Cristiane Matsuura

Chronic exercise leads to antiaggregant, antioxidant and anti-inflammatory effects in heart failure patients

Background Heart failure (HF) patients are at an increased risk of thrombotic events. Here, we investigated the effects of exercise training on platelet function and factors involved in its modulation in HF. Design and methods Thirty HF patients were randomized to 6 months of supervised exercise training or to a control group that remained sedentary. Exercise training consisted of 30 min of moderate-intensity treadmill exercise, followed by resistance and stretching exercises, performed three times a week. Blood was collected before and after the intervention for platelet and plasma obtainment. Results Peak VO2 increased after exercise training (18.0 ± 2.2 vs. 23.8 ± 0.5 mlO2/kg/min; p < 0.05). Exercise training reduced platelet aggregation induced by both collagen and ADP (approximately –6%; p < 0.05), as well as platelet nitric oxide synthase activity (0.318 ± 0.030 vs. 0.250 ± 0.016 pmol/108 cells; p < 0.05). No difference in the above-mentioned variables were observed in the control group. No significant difference was observed in intraplatelet cyclic guanosine monophosphate levels among groups. There was a significant increase in the activity of the antioxidant enzymes superoxide dismutase and catalase in plasma and platelets, resulting in a decrease in both lipid and protein oxidative damage. Systemic levels of the inflammatory markers C-reactive protein, fibrinogen, and tumour necrosis factor α were also reduced in HF after training. Conclusions Our results suggest that regular exercise training is a valuable adjunct to optimal medical management of HF, reducing platelet aggregation via antioxidant and anti-inflammatory effects, and, therefore, reducing the risk of future thrombotic events.

Platelet activation, oxidative stress and overexpression of inducible nitric oxide synthase in moderate heart failure

1. Chronic heart failure (CHF) is a common disabling disorder associated with thromboembolic events, the genesis of which is not yet fully understood. Nitric oxide (NO), derived from the vascular endothelium and platelets, has an important role in the physiological regulation of blood flow. It is generated from the amino acid l‐arginine via NO synthase (NOS).

The Role of Exercise on L-Arginine Nitric Oxide Pathway in Chronic Heart Failure

Chronic heart failure (CHF) is a pathological state with high morbidity and mortality and the full understanding of its genesis remain to be elucidated. In this syndrome, a cascade of neurohormonal and hemodynamic mechanisms, as well as inflammatory mediators, are activated to improve the impaired cardiac function. Clinical and experimental observations have shown that CHF is associated with a generalized disturbance in endothelium-dependent vasodilation, which may contribute to the progression of ventricular and vascular remodelling in this syndrome. There is also accumulating evidence that disturbances in nitric oxide (NO) availability is involved in the development of heart failure at the systemic and cardiac levels. NO is a ubiquitous signalling molecule which causes potent vasodilation, inhibits platelet activation and regulates the contractile properties of cardiac myocytes. It is generated from the amino acid L-arginine via constitutive and inducible isoforms of the enzyme NO synthase (NOS). There is evidence that exercise, a nonpharmacological tool, improves symptoms, fitness (VO2peak), quality of life and NO bioavailability in CHF population. This review examines different aspects of the L-arginine-NO pathway and inflammation in the physiopathology of CHF and highlights the important beneficial effects of exercise in this disease.

Cerebral and muscle oxygenation changes during static and dynamic knee extensions to voluntary fatigue in healthy men and women: a near infrared spectroscopy study.

The aim of the study was to examine the changes in cerebral and muscle blood volume (Cbv, Mbv) and oxygenation (Cox, Mox) during static and dynamic knee extensions to fatigue in men (N = 10; 29 ± 9 years) and women (N = 14; 27 ± 8 years). After assessment of 1 repetition maximum (1RM) during unilateral knee extensions with the dominant limb, each subject exercised at 50%, 75% and 100% of 1 RM in random order on separate occasions. Simultaneous changes in Cbv, Cox, Mbv and Mox from the contralateral prefrontal lobe and the dominant limb were measured by near infrared spectroscopy. During all three contractions, Cbv and Cox increased while Mbv and Mox decreased until fatigue in both genders. There were no signs of levelling off or decline in Cbv and Cox during any of these contractions, implying that there was no reduction in cerebral neuronal activation. Conversely, there was a rapid decline in Mbv and Mox during the early stages of the contractions, with a plateau or slight increase towards the end. The respective delta values at 50%, 75% and 100% of 1RM for Cbv (0·088 versus 0·062 versus 0·070), Cox (0·042 versus 0·033 versus 0·038), Mbv (−0·225 versus −0·198 versus −0·196), and Mox (−0·169 versus −0·146 versus −0·158) were not significantly different in the total group (N = 24). These findings suggest that fatigue during resistance exercise lasting up to 60 s is mediated peripherally because of reduced blood volume and oxygen availability and is independent of the type and intensity of muscle contraction and gender.

Exercise training in doxorubicin-induced heart failure: effects on the L-arginine–NO pathway and vascular reactivity

Heart failure (HF) is the end-stage of cardiovascular disease and is associated with a high incidence of thrombotic events. Nitric oxide (NO) mediates vasodilation and prevents platelet activation, providing an important antithrombotic effect. The aim of this study was to investigate the effects of aerobic training on survival, platelet L-arginine-NO pathway, and vasodilator properties in doxorubicin (DOX)-induced HF. Sprague Dawley rats were randomly assigned to saline/sedentary (SAL/SED), saline/exercise (SAL/EX), DOX/sedentary (DOX/SED), and DOX/exercise (DOX/EX) groups. Four weeks after intraperitoneal DOX injection (1mg/kg(-1)/d(-1); 10 days), shortening fraction in DOX/SED and DOX/EX was significantly reduced. Treadmill exercise was performed during 6 weeks, 5 days/week(-1), 30minutes/day(-1), 50% to 60% of maximum velocity. Survival was higher in DOX/EX (67%) than DOX/SED (33%). No differences were observed in intraplatelet L-arginine transport assessed by incubation with L- [(3)H]-arginine, nor in NOS activity measured by the conversion of L- [(3)H]-arginine into L- [(3)H]-citrulline among the groups. Vasodilation response to acetylcholine was impaired in DOX/SED and DOX/EX; in nitroglycerine, it was limited to DOX/SED. Aerobic training reduced mortality in DOX-induced HF animals and restored vascular smooth muscle relaxation properties. However, it did not ameliorate intraplatelet NO bioavailability and endothelial function during the period studied.

Major depression induces oxidative stress and platelet hyperaggregability.

We have previously demonstrated an impairment of intraplatelet L-arginine-nitric oxide-cGMP pathway in major depression (MD) associated to platelet dysfunction. Here, we evaluated arginase pathway and phosphodiesterase 5 (PDE5) expression in platelets, systemic and intraplatelet oxidative status in untreated MD patients, and their effects on platelet aggregation. Blood samples were collected from 22 treatment naive MD patients (31 ± 2 yr) and 27 healthy subjects (33 ± 2 yr). MD patients presented with an activation of platelet arginase II, which competes with L-arginine for the production of nitric oxide (NO). An increase in protein carbonylation, overexpression of NADPH oxidase and PDE5, an enzyme that inactivates cGMP, was observed in platelets from MD patients compared to controls. In this context, platelet hyperaggregability was found in MD patients. On the other hand, antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase activities in serum and in platelets did not differ between groups. The increased activation of intraplatelet arginase and platelet aggregability, in addition to an overexpression of PDE5 and oxidative stress may contribute to alterations in L-arginine-NO-cGMP pathway and in platelet function, and consequently to the increased thrombotic risk in MD.

Defective nitric oxide-cyclic guanosine monophosphate signaling in patients with bipolar disorder: a potential role for platelet dysfunction.

Objective Bipolar disorder (BD) is associated with elevated cardiovascular mortality rates. We investigated the modulation of L-arginine–nitric oxide (NO) signaling in platelets from patients with BD at different phases. Methods Platelets obtained from 28 patients with BD and 10 healthy volunteers were analyzed for L-arginine transport, NO synthase (NOS) activity, cyclic guanosine monophosphate content, and biomarkers of oxidative stress. Expressions of NOS isoforms, soluble guanylyl cyclase, and arginase were also measured in platelets. Amino acid and C-reactive protein levels in plasma were assessed. Results Plasma concentrations of L-arginine (mean [M] ± standard error of the mean [SEM] = 97 ± 10 versus 121 ± 10 µM) and its transport into platelets (median [interquartile range] = 26.0 [28.6] versus 26.5 [43.9] pmol/109 cells per minute) did not differ between patients with BD and controls (p > .05). Patients with BD showed reduced NOS activity (M ± SEM = 0.037 ± 0.003 versus 0.135 ± 0.022 pmol/108 cells, p < .001), but not endothelial NOS, inducible NOS, and arginase expression, compared with controls (p > .05). Cyclic guanosine monophosphate content was reduced (M ± SEM = 0.022 ± 0.003 versus 0.086 ± 0.020 pmol/108 cells, p < .05) despite the absence of changes in soluble guanylyl cyclase expression (median [interquartile range] = 21.6 [15.5] versus 9.5 [9.4] arbitrary units, p > .05) in patients with BD. Superoxide dismutase activity, but not catalase activity, was increased in patients with BD in the manic phase (M ± SEM = 2094 ± 335 versus 172 ± 17 U/mg protein, p < .001). C-reactive protein was elevated only in manic episodes (M ± SEM = 0.8 ± 0.2 versus 0.1 ± 0.02 mg/L, p < .001). Conclusions Impaired NO generation from platelets, inflammation, and oxidative stress may play pivotal roles in the multifaceted process of cardiovascular events in BD. Abbreviations NO = nitric oxide NOS = nitric oxide synthase BD = bipolar disorder

Nitric oxide activity in platelets of dengue haemorrhagic fever patients: the apparent paradoxical role of ADMA and l-NMMA

Dengue haemorrhagic fever (DHF) is a prevalent acute disease that occurs in patients infected by an arbovirus in tropical and subtropical regions. We have previously shown increased intraplatelet nitric oxide (NO) production in patients with dengue fever associated with reduced platelet aggregation. In this study, l-arginine transport as well as expression and activity of nitric oxide synthase (NOS) isoforms in the presence or absence of l-arginine analogues were examined in 23 DHF patients. l-arginine transport and NOS activity in platelets were increased in patients with DHF compared with controls. However, platelet endothelial NOS (eNOS) and inducible (iNOS) protein levels did not differ between healthy controls and DHF patients. Endogenous or exogenous analogues did not inhibit platelet NOS activity from DHF patients. In contrast, endogenous l-arginine analogues [N(G)-monomethyl-l-arginine (l-NMMA) and asymmetric dimethylarginine (ADMA)] inhibited NOS activity in platelets from healthy subjects. These results show the first evidence that the intraplatelet l-arginine-NO pathway is activated in DHF patients. The lack of inhibition of NO formation in vitro by all l-arginine analogues tested in DHF platelets may suggest another mechanism by which NOS activity can be regulated.

Gasto energético e consumo de oxigênio pós-exercício contra-resistência

The increase in energy expenditure through physical activity is recognized as an important component in weight loss programs. The impact of resistance exercise, including excess post-exercise oxygen consumption (correspond to the post-exercise energy expenditure), on energy expenditure, however, remains inconclusive. The purpose of the present review was to discuss the influence of the resistance exercise variables (intensity, rest interval, movement velocity, number of sets, and type - circuit or continuous) on energy expenditure during and after an exercise bout. The excess post-exercise oxygen consumption mechanisms were also discussed. The innumerous possibilities of combinations among resistance exercise variables result in a wide range of energy expenditure values for an exercise session (approximately between 3 to 10kcal·min-1). Nevertheless, volume appears to be determinant in the energy expenditure of resistance exercise itself, excess post-exercise oxygen consumption, on the other side, may be affected by exercise intensity. The manipulation of resistance exercise variables may affect the metabolic processes underlying excess post-exercise oxygen consumption, including resynthesis of high energy phosphates stores, resaturation of oxyhemoglobin and oxymyoglobin, thermogenic effects, lactate removal, increased protein turnover, and effects mediated by sympathetic activity. In conclusion, it might be advisable to use low intensity and high volume exercises in a training session for untrained and overweight subjects. However, trained individuals could benefit from more intense resistance exercise, due to the effects of intensity on excess post-exercise oxygen consumption. Thus, nutritionists should consider the effects of resistance exercise on total energy expenditure in order to prescribe effective diets for weight loss purposes.

Prenatal hypoxia, habituation memory and oxidative stress

Hypoxia-ischemia (HI) is characterized by a reduced supply of oxygen during pregnancy, which leads to both central nervous system and peripheral injuries in the foetus, resulting in impairment in its development. The purpose of this study was to investigate behavioural changes and systemic oxidative stress in adult animals that have been affected by HI during pregnancy. HI was induced by the occlusion of the maternal uterine artery with aneurysm clamps for a period of 45 min on the 18th gestational day. Animals from the sham group were submitted to same surgical procedure as the HI animals, without occlusion of the maternal uterine artery. The control group consisted of non-manipulated healthy animals. At postnatal day 90, the pups were submitted to behavioural tests followed by blood collection. HI adult animals presented an increase in anxiety behaviour and a lack of habituation compared to both sham and control groups. Oxidative damage, assessed by protein and lipid oxidation in serum, did not differ between HI and sham-operated animals. However, HI animals presented reduced activity of the glutathione peroxidase enzyme and increased formation of nitrite, indicating alterations in the systemic antioxidant repair system. Our results suggest an association among HI, systemic oxidative stress and behavioural alterations.