Objective-Obesity and diabetes remain among the world's most pervasive health problems. Although the importance of angiotensin II for metabolic regulation is well documented, the role of the angiotensin-(1-7)/Mas axis in this process is poorly understood. The aim of this study was to evaluate the effect of increased angiotensin-(1-7) plasma levels in lipid and glucose metabolism using transgenic rats that express an angiotensin-(1-7)-releasing fusion protein, TGR(A1-7)3292 (TGR). Methods and Results-The increased angiotensin-(1-7) levels in TGR induced enhanced glucose tolerance, insulin sensitivity, and insulin-stimulated glucose uptake. In addition, TGR presented decreased triglycerides and cholesterol levels, as well as a significant decrease in abdominal fat mass, despite normal food intake. These alterations were accompanied by a marked decrease of angiotensinogen expression and increased Akt in adipose tissue. Furthermore, augmented plasma levels and expression in adipose tissue was observed for adiponectin. Accordingly, angiotensin-(1-7) stimulation increased adiponectin production by primary adipocyte culture, which was blocked by the Mas antagonist A779. Circulating insulin and muscle glycogen content were not altered in TGR. Conclusion-These

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BACKGROUND: Despite the clinical improvements attributed to noninvasive ventilation (NIV) during asthma crises, and the well established effects of nebulization, there are few studies on the effects of these interventions together. We hypothesized that nebulization coupled to NIV should raise radio-aerosol pulmonary deposition in asthmatics. The aims of this study were to assess the effects of coupling ␤-agonist nebulization and NIV during asthma exacerbations on radio-aerosol pulmonary deposition, using scintigraphy and cardiopulmonary parameters, to correlate pulmonary function with radio-aerosol deposition index, radio-aerosol penetration index, and pulmonary clearance. METHODS: In this controlled trial, 21 adults with moderate to severe asthma attack were randomized to a control group (n ‫؍‬ 11) or experimental group (NIV ؉ nebulizer group, n ‫؍‬ 10). All subjects inhaled bronchodilators for 9 minutes, and after particles were counted with a gamma camera to analyze regions of interest and pulmonary clearance at 0, 15, 30, 45, and 60 min. RESULTS: Breathing frequency (P ‫؍‬ < .001) and minute ventilation (P ‫؍‬ .01) were reduced, and tidal volume was increased (P ‫؍‬ .01) in the NIV ؉ nebulizer group, compared with the control group. The NIV ؉ nebulizer group had improvement from baseline values, compared to the control group in the following parameters: FEV 1 46.7 ؎ 0.5% of predicted vs 29.8 ؎ 8.9% of predicted, P ‫؍‬ .02), FVC (41.2 ؎ 1.5% of predicted vs 23.2 ؎ 7.1% of predicted, P ‫؍‬ .02), peak expiratory flow (67.3 ؎ 38.3% of predicted vs 26.9 ؎ 12.1% of predicted, P ‫؍‬ .01), and inspiratory capacity (54.9 ؎ 28.8% of predicted vs 31.2 ؎ 9.1% of predicted, P ‫؍‬ .01). No differences were observed between groups regarding radio-aerosol deposition index or pulmonary clearance. Negative correlations were found between FEV 1 , forced expiratory flow during the middle half of the FVC maneuver (FEF 25-75% ), inspiratory capacity, and radio-aerosol penetration index. CONCLUSIONS: Coupling nebulization and NIV during asthma exacerbation did not improve radio-aerosol pulmonary deposition, but we observed clinical improvement of pulmonary function in these subjects. (ClinicalTrials.gov registration NCT01012050)

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Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα 1 ), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα 1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα 1 -deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling. IntroductionSystemic arterial hypertension is one of the most widespread public health problems in the developed world and the most prevalent modifiable risk factor for cardiovascular disease (CVD) in both women and men (1). The pathogenesis of essential hypertension is multifactorial, and in the vast majority of cases the etiology of hypertension is unknown. Although major advances in the treatment of hypertension have decreased CVD-related deaths over the last decade (2), many of the molecular mechanisms underlying the development of hypertension remain elusive. Genome-wide association studies (GWAS) suggest that there is a substantial heritable component to blood pressure (3, 4). Although GWAS have identified several loci associated with blood pressure in human beings, including loci containing genes that either regulate cGMP levels (4-7) or the renin-angiotensin-aldosterone system (RAAS) (8), many of the genetic factors determining blood pressure and how these factors interact remain to be identified.Renal abnormalities, such as decreased urinary sodium excretion in response to increasing renal perfusion pressure, and increased activity of the RAAS are generally considered to be a major contributor to the development of high blood pressure (9). However, other studies support the idea that hypertension can arise from primary vascular abnormalities (10, 11). The ability of NO to relax vascular smooth muscle and its essential role in the regulation of blood flow are well characterized (12, 13). Ample evidence suggests that altered NO signaling is involved in the pathogenesis of hypertension (14).One of the primary receptors for NO is soluble guanylate cyclase (sGC), a heme-containing enzyme that generates cGMP. The

The interstitial lung diseases are poorly understood and there are currently no studies evaluating the association of physical exercise with an ACE2 activator (DIZE) as a possible treatment for this group of diseases. We evaluate the effects of pharmacological treatment with an angiotensin-converting enzyme 2 activator drug, associated with exercise, on the pulmonary lesions induced by bleomycin. From the 96 male Balb/c mice used in the experiment, only 49 received 8 U/kg of bleomycin (BLM, intratracheally). The mice were divided into control (C) and bleomycin (BLM) groups, sedentary and trained (C-SED, C-EXE, BLM-SED, BLM-EXE), control and bleomycin and also sedentary and trained treated with diminazene (C-SED/E, C-EXE/E, BLM-SED/E, BLM-EXE/E). The animals were trained five days/week, 1 h/day with 60% of the maximum load obtained in a functional capacity test, for four weeks. Diminazene groups were treated (1 mg/kg, by gavage) daily until the end of the experiment. The lungs were collected 48 h after the training program, set in buffered formalin and investigated by Gomori's trichrome, immunohistochemistry of collagen type I, TGF-b 1 , beta-prolyl-4-hydroxylase, MMP-1 and -2. The BLM-EXE/E group obtained a significant increase in functional capacity, reduced amount of fibrosis and type I collagen, decreased expression of TGF-b 1 and beta-prolyl-4-hydroxylase and an increase of metalloproteinase À1, À2 when compared with the other groups. The present research shows, for the first time, that exercise training associated with the activation of ACE2 potentially reduces pulmonary fibrosis.

The angiotensin-(1-7) [ANG-(1-7)]/Mas receptor pathway is currently recognized as a counterbalancing mechanism of the renin-angiotensin system in different pathophysiological conditions. We have previously described that treatment with ANG-(1-7) attenuates lung inflammation and remodeling in an experimental model of asthma. In the present study, we investigated whether lack of the Mas receptor could alter the inflammatory response in a model of chronic allergic lung inflammation induced by ovalbumin (OVA). Mas receptor wild-type (MasWT) and knockout (MasKO) mice were subjected to four doses of OVA (20 μg/mice ip) with a 14-day interval. At the 21st day, nebulization with OVA (1%) was started, three times per week until the 46th day. Control groups received saline (0.9% ip) and were nebulized with saline (0.9%). MasWT-OVA developed a modest inflammatory response and minor pulmonary remodeling to OVA challenge. Strikingly, MasKO-OVA presented a significant increase in inflammatory cell infiltrate, increase in extracellular matrix deposition, increase in thickening of the alveolar parenchyma, increase in thickening of the smooth muscle layer of the pulmonary arterioles, increase in proinflammatory cytokine and chemokine levels in the lungs, characteristic of chronic asthma. Additionally, MasKO-OVA presented an increase in ERK1/2 phosphorylation compared with MasWT-OVA. Furthermore, MasKO-OVA showed a worse performance in a test of maximum physical exercise compared with MasWT-OVA. Our study shows that effects triggered by the Mas receptor are important to attenuate the inflammatory and remodeling processes in a model of allergic lung inflammation in mice. Our data indicate that impairment of the ANG-(1-7)/Mas receptor pathway may lead to worsening of the pathophysiological changes of asthma.

BackgroundDespite significant advances in understanding the pathophysiology and management of asthma, some of systemic effects of asthma are still not well defined.ObjectivesTo compare heart function, baseline physical activity level, and functional exercise capacity in young patients with mild-to-moderate asthma and healthy controls.MethodsEighteen healthy (12.67 ± 0.39 years) and 20 asthmatics (12.0 ± 0.38 years) patients were enrolled in the study. Echocardiography parameters were evaluated using conventional and tissue Doppler imaging (TDI).ResultsAlthough pulmonary acceleration time (PAT) and pulmonary artery systolic pressure (PASP) were within normal limits, these parameters differed significantly between the control and asthmatic groups. PAT was lower (p < 0.0001) and PASP (p < 0.0002) was higher in the asthma group (114.3 ± 3.70 ms and 25.40 ± 0.54 mmHg) than the control group (135.30 ± 2.28 ms and 22.22 ± 0.40 mmHg). The asthmatic group had significantly lower early diastolic myocardial velocity (E', p = 0.0047) and lower E' to late (E'/A', p = 0.0017) (13.75 ± 0.53 cm/s and 1.70 ± 0.09, respectively) compared with control group (15.71 ± 0.34 cm/s and 2.12 ± 0.08, respectively) at tricuspid valve. In the lateral mitral valve tissue Doppler, the asthmatic group had lower E' compared with control group (p = 0.0466; 13.27 ± 0.43 cm/s and 14.32 ± 0.25 cm/s, respectively), but there was no statistic difference in the E'/A' ratio (p = 0.1161). Right isovolumetric relaxation time was higher (p = 0.0007) in asthmatic (57.15 ± 0.97 ms) than the control group (52.28 ± 0.87 ms), reflecting global myocardial dysfunction. The right and left myocardial performance indexes were significantly higher in the asthmatic (0.43 ± 0.01 and 0.37 ± 0.01, respectively) compared with control group (0.40 ± 0.01 and 0.34 ± 0.01, respectively) (p = 0.0383 and p = 0.0059, respectively). Physical activity level, and distance travelled on the six-minute walk test were similar in both groups.ConclusionChanges in echocardiographic parameters, evaluated by conventional and TDI, were observed in mild-to-moderate asthma patients even with normal functional exercise capacity and baseline physical activity level. Our results suggest that the echocardiogram may be useful for the early detection and evoluation of asthma-induced cardiac changes.