Cláudio H. Balthazar

Evidence that brain nitric oxide inhibition increases metabolic cost of exercise, reducing running performance in rats.

To assess the role of nitric oxide (NO) in the metabolic rate and running performance of rats submitted to exercise on a treadmill, 1.43 micromol (2 microL) of Nomega-nitro-L-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microL of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18m min(-1), 5% inclination). Oxygen consumption (VO2) was measured at rest, during the exercise until fatigue and thereafter during the 30 min of recovery using the indirect calorimetry system. Mechanical efficiency (ME) was also calculated during the running period. During the first 11 min of exercise, there was a similar increase in VO2 while ME remained the same in both groups. Thereafter, VO2 remained stable in the SAL group but continued to increase and remained higher in the L-NAME group until fatigue. The L-NAME-treated rats also showed a sharper decrease in ME than controls. In addition, there was a significant reduction in workload performance by L-NAME-treated animals compared to SAL-treated animals. This suggests that central blockage of nitric oxide increases metabolic cost during exercise, reduces mechanical efficiency and decreases running performance in rats.

Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation, metabolic rate and running performance

To assess the effects of a blockade of central D1- and D2-dopaminergic receptors on metabolic rate, heat balance and running performance, 10 nmol (2 microl) of a solution of the D(1) antagonist SCH-23390 hydrochloride (SCH, n = 6), D2 antagonist eticlopride hydrochloride (Eti, n = 6), or 2 microl of 0.15 M NaCl (SAL, n = 6) was injected intracerebroventricularly into Wistar rats before the animals began graded running until fatigue (starting at 10 m/min, increasing by 1 m/min increment every 3 min until fatigue, 5% inclination). Oxygen consumption and body temperature were recorded at rest, during exercise and following 30 min of recovery. Control experiments with injection of two doses (10 and 20 nmol/rat) of either SCH or Eti solution were carried out in resting rats as well. Body heating rate, heat storage, workload and mechanical efficiency were calculated. Although SCH and Eti treatments did not induce thermal effects in resting animals, they markedly reduced running performance (-83%, SCH; -59% Eti, p < 0.05) and decreased maximal oxygen uptake (-79%, SCH; -45%, Eti, p < 0.05) in running rats. In addition, these treatments induced a higher body heating rate and persistent hyperthermia during the recovery period. Our data demonstrate that the alteration in dopamine transmission induced by the central blockade of dopamine- D1 and D2 receptors impairs running performance by decreasing the tolerance to heat storage. This blockade also impairs the dissipation of exercise-induced heat and metabolic rate recovery during the post-exercise period. Our results provide evidence that central activation of either dopamine- D1 or D2 receptors is essential for heat balance and exercise performance.

Exercise capacity is related to calcium transients in ventricular cardiomyocytes

The aim of the present study was to evaluate the Ca2+ handling and contractility properties of cardiomyocytes isolated from rats with high intrinsic aerobic exercise capacity. Standard-performance (SP) and high-performance (HP) rats were categorized with a treadmill progressive exercise test according to the exercise time to fatigue (TTF). The SP group included rats with TTF between 16.63 and 46.57 min, and the HP group included rats with TTF>46.57 min. Isolated ventricular cardiomyocytes were dissociated from the hearts of SP and HP rats, and intracellular global Ca2+ ([Ca2+]i) transients were measured. The [Ca2+]i transient peak was increased in the HP group relative to the SP group (5.54+/-0.31 vs. 4.18+/-0.12 F/F0; P<or=0.05) and was positively correlated with the TTF attained during the progressive test (r=0.81). We also performed contractility measurements in isolated cardiomyocytes and found higher amplitude of contraction in the HP group compared with the SP group (6.7+/-0.2 vs. 6.0+/-0.3% resting cell length; P<or=0.05). To reinforce the intrinsic differences between SP and HP rats, we performed Western blot experiments and observed increased expression of sarco(endo)plasmic reticulum Ca2+-ATPase type 2a (1.30+/-0.07 vs. 1.74+/-0.18 arbitrary units; P<or=0.05) and ryanodine receptor type 2 (1.86+/-0.13 vs. 3.57+/-0.12 arbitrary units; P<or=0.05) in HP rats. In summary, our data showed important intrinsic differences in cardiomyocyte properties that could explain some of the divergence observed in rats with high intrinsic aerobic exercise capacity.

Central nitric oxide inhibition modifies metabolic adjustments induced by exercise in rats.

The influence of the central nervous system on metabolic function is of interest in situations deviating from basal states, such as during exercise. Our previous study in rats demonstrated that central nitric oxide (NO) blockade increases metabolic rate, reducing mechanical efficiency during exercise. To assess the role of brain nitric oxide in the plasma glucose, lactate and free fatty acids (FFAs) concentrations of rats submitted to an incremental exercise protocol on a treadmill until fatigue, 1.43 micromol (2 microl) of N(omega)-nitro-l-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microl of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle (icv) of male Wistar rats immediately before exercise (starting at 10 m/min, with increments of 1m/min every 3 min until fatigue, 10% inclination). Blood samples were collected through a chronic jugular catheter at rest and during exercise until fatigue. During exercise, the L-NAME-treated animals had the following metabolic response compared to controls: (1) an increased hyperglycemic response during the first 60% of time to fatigue; (2) higher plasma lactate levels; and (3) a significant transitory increase in plasma free fatty acids during the dynamic phase of exercise that returned to basal levels earlier than controls during the steady state phase of exercise. In addition L-NAME-treated rats fatigued earlier than controls. The data indicate that the inhibition of the brain nitrergic system induced by icv L-NAME treatment disrupted the accuracy of the neural mechanism that regulates plasma glucose and free fatty acids mobilization during exercise in rats.

Performance-enhancing and thermoregulatory effects of intracerebroventricular dopamine in running rats.

To assess the role of central dopamine on metabolic rate, heat balance and running performance, 2.0 microL of 5 x 10(-3)M dopamine solution (DA) or 0.15M NaCl (SAL) was intracerebroventricularly injected in Wistar rats 1 min before running on a motor-driven treadmill, according to a graded exercise protocol, until fatigue. Oxygen consumption (VO(2)) and body temperature (T(b)) were recorded at rest, during exercise, and after 30 min of recovery. DA induced a marked increase in workload (approximately 45%, p<0.05). At fatigue point, DA-injected rats attained approximately 29% higher maximum oxygen consumption (VO(2max)) and approximately 0.75 degrees C higher T(b) than SAL-injected rats. Despite the higher VO(2max) and T(b) attained during exercise, DA-treated rats reached VO(2) basal values within the same recovery period and dissipated heat approximately 33% faster than SAL-treated rats (p<0.05). The mechanical efficiency loss rate was approximately 40% lower in DA than in SAL-treated rats (p<0.05), however, the heat storage was approximately 35% higher in the DA group (p<0.05). Our results demonstrate that increased DA availability in the brain has a performance-enhancing effect, which is mediated by improvements in the tolerance to heat storage and increases in the metabolic rate induced by graded exercise. These data provide further evidence that central activation of dopaminergic pathways plays an important role in exercise performance.

Central AT1 receptor blockade increases metabolic cost during exercise reducing mechanical efficiency and running performance in rats

The effect of central angiotensin AT(1) receptor blockade on metabolic rate and running performance in rats during exercise on a treadmill (18 m x min(-1), 5% inclination) was investigated. Oxygen consumption (VO(2)) was measured, using the indirect calorimetry system, while the animals were exercising until fatigue after injection of 2 microL of losartan (Los; 60 nmol, n=9), an angiotensin II AT(1) receptor antagonist, or 2 microL of 0.15 M NaCl (Sal, n=9) into the right lateral cerebral ventricle. Mechanical efficiency (ME) and workload (W) were calculated. The W performance by Los-treated animals was 29% lesser than in Sal-treated animals (p<0.02). During the first 10 min of exercise (dynamic state of exercise), there was a similar increase in VO(2), while ME remained the same in both groups. Thereafter (steady state of exercise), VO(2) remained stable in the Sal group but continued to increase and stabilized at a higher level in Los-treated animals until fatigue. During the steady state of exercise there was a sharper reduction in ME in Los-treated rats compared to Sal-treated animals (p<0.01) that was closely correlated to W (r=0.74; p<0.01). Our data showed that AT(1) receptor blockade increases metabolic cost during exercise, reducing mechanical efficiency. These results indicate that central angiotensinergic transmission modulates heat production, improving ME during the steady state of exercise.

Central angiotensin AT1 receptors are involved in metabolic adjustments in response to graded exercise in rats

To investigate the influence of central angiotensin AT1-receptors blockade on metabolic adjustments during graded exercise, Losartan (Los) was intracerebroventricularly injected in rats before running until fatigue. Oxygen consumption (VO2) was measured (n=6) and blood samples collected (n=7) to determine variations of glucose, lactate and free fatty acids (FFA). Los-rats exhibited a hyperglycemic response, already observed at 20% of maximal work, followed by a higher lactate levels and FFA mobilization from adipose tissue. Despite the reduced total time to fatigue and the higher VO2 associated with reduced mechanical efficiency, exercise led to the attainment of similar levels of effort in both groups. In summary, central AT1-receptor blockade during graded exercise induces hyperglycemia and higher FFA mobilization from adipose tissue at low exercise intensities in rats running at the same absolute exercise intensity. These data suggest that the central angiotensinergic system is involved in metabolic adjustments during exercise since central blockade of AT1-receptors shifts energy balance during graded exercise, similarly to situations of higher and premature sympathetic activation.

Effects of the inspiratory muscle training and aerobic training on respiratory and functional parameters, inflammatory biomarkers, redox status and quality of life in hemodialysis patients: A randomized clinical trial

Objective Evaluate and compare the isolated and combined effects of Inspiratory Muscle Training (IMT) and Aerobic Training (AT) on respiratory and functional parameters, inflamatory biomarkers, redox status and health-related quality of life (HRQoL) in hemodialysis patients. Methods A randomised controlled trial with factorial allocation and intention-to-treat analysis was performed in hemodialysis patients. Volunteers were randomly assigned to performe 8-weeks of IMT at 50% of maximal inspiratory pressure (MIP), low intensity AT or combined training (CT). Before the interventions, all the volunteers went 8-weeks through a control period (without training). Measures are taken at baseline, 8-week (after control period) and 16-week (after the interventions). Primary outcomes were functional capacity (incremental shuttle walk test), MIP and lower limbs strength (Sit-to-Stand test of 30 seconds). Plasma levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor 1 (sTNFR1) and 2 (sTNFR2), adiponectin, resistin and leptin, redox status parameters and HRQoL (KDQOL-SF questionnaire) were the scondary outcomes. Data analyses were performed by two-way repeated measurements ANOVA. Results 37 hemodialysis patients aged 48.2 years old (IC95% 43.2–54.7) were randomized. Increase of MIP, functional capacity, lower limbs strength and resistin levels, and reduction of sTNFR2 levels in 16-week, compared to baseline and 8-week, were observed in all the groups (p<0.001). IMT improved functional capacity, MIP and lower limbs strength in 96.7m (IC95% 5.6–189.9), 34.5cmH2O (IC95% 22.4–46.7) and 2.2repetitions (IC95% 1.1–3.2) respectively. Increase in resistin leves and reduction in sTNFR2 leves after IMT was 0.8ng/dL (IC95% 0.5–1.1) and 0.8ng/dL (IC95% 0.3–1.3), respectively, without between-group differences. Compared to baseline and 8-week, adiponectin levels (p<0.001) and fatigue domain of the HRQoL (p<0.05) increased in 16-week only in CT. Conclusion IMT, AT and CT improved functional parameters and modulated inflammatory biomarkers, in addition, IMT provoked a similar response to low intensity AT in hemodialysis patients. Trial registration Registro Brasileiro de Ensaios clínicos RBR-4hv9rs.