Tadeu Uggere de Andrade

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.

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.

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 17β-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.

The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

Evaluation of the satisfaction level of patients attended by a pharmaceutical care program in a private communitarian pharmacy in Vitória (ES, Brazil)

The present study was designed to evaluate the satisfaction of users of a Pharmaceutical Care (PC) service in a private communitarian pharmacy in Vitoria (ES, Brazil). In this transversal observational study, patient interviews were performed by an experimenter that had no relationship with the establishments evaluated. Data were collected using a structured questionnaire. The questionnaire used a five point Likert scale, in which smaller numbers represented lower levels of satisfaction. For comparison, user satisfaction was also evaluated for two pharmaceutical establishments that do not have standardized PC services. In these cases, age-matched patients were selected randomly. A higher level of satisfaction was reported by users of the PC service, with values between three and five. The higher averages for the establishment with PC service were the result of greater perceived pharmacist interest in the patients health. As the same results were not obtained by the services without PC, it was concluded that this practice is very important to the satisfaction level of users of pharmacy services.

ROLE OF CARDIAC HYPERTROPHY IN REDUCING THE SENSITIVITY OF CARDIOPULMONARY REFLEX CONTROL OF RENAL SYMPATHETIC NERVE ACTVITY IN SPONTANEOUSLY HYPERTENSIVE RATS

1 The gain of the volume‐sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. 2 The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. 3 Rats (SHR or Wistar‐Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. 4 Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. 5 Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion‐induced decrease in RSNA in SHRE (–41 ± 8%) compared with WKY rats (–44 ± 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 ± 5, 133 ± 6 and 160 ± 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 ± 0.14 vs 1.98 ± 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 ± 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 ± 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. 6 Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.

Metformin ameliorates ovariectomy-induced vascular dysfunction in non-diabetic Wistar rats

Metformin is an antihyperglycaemic drug with pleiotropic effects that result in cardiovascular improvement. The aim of the present study was to evaluate the effects of metformin treatment on vascular dysfunction in ovariectomized rats. At 8 weeks of age, female Wistar rats were subjected to ovariectomy or a sham surgery. After 21 days, the animals were divided into three groups: SHAM (sham-operated rats), OVX (ovariectomized rats) and MET (ovariectomized rats treated with metformin at 300 mg/kg of body weight per day), and treated for 14 days. The vasorelaxation responses to ACh (acetylcholine) and SNP (sodium nitroprusside) were evaluated in mesenteric vascular beds, oxidative stress was evaluated and Western blot analysis of eNOS (endothelial NO synthase) and the NADPH oxidase Nox2 was performed. ACh-induced relaxation was reduced in the OVX group and partially restored in the MET group. L-NAME (NG-nitro-L-arginine methyl ester) attenuated and equalized the ACh-induced response in all groups. Attenuation of the ACh-induced responses by 4-aminopyridine (a blocker of voltage-gated potassium channels) was greater in the MET group compared with the OVX group. The SNP-induced responses were reduced in the OVX group and restored in the MET group. Inhibition of NADPH oxidase by apocynin (10 μM) restored the SNP-induced responses in the OVX group, enhanced these responses in the MET group and had no effect in the SHAM group. The OVX group exhibited reduced levels of eNOS protein and increased levels of oxidative stress and Nox2 protein; metformin treatment corrected all of these parameters. In conclusion, the pathophysiological changes observed in the mesenteric beds of ovariectomized rats were ameliorated by metformin. If this translates to humans, metformin could have additional benefits for post-menopausal women treated with this drug for glycaemic control.

Reduction of cardiovascular risk in patients with metabolic syndrome in a community health center after a pharmaceutical care program of pharmacotherapy follow-up

The objective of this study was to determine the impact of a pharmaceutical care (PC) program in a sample of public outpatients with metabolic syndrome (MS) who were being treated in Brazils health system; the patients were randomized into PC or standard care. The pharmacotherapy follow-up (PF) was performed in a total of 120 patients with type 2 diabetes for 6 months. Adherence to treatment (measured with the Morisky test), negative outcomes associated with medication (NOM) and anthropometric and biochemical parameters were measured before and after PF. The Framingham scoring method was used to estimate changes in 10-year coronary heart disease risk scores in all patients. Ninety-six of 120 patients had characteristics of MS and were randomized into two groups (G): the control group (CG: 36) and the intervention group (IG: 38). Among the MS patients, 100% were taking a glucose-lowering drug; many were also taking anti-hypertensive drugs (CG: 72%; IG: 73%), and some patients were also taking hypolipemic drugs (CG: 12.0%; IG: 14.7%). Only 20.7% of the IG patients were considered adherent to their prescribed drugs. In the CG, an increase of coronary heart disease (CHD) risk (22±2 to 26±3; p<0.05) was observed, while in the IG, there was a reduction in CHD risk (22±2 to 14±2%; p<0.01). The PC program administered to patients with MS monitored through the primary healthcare services of the Brazilian public health system improved patient health, resulting in clinical improvements and a decrease in cardiovascular risk in IG patients over a period of ten years.

Influence of renal denervation on blood pressure, sodium and water excretion in acute total obstructive apnea in rats

Obstructive apnea (OA) can exert significant effects on renal sympathetic nerve activity (RSNA) and hemodynamic parameters. The present study focuses on the modulatory actions of RSNA on OA-induced sodium and water retention. The experiments were performed in renal-denervated rats (D; N = 9), which were compared to sham (S; N = 9) rats. Mean arterial pressure (MAP) and heart rate (HR) were assessed via an intrafemoral catheter. A catheter was inserted into the bladder for urinary measurements. OA episodes were induced via occlusion of the catheter inserted into the trachea. After an equilibration period, OA was induced for 20 s every 2 min and the changes in urine, MAP, HR and RSNA were recorded. Renal denervation did not alter resting MAP (S: 113 +/- 4 vs D: 115 +/- 4 mmHg) or HR (S: 340 +/- 12 vs D: 368 +/- 11 bpm). An OA episode resulted in decreased HR and MAP in both groups, but D rats showed exacerbated hypotension and attenuated bradycardia (S: -12 +/- 1 mmHg and -16 +/- 2 bpm vs D: -16 +/- 1 mmHg and 9 +/- 2 bpm; P < 0.01). The basal urinary parameters did not change during or after OA in S rats. However, D rats showed significant increases both during and after OA. Renal sympathetic nerve activity in S rats increased (34 +/- 9%) during apnea episodes. These results indicate that renal denervation induces elevations of sodium content and urine volume and alters bradycardia and hypotension patterns during total OA in unconscious rats.

Struthanthus vulgaris ointment prevents an over expression of inflammatory response and accelerates the cutaneous wound healing

ETHNOPHARMACOLOGICAL RELEVANCE Struthanthus vulgaris (Vell.) Mart. (Loranthaceae) has been largely used in traditional folk medicine in Brazil as an anti-inflammatory agent and to treat various skin disorders, including wounds. AIMS OF THE STUDY To investigated the influence of 5% Struthanthus vulgaris ointment during cutaneous wound healing in rats. MATERIALS AND METHODS Twenty Wistar rats were used in each group according the daily treatment, S. vulgaris 5% ointment (SV 5%) and vehicle control groups. Four full thicknesses wounds were punched in back side skin of each animal, and five animals were sacrificed after 2, 7, 14 and 21 days after surgery for histological, immunological and biochemical analysis. RESULTS A significant wound closured area in the S. vulgaris 5% group of about 38% and 35% as compared to 19% and 21% in the control group was observed after 2 and 5 days, respectively. Histological and biochemical analysis of the skin biopsies showed that S. vulgaris treated wounds exhibited increased granulation tissue and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines like IL-1α, TNF-α and IL-10, nitric oxide and, growth factors like TGF-β. Moreover, S. vulgaris showed a marked and robust increase in the deposition and organization of collagen fibers in the wounds, and improve the quality of the scar tissue. CONCLUSIONS Altogether these data revealed that S. vulgaris seems to prevent an over expression of inflammation and accelerates wound epithelialization and might be beneficial for treating healing disorders.