Role of the renin-angiotensin system in the nandrolone-decanoate-induced attenuation of the Bezold-Jarisch reflex.

The androgen nandrolone decanoate (ND) is known to cause cardiovascular abnormalities, such as attenuation of the Bezold-Jarisch Reflex (BJR), cardiac hypertrophy, and elevation of mean arterial pressure (MAP). Futhermore, a relationship between androgens and the renin-angiotensin system (RAS) has been reported. The purpose of this study was to evaluate the influence of RAS on the BJR, cardiac and prostatic hypertrophy, and MAP evoked by ND. For this, male Wistar rats were treated with ND (10 mg·(kg body mass)(-1) for 8 weeks; DECA), or vehicle (control animals; CON), or enalapril (10 mg·(kg body mass)(-1), daily; CONE), or ND and enalapril (10 mg ND + 10 mg enalapril per kilogram of body mass; DECAE). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotensive responses that were elicited by serotonin administration (2-32 µg·(kg body mass)(-1)). MAP was assessed; cardiac and prostate hypertrophy were determined by the ratio of the tissue mass:body mass, and by histological analysis of the heart. Animals from the DECA group showed prostatic and cardiac hypertrophy, elevation in mean arterial pressure, and an impairment of BJR. Co-treatment with enalapril inhibited these changes. The data from the present study suggest that RAS has an impact on BJR attenuation, cardiac and prostatic hypertrophy, and the elevation in MAP evoked by ND.

Long-term treatment with supraphysiological doses of nandrolone decanoate reduces the sensitivity of Bezold-Jarisch reflex control of heart rate and blood pressure.

We investigated the influence of long-term treatment with supraphysiological doses of an anabolic-androgenic steroid on the Bezold-Jarisch reflex (BJR) control of heart rate (HR) and diastolic arterial pressure (DAP), and whether this treatment induced cardiac hypertrophy. Male rats were treated with nandrolone decanoate (ND) (10 mg kg(-1) body weight for 8 weeks; DECA) or vehicle (control animals; CON). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotension responses that were elicited by serotonin administration (2-32 microg kg(-1)). Mean arterial pressure (MAP) was assessed and cardiac hypertrophy was determined by the ratio of the left and right ventricle weight/body weight (LVW/BW and RVW/BW, respectively) and by histological analysis. Total body protein (TBP) content was also evaluated. Nandrolone decanoate treatment increased MAP (CON=99+/- 1 mmHg; DECA=109+/-2 mmHg; p<0.01) but did not change the mean basal HR (CON=356+/-13 bpm; DECA=367+/-11 bpm). The treatment also induced LV and RV hypertrophy (LVW/BW: CON=1.86+/-0.04 mg g(-1), DECA=2.17+/-0.04 mg g(-1), p<0.01; RVW/BW: CON=0.42+/-0.02 mg g(-1), DECA=0.53+/-0.03 mg g(-1), p<0.05) and reduced the number of myocyte nuclei/high-power field (CON=23.0+/-2; DECA=9.4+/-1.0; p<0.01). ND treatment blunted the HR and DAP decreases induced by serotonin. ND determines an increase in the TBP content in DECA group (35+/-3%; p<0.01) compared with control animals (18+/-1%). We conclude that 8 weeks of ND treatment induces anabolic effect, cardiac hypertrophy and an elevation of MAP. This treatment also reduces the sensitivity of the BJR control of bradycardia and blood pressure, possibly due to cardiac hypertrophy. The blunted BJR response could contribute to the MAP elevation in DECA animals.

Bone mineral density is reduced by telmisartan in male spontaneously hypertensive rats.

BACKGROUND: Telmisartan, an angiotensin AT1 receptor blocker, and treadmill running were compared for their effects on bone mineral density (BMD) and biomechanical properties of male spontaneously hypertensive rats (SHR). It was hypothesized that running (18m/min/60min/d) and telmisartan (5mg/kg/d) would have a positive effect on bone parameters. METHODS: Three-month-old male SHRs were divided into three groups: sedentary (S), telmisartan (T), and exercise (E). At the end of an 8-week protocol, femur and lumbar vertebrae were analyzed by dual-energy X-ray absorptiometry (DXA) for bone mineral density and by the three-point bending test for biomechanical properties. Blood pressure in all groups was measured by a tail-cuff manometer. RESULTS: Telmisartan and treadmill running reduced blood pressure when compared to the sedentary group; however, telmisartan did not improve bone characteristics. Instead, it reduced BMD of femur total and lumbar vertebrae and worsened bone biomechanic properties. Treadmill running maintained bone characteristics and hence was effective in maintaining bone health. CONCLUSION: Results showed that telmisartan negatively affected bones suggesting that caution should be taken in possible therapeutic applications for protecting bone health in hypertensive conditions. More studies are necessary to clarify the mechanisms through which telmisartan favors bone loss in this model.

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.

Endothelial relaxation mechanisms and oxidative stress are restored by atorvastatin therapy in ovariectomized rats.

The studies on hormone replacement therapy (HRT) in females with estrogen deficiency are not conclusive. Thus, non-estrogen therapies, such as atorvastatin (ATO), could be new strategies to substitute or complement HRT. This study evaluated the effects of ATO on mesenteric vascular bed (MVB) function from ovariectomized (OVX) female rats. Female rats were divided into control SHAM, OVX, and OVX treated with 17ß-estradiol (EST) or ATO groups. The MVB reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine staining, and the expression of target proteins by western blot. The reduction in acetylcholine-induced relaxation in OVX rats was restored by ATO or EST treatment. The endothelium-dependent nitric oxide (NO) component was reduced in OVX rats, whereas the endothelium-derived hyperpolarizing factor (EDHF) component or prostanoids were not altered in the MVBs. Endothelial dysfunction in OVX rats was associated with oxidative stress, an up-regulation of iNOS and NADPH oxidase expression and a down-regulation of eNOS expression. Treatment with ATO or EST improved the NO component of the relaxation and normalized oxidative stress and the expression of those signaling pathways enzymes. Thus, the protective effect of ATO on endothelial dysfunction caused by estrogen deficiency highlights a significant therapeutic benefit for statins independent of its effects on cholesterol, thus providing evidence that non-estrogen therapy could be used for cardiovascular benefit in an estrogen-deficient state, such as menopause.

Tibolone has anti-inflammatory effects in estrogen-deficient female rats on the natriuretic peptide system and TNF-alpha.

Cardiovascular and immune system abnormalities have been reported in females with estrogen deficiency. To control these disorders in post-menopausal women, hormone replacement therapy (HRT) has been used. Tibolone has been used as a HRT, but the effects of tibolone on the natriuretic peptide system have not been determined. We investigated the effects of tibolone on the natriuretic peptide system and pro-inflammatory cytokines in ovariectomized (OVX) rats. Female rats were divided into four groups: SHAM, OVX, OVX treated with 17ß-estradiol (OVX+E: 14 days) and OVX treated with tibolone (OVX+T: 14 days) beginning 21 days after ovariectomy. On day 35, blood was collected to determine atrial natriuretic peptide (ANP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels. In addition, tissues were collected for determining ANP, natriuretic peptide receptor type-A (NPR-A), and NPR type-C (NPR-C) gene expression levels by RT-PCR. The cytokine levels of both IL-6 and TNF-α were increased in OVX animals. In comparison, IL-6 and TNF-α levels were reduced in OVX+E animals. TNF-α levels were reduced similarly in OVX+T animals, but IL-6 levels remained elevated in this group. The concentrations of ANP in the left atrium tissue and plasma were decreased after ovariectomy, as were ANP mRNA levels in the left atrium and NPR-A mRNA levels in kidney. No variation in NPR-C gene expression in the kidney tissue was observed among the groups. Tibolone and 17ß-estradiol effectively increased plasma ANP and ANP mRNA levels in the left atrium, but did not normalize renal NPR-A levels. Since HRT with tibolone normalizes plasma ANP and serum TNF-alpha levels our results suggest that treatment with tibolone has anti-inflammatory effects and could prevent cardiovascular disease in the long-term.