The anabolic androgenic steroid nandrolone decanoate disrupts redox homeostasis in liver, heart and kidney of male Wistar rats.

The abuse of anabolic androgenic steroids (AAS) may cause side effects in several tissues. Oxidative stress is linked to the pathophysiology of most of these alterations, being involved in fibrosis, cellular proliferation, tumorigenesis, amongst others. Thus, the aim of this study was to determine the impact of supraphysiological doses of nandrolone decanoate (DECA) on the redox balance of liver, heart and kidney. Wistar male rats were treated with intramuscular injections of vehicle or DECA (1 mg.100 g(-1) body weight) once a week for 8 weeks. The activity and mRNA levels of NADPH Oxidase (NOX), and the activity of catalase, glutathione peroxidase (GPx) and total superoxide dismutase (SOD), as well as the reduced thiol and carbonyl residue proteins, were measured in liver, heart and kidney. DECA treatment increased NOX activity in heart and liver, but NOX2 mRNA levels were only increased in heart. Liver catalase and SOD activities were decreased in the DECA-treated group, but only catalase activity was decreased in the kidney. No differences were detected in GPx activity. Thiol residues were decreased in the liver and kidney of treated animals in comparison to the control group, while carbonyl residues were increased in the kidney after the treatment. Taken together, our results show that chronically administered DECA is able to disrupt the cellular redox balance, leading to an oxidative stress state.

Exercise-induced cardioprotection is impaired by anabolic steroid treatment through a redox-dependent mechanism.

High doses of anabolic androgenic steroids (AAS) impair the cardioprotective effects of exercise against ischemia/reperfusion (I/R) insult, possibly through cellular redox imbalance. Here, the effect of nandrolone decanoate (DECA) treatment on heart redox metabolism was investigated during I/R in sedentary and exercised rats. DECA treatment significantly reduced superoxide dismutase and glutathione reductase activities in exercised rats after heart reperfusion. Catalase and glutathione peroxidase activities were not affected by DECA in both sedentary and trained rats, regardless the I/R period. DECA also induced myocardial oxidative stress, as evidenced by the reduced levels of total reduced thiols after heart reperfusion in exercised rats treated with the anabolic steroid. These results indicate that cardiotoxic effects of supraphysiological doses of AAS involve reduced heart antioxidant capacity.

Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease.

Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M(2)-muscarinic acetylcholine receptors (M(2)AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M(2)AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M(2)AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [(3)H]-N-methyl scopolamine ([(3)H]-NMS) in allosterism binding assays. A peptide corresponding to the M(2)AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [(3)H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [(3)H]-NMS dissociation right shifted from an IC(50) of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 x 10(- 8), 1.33 x 10(- 7), and 2.0 x 10(- 7) mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M(2)AChRs as a positive cooperativity effect on acetylcholine action.

Human antibodies with muscarinic activity modulate ventricular repolarization: basis for electrical disturbance.

INTRODUCTION: In chronic chagasic patients sudden death has been reported when QT interval dispersion is increased and antibodies with muscarinic-like activity have been demonstrated to trigger arrhythmias. The aims were to investigate, in vivo and in vitro, relation between these antibodies and heterogeneity of ventricular repolarization and to identify predictors of cardiac death in chronic chagasic patients. METHODS AND RESULTS: Clinical, electrocardiograph and echocardiograph variables from 32 chronic chagasic patients with moderate to severe left ventricular dysfunction, followed-up for 10 years were analyzed. Sera from chronic chagasic patients with or without muscarinic activity were tested in isolated rabbit hearts to study ventricular repolarization. Stepwise multivariate logistic analysis was applied to identify independent predictors of cardiac death. QT interval dispersion of patients with muscarinic activity (75.9+/-5.5 ms) was larger than that of patients without muscarinic activity (51.3+/-4.0 ms, p<0.001). Maximum uncorrected and corrected QT intervals were not significantly different between groups of patients. Sera from patients with muscarinic activity significantly and reversibly increased QT interval in isolated rabbit hearts (p=0.002). This effect was abolished in the presence of the muscarinic antagonist atropine. Multivariate analysis identified maximum corrected QT intervals and left ventricular end diastolic index as independent predictors of cardiac death (p=0.03 and p=0.02, respectively). CONCLUSIONS: Sera with muscarinic activity from chagasic patients have a strong contribution to evoke ventricular repolarization rhythm disorder. In these patients, ventricular repolarization heterogeneity is increased significantly. In vitro, muscarinic sera reversibly increased repolarization duration. Maximum corrected QT intervals and left ventricular end diastolic index are independent predictors of cardiac death.

Chronic administration of anabolic androgenic steroid alters murine thyroid function.

PURPOSE: The administration of anabolic-androgenic steroids (AAS) to improve athletic performance has increased notably during the past three decades, even among nonathletes. Thyroid function is affected by AAS use in humans, although the mechanisms of the effects of AAS are unclear. We evaluated the effects on thyroid function of supraphysiologic doses of nandrolone decanoate (DECA), which is one of the most anabolic-androgenic steroids (AAS) used. METHODS: Male Wistar rats were treated with vehicle or 1 mg.100 g(-1) body weight (b.w.) of DECA, once a week for 8 wk, intramuscularly. We analyzed thyroperoxidase (TPO) activity, type 1 iodothyronine deiodinase (D1) activities in liver, kidney, pituitary, and thyroid, and serum levels of total T3, total T4, free T4, and TSH. Parametric and nonparametric t-tests were employed for statistical analyses. RESULTS: Treated animals showed a significant increase in the weight of kidneys and heart, and a decrease in the relative testis weight. Retroperitoneal adipose tissue was only slightly decreased. DECA treatment induced a significant increase in the absolute and relative thyroid gland weight. The concentrations of total serum T3, free T4, and TSH decreased significantly with treatment, but total serum T4 levels were unchanged. Thyroperoxidase activity was unaltered, whereas liver and kidney D1 activities were significantly increased, but pituitary and thyroid D1 did not change. CONCLUSION: Our data indicate that DECA exerts direct actions on the thyroid gland and in the peripheral metabolism of thyroid hormones and might lead to thyroid dysfunction.

Cardiac autonomic dysfunction in rats chronically treated with anabolic steroid.

To date no published data exist regarding the effects of chronic high-dose anabolic-androgenic steroid administration on tonic cardiac autonomic control. The aim of this study was to evaluate, by power spectral analysis of heart rate variability (HRV), the effects of chronic treatment with supraphysiological doses of nandrolone decanoate (DECA) on tonic cardiac autonomic regulation in sedentary rats. Male Wistar rats were treated weekly with 10 mg kg(-1) of DECA (n=7) or vehicle (CONTROL, n=7) for 10 weeks. At the 8th week of treatment, electrocardiogram was recorded in the conscious state, for time- and frequency-domain HRV analysis. Parasympathetic indexes were reduced in DECA group: high-frequency power (CONTROL=11.1+/-3.0 ms2 vs. DECA=3.8+/-0.6 ms2, P<0.05), RMSSD (CONTROL=5.9+/-0.9 ms vs. DECA 3.5+/-0.3 ms; P<0.05) and pNN5 (CONTROL=31.5+/-7.5 ms vs. DECA=13.2+/-2.6 ms; P<0.05). The sympathetic index LF/HF tended to be higher in DECA group (CONTROL=0.65+/-0.15 vs. DECA=1.17+/-0.26, P=0.0546). In conclusion, chronic treatment with DECA, in rats, impairs tonic cardiac autonomic regulation, which may provide a key mechanism for anabolic steroid-induced arrhythmia and sudden cardiac death.