0.2; and CAS21D: 2.2 ± 0.3 ng/dL; p < 0.05); (ii) no changes in 17ß-estradiol; (iii) a reduced BJR sensitivity (PBG 6 µg/kg; SHAM: 77 ± 7; CAS24H: 63 ± 10; CAS72H: 55 ± 6; CAS7D: 54 ± 4; and CAS21D: 35 ± 2%; p < 0.01); (iv) a decrease in cardiac (SHAM: 107 ± 6; CAS24H: 92 ± 2; CAS72H: 82 ± 3; CAS7D: 54 ± 3; and CAS21D: 43 ± 4%; p < 0.05) and plasmatic (SHAM: 135 ± 8; CAS24H: 102 ± 5; CAS72H: 99 ± 3; CAS7D: 89 ± 4; and CAS21D: 56 ± 6%; p < 0.05) ACE activity. No changes were observed in cardiac morphometry and hemodynamic parameters. Therefore, castration leads to decrease in testosterone levels as early as 24 h, reduction in ACE activity and loss of BJR sensitivity 7 days after castration. The loss of BJR sensitivity was not related to cardiac morphometric changes and cardiovascular hemodynamics.

Cardiopulmonary reflex, cardiac cytokines, and nandrolone decanoate: response to resistance training in rats.

This study evaluated the effects of nandrolone associated with resistance training (RT) on cardiac cytokines, angiotensin-converting enzyme activity (ACEA), and the sensitivity of the Bezold-Jarisch reflex (BJR). Male Wistar rats were divided into 3 groups: CONT (received vehicle, no training); EXERC (RT: after one week of water adaptation, rats were exercised by jumping into water twice a week for 4 weeks), and ND+EXERC (received nandrolone decanoate 10 mg/kg, twice/week, i.m, associated with RT). The BJR was analysed by measuring bradycardic and hypotensive responses elicited by serotonin administration. Myocyte hypertrophy and matrix collagen deposition were determined by morphometric analysis of H&E and picrosirius red-stained samples, respectively. TNF-α and ACEA were also studied. RT promoted physiological myocyte hyrpertrophy but did not cause changes in the other parameters. The association of ND with RT increased myocyte hypertrophy, deposition of matrix type I collagen, TNF-α and ACEA; decreased IL-10, and impairment in the BJR were observed in ND+EXERC compared with CONT and EXERC. ND is associated with alterations in cardiac structure and function as a result of the development of pathological cardiac hypertrophy (cardiac cytokine imbalance, elevation of ACEA) and cardiac injury, even when combined with resistance training.

Antihypertensive effect of Carica papaya via a reduction in ACE activity and improved baroreflex.

The aims of this study were to evaluate the antihypertensive effects of the standardised methanolic extract of Carica papaya, its angiotensin converting enzyme inhibitory effects in vivo, its effect on the baroreflex and serum angiotensin converting enzyme activity, and its chemical composition. The chemical composition of the methanolic extract of C. papaya was evaluated by liquid chromatography-mass/mass and mass/mass spectrometry. The angiotensin converting enzyme inhibitory effect was evaluated in vivo by Ang I administration. The antihypertensive assay was performed in spontaneously hypertensive rats and Wistar rats that were treated with enalapril (10 mg/kg), the methanolic extract of C. papaya (100 mg/kg; twice a day), or vehicle for 30 days. The baroreflex was evaluated through the use of sodium nitroprusside and phenylephrine. Angiotensin converting enzyme activity was measured by ELISA, and cardiac hypertrophy was evaluated by morphometric analysis. The methanolic extract of C. papaya was standardised in ferulic acid (203.41 ± 0.02 µg/g), caffeic acid (172.60 ± 0.02 µg/g), gallic acid (145.70 ± 0.02 µg/g), and quercetin (47.11 ± 0.03 µg/g). The flavonoids quercetin, rutin, nicotiflorin, clitorin, and manghaslin were identified in a fraction of the extract. The methanolic extract of C. papaya elicited angiotensin converting enzyme inhibitory activity. The antihypertensive effects elicited by the methanolic extract of C. papaya were similar to those of enalapril, and the baroreflex sensitivity was normalised in treated spontaneously hypertensive rats. Plasma angiotensin converting enzyme activity and cardiac hypertrophy were also reduced to levels comparable to the enalapril-treated group. These results may be associated with the chemical composition of the methanolic extract of C. papaya, and are the first step into the development of a new phytotherapic product which could be used in the treatment of hypertension.

Eight weeks of treatment with nandrolone decanoate in female rats promotes disruption in the redox homeostasis and impaired renal function.

INTRODUCTION: Misuse of AAS is emergent among both genders, however, few studies were performed evaluating AAS effects on female body and none evaluate the impact of nandrolone decanoate (ND) in renal function. AIM: Determine the effects of chronic treatment with ND on kidney function of female rats and evaluate the influence of oxidative stress on it. MATERIAL AND METHODS: Female rats were separated into two groups (n = 8 each), the treated group (DECA), which received ND at a dose of 20 mg/kg/week (i.m), and the control group (C), which was treated with the vehicle (peanut oil, i.m.). All treatments were performed during eight weeks. After this period, 24 h urine, blood and organs (heart, gastrocnemius muscle, liver and kidney) were collected. Organ hypertrophy was calculated, and kidney collagen content was evaluated. AOPP, TBARS, SOD and catalase activity were determined in the kidney. Moreover, proteinuria and creatinine clearance were also investigated. KEY-FINDINGS: Hypertrophy was observed in the liver, gastrocnemius muscle, heart and kidney. Kidney hypertrophy was followed by a reduced organ function and an increase in collagen deposition. Oxidative stress upsurge occurred in both proteins and lipids, followed by a reduction in SOD activity. SIGNIFICANCE: Administration of DN in rats was followed by renal damage and kidney fibrosis due to increased oxidative stress on that organ.

Stanozolol promotes lipid deposition in the aorta through an imbalance in inflammatory cytokines and oxidative status in LDLr knockout mice fed a normal diet.

The aim of the study was to evaluate the effect of an anabolic steroid, stanozolol, in a model of atherosclerosis and to investigate the involvement of the modulation of the inflammatory cytokines and oxidative stress in vascular lipid deposition. Low-density lipid receptor-deficient (LDLr-/-) mice were fed a standard chow diet and were each week injected subcutaneously either saline (control C group) or 20 mg/kg stanozolol (S group). After 8 weeks, the levels of cholesterol, oxidized LDL (OxLDL) and cytokines were measured in plasma, lipid deposition in aorta was evaluated by en face analysis, and thiobarbituric acid-reactive substances and oxidation protein were determined in liver. The S group demonstrated increases in vascular lipid deposition, triglycerides and non-HDL cholesterol levels. Stanozolol increased tumour necrosis factor alpha (TNF-α) and decreased interleukin-10 as well as increased the TNF-α/IL-10 ratio. Furthermore, oxidative stress was observed in the S group, as indicated by an increase in the plasma OxLDL, as well as by lipid peroxidation and oxidation of proteins in the liver. Chronic treatment with stanozolol promoted lipid deposition in the LDLr-/- mice that could be attributed to a modification of the circulating cytokine levels and systemic oxidative stress. Our results suggest that the anabolic steroid stanozolol in the absence of functional LDL receptors by increasing systemic inflammation and oxidative stress may increase the risk of development and progression of atherosclerosis.

Finasteride promotes worsening of the cardiac deleterious effects of nandrolone decanoate and protects against genotoxic and cytotoxic damage

Metabolism of anabolic androgenic steroids is important for its physiological effects. The aim was to investigate the effects of finasteride (a 5α-reductase inhibitor - 5αR) on cardiac and mutagenic effects promoted by ND. Male Wistar rats were separated into three groups: CONT, received the vehicles of ND and finasteride (Peanut oil+Saline); DECA group, received ND (20 mg.kg.week-1, i.m.), and DECAF received ND and finasteride (100 µg.kg-1, i.p.), for four weeks. After, hypertrophy, cytokines and Angiotensin Converting Enzyme (ACE) activity was determined in heart. Bone marrow was used for micronucleus evaluation. Treatment with ND promotes increase in cardiac hypertrophy, ACE activity and disbalance among pro- and anti-inflammatory cytokines, and combination with finasteride worsened those effects. Association with finasteride ameliorates the toxic effects of ND on bone marrow cells, as was observed by a normalization of the number of micronucleate polychromatic erythrocytes and the mitotic index. Our data demonstrates that deleterious effects promoted by ND are depend, at least in part, of its metabolization. Also, inhibition of 5αR by finasteride present variated effects dependent on organ studied. It can promote increase on cardiac damage and a reduction on mutagenic effects of ND, which demonstrated that dehydronandrolone has diverse role on ND effects..

Phytochemical and in vitro and in vivo biological investigation on the antihypertensive activity of mango leaves (Mangifera indica L.).

AIMS: The aim of this study was to investigate the antihypertensive effect of leaves Mangifera indica L. using in vitro and in vivo assays. METHODOLOGY: The ethanol extract of leaves of M. indica was fractionated to dichloromethanic, n-butyl alcohol and aqueous fractions. The chemical composition of ethanolic extract and dichloromethanic fraction were evaluated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Antioxidant activity was evaluated in the DPPH scavenging activity assay. Angiotensin-converting enzyme (ACE) inhibitory activity was investigated using in vitro and in vivo assays. The chronic antihypertensive assay was performed in spontaneously hypertensive rats (SHRs) and Wistar rats treated with enalapril (10 mg/kg), dichloromethanic fraction (100 mg/kg; twice a day) or vehicle control for 30 days. The baroreflex sensitivity was evaluated through the use of sodium nitroprusside and phenylephrine. Cardiac hypertrophy was evaluated by morphometric analysis. RESULTS: The dichloromethanic fraction exhibited the highest flavonoid, total phenolic content and high antioxidant activity. Dichloromethanic fraction elicited ACE inhibitory activity in vitro (99 ± 8%) similar to captopril. LC-MS/MS analysis revealed the presence of ferulic acid (48.3 ± 0.04 µg/g) caffeic acid (159.8 ± 0.02 µg/g), gallic acid (142.5 ± 0.03 µg/g), apigenin (11.0 ± 0.01 µg/g) and quercetin (203.3 ± 0.05 µg/g). The chronic antihypertensive effects elicited by dichloromethanic fraction were similar to those of enalapril, and the baroreflex sensitivity was normalized in SHR. Plasma ACE activity and cardiac hypertrophy were comparable with animals treated with enalapril. CONCLUSIONS: Dichloromethanic fraction of M. indica presented an antihypertensive effect, most likely by ACE inhibition, with benefits in baroreflex sensitivity and cardiac hypertrophy. Altogether, the results of the present study suggest that the dichloromethanic fraction of M. indica leaves may have potential as a promoting antihypertensive agent.

Nandrolone decanoate induces cardiac and renal remodeling in female rats, without modification in physiological parameters: The role of ANP system.

UNLABELLED: Anabolic-androgenic steroids are misused, including women, but little is known about the cardiovascular effects of these drugs on females. AIM: Evaluated the effects of nandrolone decanoate (ND), physical exercise and estrogen deficiency on female rats. MAIN METHODS: Female Wistar rats were divided into 8 groups: S and OVX: (SHAM: sham surgery; OVX: ovariectomy, vehicle), SE and OVXE (resistance exercise 5 times a week, vehicle), SD and OVXD (treated with ND, 20 mg/kg/week for 4 weeks); SDE and OVXDE. Treatments were initiated 21 days after surgery. The Bezold­Jarisch reflex was assessed by Phenylbiguanide administration. The right atrium, kidney, and serum were collected for molecular analyses by RT-PCR of atrial natriuretic peptide (ANP), A-type natriuretic peptide receptor (NPR-A) and NPR-C. ELISA assay to estradiol and testosterone concentrations. The gastrocnemius muscle, heart and kidney weights/tibia length were measured.Morphometric analysis of heart was made (H/E) and collagen content of heart and kidney were evaluated using Pirossirius Red. KEY FINDINGS: ND treatment increased ANP expression on atrium and decreased NPR-A expression in kidney. Physical exercise and ovariectomy did not alter this parameter. NPR-C level was reduced in the SDE and OVXDE. Renal and cardiac hypertrophy was observed after ND treatment, with collagen deposition. Plasma estrogen concentrations were reduced and serum testosterone concentrations were increased after ND treatment. SIGNIFICANCE: ANP has an important role in modulating the cardiovascular effects of ND in females. Thismodulating may have occurred by the increasing ANP expression, reducing NPR-A and NPR-C expression levels, and changing sex hormone levels.

Nandrolone decanoate determines cardiac remodelling and injury by an imbalance in cardiac inflammatory cytokines and ACE activity, blunting of the Bezold-Jarisch reflex, resulting in the development of hypertension.

The aims of this study were to evaluate the effects of nandrolone (ND) on cardiac inflammatory cytokines, ACE activity, troponin I, and the sensitivity of the Bezold-Jarisch reflex (BJR). Male Wistar rats were administered either ND (20 mg/kg; DECA) or vehicle (control animals; CONT) for 4 weeks. BJR was analyzed by measuring the bradycardia and hypotension responses elicited by serotonin administration (2-32 µg/kg). Mean arterial pressure (MAP) was assessed and myocyte hypertrophy was determined by the heart weight/body weight ratio and by morphometric analysis. Matrix collagen deposition was assessed by histological analysis of the picrosirius red-stained samples. Mesenteric vascular reactivity was performed and central venous pressure (CVP) evaluated. Cardiac inflammatory cytokine levels and angiotensin-converting enzyme (ACE) activity were studied as well the biomarker of cardiac lesion, troponin I. DECA group showed enhancement of matrix type I collagen deposition (p < 0.01) and cardiac ACE activity (p < 0.01) compared with the CONT. Interleukin (IL)-10 was reduced (p < 0.01) and pro-inflammatory cytokines (TNF-α and IL-6; p < 0.01) were increased in the DECA group compared with CONT. Cardiac injury was observed in the DECA group shown by the reduction in cardiac troponin I (p < 0.01) compared with the CONT group. Animals in the DECA group also developed myocyte hypertrophy and reduction of BJR sensitivity. The MAP of animals treated with ND reached hypertensive levels (p < 0.01; compared with CONT). No changes in CVP and vascular reactivity were observed in both experimental groups. We conclude that high doses of ND elicit cardiotoxic effects with cardiac remodelling and injury. Cardiac changes reduce the BJR sensitivity. Together, these abnormalities contributed to the development of hypertension in animals in the DECA group.

Hypotensive effect and endothelium-dependent vascular action of leaves of Alpinia purpurata (Vieill) K. Schum

The aims of this study were to evaluate the chemical profile, vascular reactivity, and acute hypotensive effect (AHE) of the ethanolic extract of leaves of Alpinia purpurata (Vieill) K. Schum (EEAP). Its chemical profile was evaluated using HPLC-UV, ICP-OES, and colorimetric quantification of total flavonoids and polyphenols. The vascular reactivity of the extract was determined using the mesenteric bed isolated from WKY. AHE dose-response curves were obtained for both EEAP and inorganic material isolated from AP (IAP) in WKY and SHR animals. Cytotoxic and mutagenic safety levels were determined by the micronucleus test. Rutin-like flavonoids were quantified in the EEAP (1.8 ± 0.03%), and the total flavonoid and polyphenol ratios were 4.1 ± 1.8% and 5.1 ± 0.3%, respectively. We observed that the vasodilation action of EEAP was partially mediated by nitric oxide (·NO). The IAP showed the presence of calcium (137.76 ± 4.08 μg mg-1). The EEAP and IAP showed an AHE in WKY and SHR animals. EEAP did not have cytotoxic effects or cause chromosomic alterations. The AHE shown by EEAP could result from its endothelium-dependent vascular action. Rutin-like flavonoids, among other polyphenols, could contribute to these biological activities, and the calcium present in EEAP could act in a synergistic way.

Os objetivos deste estudo foram avaliar o perfil químico de folhas de Alpinia purpurata K. Schum (AP), assim como a reatividade vascular e o efeito hipotensor agudo (EHA) do extrato etanólico de folhas de AP (EEAP). Avliou-se o perfil químico utilizando-se HPLC-UV, ICP-OES e quantificação colorimétrica de flavonoides e polifenóis totais. A reatividade vascular foi determinada utilizando leito mesentérico isolado de ratos WKY. Curvas dose-resposta do EEAP e do material inorgânico da AP (IAP) foram realizadas em animais SHR e WKY. Determinaram-se a segurança citotóxica e mutagênica pelo teste de micronúcleos. Flavonoides tipo rutina foram quantificados no EEAP (1,8±0,03%) e flavonoide total e polifenóis foram de 4,1±1,8% e 5,1±0,3%, respectivamente. Observou-se ação vasodilatadora do EEAP, mediada parcialmente pelo óxido nítrico (·NO). O IAP revelou a presença de cálcio (137,76±4.08 μg.mg-1 de Ca). O EEAP e IAP apresentaram EHA em animais WKY e SHR. Não se observaram efeitos citotóxicos e alterações cromossômicas provocadas pelo EEAP. O EEAP mostrou um EHA que poderia resultar de ação vascular dependente do endotélio. Rutina, entre outros polifenóis e flavonoides, poderia estar contribuindo para essas atividades biológicas e o cálcio presente no EEAP, poderia agir de maneira sinérgica.