Evaluation of coronary function in female rats with severe type 1 diabetes: Effects of combined treatment with insulin and pyridoxamine.

BACKGROUND: This study aimed to evaluate the coronary function, myocardium, and epicardial adipose tissue (EAT) in female rats with severe type 1 diabetes and the effects of combined treatment with insulin and pyridoxamine (AGEs inhibitor). METHODS: Female Wistar rats were divided into groups: control (CTR, n = 13), type 1 diabetes (DM1, n = 12), type 1 diabetes treated with insulin (DM1 + INS, n = 11), and type 1 diabetes treated with insulin and pyridoxamine (DM1 + INS + PDX, n = 14). The vascular responsiveness was performed in the septal coronary artery and the protein expressions of AGE, RAGE, GPER, NF-kB was evaluated in the left ventricle (LV), as well as the reactive oxygen species (ROS) was measured in LV and in EAT. We analyzed plasma levels of glucose, estradiol, Nε-carboxymethylisine (CML), thiobarbituric acid reactive substances (TBARS), catalase (CAT), and superoxide dismutase (SOD). RESULTS: The maximal responses to ACh were reduced in the DM1 compared with the CTR group, accompanied by an increase in circulating glucose, CML, and TBARS. Additionally, the expression of NF-kB in LV and generation of ROS in the presence of MnTMPyP (SOD mimetic) were increased in the DM1 group compared with CTR. Only the combined treatment was effective for fully re-establish ACh relaxation response, NF-kB protein expression, ROS generation, and increased SOD activity in the DM1 + INS + PDX group. CONCLUSION: The reduction of the endothelium-dependent relaxation response in the septal coronary artery of female rats with severe type 1 diabetes was normalized with the combined treatment with insulin and pyridoxamine, associated with reduced inflammation and oxidative stress in the myocardium and increased circulating antioxidant activity.

Perivascular adipose tissue and microvascular endothelial dysfunction in obese mice: Beneficial effects of aerobic exercise in adiponectin receptor (AdipoR1) and peNOSSer1177.

In the present study, we aim to investigate the effects of aerobic physical training on perivascular adipose tissue (PVAT)-induced microvascular dysfunction of the femoral artery in obese mice. Microvascular reactivity was evaluated in control sedentary (c-SD), obese sedentary (o-SD) and obese trained (o-TR) male mice (C57BL6/JUnib), in the absence (PVAT-) or the presence (PVAT+) of femoral artery PVAT. We also analyzed protein expression, vascular nitric oxide (NO) production and reactive oxygen species (ROS) generation in PVAT. The blood glucose, triglycerides and total cholesterol levels were increased in the o-SD group, when compared with the c-SD group. The maximal responses and the potency to acetylcholine (ACh) were decreased in PVAT+ compared with PVAT- rings in the o-SD group, accompanied by a decrease in vascular protein expression of peNOSSer1177 , Cu/Zn-SOD, leptin receptor (Ob-R) and adiponectin receptor (AdipoR1). The protein expression of leptin increased and that of adiponectin decreased in PVAT. Additionally, vascular NO production was reduced and ROS generation was enhanced in PVAT in the o-SD group. Aerobic exercise training was effective for normalizing ACh relaxation response, vascular NO production and ROS generation in the o-TR group. It partially re-established the vascular protein expression of peNOSSer1177 and the PVAT leptin; normalized the vascular Cu/Zn-SOD and AdipoR1 protein expressions. In obese sedentary mice, the presence of PVAT is involved in the process of microvascular dysfunction of the femoral artery in a pathway associated with increased inflammation and ROS generation. The aerobic exercise training normalized the vascular response, the NO production and/or bioavailability and oxidative stress, with improved vascular expressions of Cu/Zn-SOD, peNOSser1177 , and AdipoR1.

Aerobic Exercise Training Prevents Perivascular Adipose Tissue-Induced Endothelial Dysfunction in Thoracic Aorta of Obese Mice.

Background: The mechanisms underlying the perivascular adipose tissue (PVAT) dysfunction in obesity are closely related to inflammation and oxidative stress. The present study aimed to investigate the effects of aerobic exercise training on PVAT-induced endothelial dysfunction of thoracic aorta of obese mice. Methods: Male mice C57BL6/JUnib (6-7 weeks) were divided into: sedentary (c-SD), trained (c-TR), obese sedentary (o-SD), and obese trained (o-TR). Obesity was induced by 16 weeks of high-fat diet and exercise training of moderate intensity started after 8 weeks of protocol and was performed on a treadmill, 5 days/week, for more 8 weeks, 60 min per session. The vascular responsiveness was performed in thoracic aorta in the absence (PVAT-) or in the presence (PVAT+) of PVAT. We analyzed circulatory parameters, protein expression, vascular nitric oxide (NO) production, and reactive oxygen species (ROS) in PVAT. Results: The maximal responses to acetylcholine (ACh) were reduced in PVAT+ compared with PVAT- rings in the o-SD group, accompanied by an increase in circulating glucose, insulin, resistin, leptin, and TNF-α. Additionally, the protein expression of iNOS and generation of ROS were increased in PVAT and production of vascular NO was reduced in the o-SD group compared with c-SD. In the o-TR group, the relaxation response to ACh was completely restored and the circulatory TNF-α, iNOS protein expression, and ROS were normalized with increased expression of Mn-SOD in PVAT, resulting in enhanced vascular NO production. Conclusion: The PVAT-induced endothelial dysfunction in thoracic aorta of obese mice, associated with circulatory inflammation and oxidative stress. Aerobic exercise training upregulated the anti-oxidant expression and decreased PVAT oxidative stress with beneficial impact on endothelium-dependent relaxation.

Importance of AT1 and AT2 receptors in the nucleus of the solitary tract in cardiovascular responses induced by a high-fat diet.

A high-fat diet (HFD) induces an increase in arterial pressure and a decrease in baroreflex function, which may be associated with increased expression of angiotensin type 1 receptor (AT1R) and pro-inflammatory cytokine genes and reduced expression of the angiotensin type 2 receptor (AT2R) gene within the nucleus of the solitary tract (NTS), a key area of the brainstem involved in cardiovascular control. Thus, in the present study, we evaluated the changes in arterial pressure and gene expression of components of the renin-angiotensin system (RAS) and neuroinflammatory markers in the NTS of rats fed a HFD and treated with either an AT1R blocker or with virus-mediated AT2R overexpression in the NTS. Male Holtzman rats (300-320 g) were fed either a standard rat chow diet (SD) or HFD for 6 weeks before commencing the tests. AT1R blockade in the NTS of HFD-fed rats attenuated the increase in arterial pressure and the impairment of reflex bradycardia, whereas AT2R overexpression in the NTS only improved the baroreflex function. The HFD also increased the hypertensive and decreased the protective axis of the RAS and was associated with neuroinflammation within the NTS. The expression of angiotensin-converting enzyme and neuroinflammatory components, but not AT1R, in the NTS was reduced by AT2R overexpression in this site. Based on these data, AT1R and AT2R in the NTS are differentially involved in the cardiovascular changes induced by a HFD. Chronic inflammation and changes in the RAS in the NTS may also account for the cardiovascular responses observed in HFD-fed rats.

Pyridostigmine Improves the Effects of Resistance Exercise Training after Myocardial Infarction in Rats.

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Exercise training and pharmacological treatments are important strategies to minimize the deleterious effects of MI. However, little is known about the effects of resistance training combined with pyridostigmine bromide (PYR) treatment on cardiac and autonomic function, as well as on the inflammatory profile after MI. Thus, in the present study, male Wistar rats were randomly assigned into: control (Cont); sedentary infarcted (Inf); PYR - treated sedentary infarcted rats (Inf+P); infarcted rats undergoing resistance exercise training (Inf+RT); and infarcted rats undergoing PYR treatment plus resistance training (Inf+RT+P). After 12 weeks of resistance training (15-20 climbs per session, with a 1-min rest between each climb, at a low to moderate intensity, 5 days a week) and/or PYR treatment (0.14 mg/mL of drink water), hemodynamic function, autonomic modulation, and cytokine expressions were evaluated. We observed that 3 months of PYR treatment, either alone or in combination with exercise, can improve the deleterious effects of MI on left ventricle dimensions and function, baroreflex sensitivity, and autonomic parameters, as well as systemic and tissue inflammatory profile. Furthermore, additional benefits in a maximal load test and anti-inflammatory state of skeletal muscle were found when resistance training was combined with PYR treatment. Thus, our findings suggest that the combination of resistance training and PYR may be a good therapeutic strategy since they promote additional benefits on skeletal muscle anti-inflammatory profile after MI.

Anti-contractile effects of perivascular adipose tissue in thoracic aorta from rats fed a high-fat diet: role of aerobic exercise training.

The aim of the present study was to evaluate the effects of aerobic exercise training on perivascular adipose tissue (PVAT) function in thoracic aorta from rats fed a high-fat diet. Aortic vascular reactivity was performed in sedentary (SD), trained (TR), sedentary high-fat diet (SD-HF), and trained high-fat diet (TR-HF) male Wistar rats in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also measured circulatory concentrations of leptin and tumour necrosis factor alpha (TNF-α), as well as the protein expressions of TNF-α receptor 1 (TNFR1) and inducible nitric oxide synthase (iNOS) on PVAT. In the SD-HF group, the body weight, epididymal fat pad, thoracic PVAT, circulatory triglycerides, insulin, leptin and TNF-α were increased when compared with the SD group, whereas exercise training reduced these values in TR-HF group. The relaxing response curves to acetylcholine and sodium nitroprusside were not modified by either intervention (high-fat diet or exercise training) or the presence of PVAT. The presence of PVAT had an anti-contractile effect in response to serotonin in all groups. In SD-HF group, the increased magnitude of anti-contractile effects was in parallel with an up-regulation of iNOS protein expression in PVAT without alteration in TNFR1. Exercise training was effective in normalizing the vascular reactivity in rings PVAT+ and in reducing the iNOS protein expression. Exercise training prevented the PVAT-induced alteration in thoracic aorta from rats fed a high-fat diet.

Circulating Concentrations of Adipocytokines and Their Receptors in the Isolated Corpus Cavernosum and Femoral Artery from Trained Rats on a High-Fat Diet.

BACKGROUND: The aim of the present study was to evaluate different signaling pathways by which exercise training would interfere in endothelial function in obesity. Therefore, we examined adipocytokine levels and their receptors in the corpus cavernosum and femoral artery from trained rats on a high-fat diet. METHODS: Functional experiments were performed in control sedentary and trained rats, and sedentary (h-SD) and trained male Wistar rats on a high-fat diet (h-TR). Nitric oxide (NO) and reactive oxygen species (ROS) were evaluated in vascular tissue. Circulating adipocytokines and their receptors were analyzed. RESULTS: In the h-SD group, the maximal responses to acetylcholine (ACh) were reduced in the femoral artery and corpus cavernosum as well as the electrical field stimulation, accompanied by an increase in circulating insulin, leptin, TNF-α, MCP-1, and PAI-1. Downregulation of ObR protein expression in the femoral artery was observed without alterations in AdipoR1 and TNFR1 in both preparations. A positive effect was observed in the h-TR group regarding the relaxation response to ACh and circulating adipocytokines, resulting in increased NO production and reduced ROS generation. Exercise restored the ObR protein expression only in the femoral artery. CONCLUSION: Aerobic exercise training ameliorated the inflammatory adipocytokines and restored the relaxation responses in the corpus cavernosum and femoral artery in rats on a high-fat diet.

Effect of aerobic exercise training on cGMP levels and blood pressure in treated hypertensive postmenopausal women

Abstract The second messenger cGMP has been largely studied as a therapeutic target in a variety of disorders such as erectile dysfunction, arterial hypertension and heart failure. Evidence has shown thatcGMP activators are less efficient in estrogen-deficiency animals, but no studies exist involving non-pharmacological approacheson NO/cGMP signaling pathway in hypertensive postmenopausal women. The aim of this study is to examine NO/cGMP pathway, redox state and blood pressure in trained treatedhypertensive (HT) postmenopausal women comparing with normotensive (NT) group. The rationale for that is most of HT patients is encouraged by physician to perform exercise associated with pharmacological treatments.Aerobic exercise training (AET) consisted of 24 sessions, 3 times/week.Parameters were evaluated at baseline and after AET for both groups (HT=28; NT=33).In treatedHT group, AET was significantly effective in increasing cGMP concentrations (28%) accompanied by an up-regulation of SOD (97%) and catalase activity (37%). In NT group, we found an increasein SOD activity (58%). TreatedHT postmenopausal women were still responsive to AET increasing cGMP levels and up-regulating antioxidant system. It should also be emphasized that these findings provide information on the circulating biomarkers that might delay the developing of cardiovascular events in this particular population.(AU)

Aerobic exercise training protects against endothelial dysfunction by increasing nitric oxide and hydrogen peroxide production in LDL receptor-deficient mice.

BACKGROUND: Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr(-/-)), a genetic model of familial hypercholesterolemia. METHODS: Twelve-week-old C57BL/6J (WT) and LDLr(-/-) mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 × per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined. RESULTS: Total cholesterol and triglycerides were increased in sedentary and exercised LDLr(-/-) mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr(-/-) mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr(-/-) mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr(-/-) mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr(-/-) mice. Furthermore, the aortas of sedentary LDLr(-/-) mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr(-/-) mice. CONCLUSION: The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.

Chronic treatment with resveratrol improves overactive bladder in obese mice via antioxidant activity.

The objective of the present work was to evaluate whether oral intake with resveratrol ameliorates overactive bladder in high-fat fed mice. Male C57BL6 mice fed with standard chow or high-fat diet to induce obesity received a two-week therapy with resveratrol (100mg/kg, given as a daily gavage). Weight and metabolic profile, together with cystometry and in vitro bladder contractions were evaluated. Measurements of gp91phox and SOD1 mRNA expressions and reactive-oxygen species (ROS) in bladder tissues, and serum TBARS were performed. Obese mice exhibited increases in body weight and epididymal fat mass, which were significantly reduced by oral treatment with resveratrol. Cystometric study in obese mice showed increases in non-voiding contractions, post-voiding pressure and voiding frequency that were reversed by resveratrol treatment. Likewise, the in vitro bladder overactivity in response to electrical-field stimulation (80V, 1-32Hz) or carbachol (1nM to 10mM) were normalized by resveratrol. The gp91phox and SOD1 mRNA expressions in bladder tissues were markedly higher in obese mice compared with lean group. In addition, ROS levels in bladder tissues and serum lipid peroxidation (TBARS assay) were markedly higher in obese compared with lean mice, all of which were reduced by resveratrol treatment. In lean group, resveratrol had no effect in any parameter evaluated. Our results show that two-week therapy of obese mice with resveratrol reduces the systemic and bladder oxidative stress, and greatly ameliorated the cystometry alterations and in vitro bladder overactivity. Resveratrol treatment could be an option to prevent obesity-associated overactive bladder.

Resistance training prevents the cardiovascular changes caused by high-fat diet.

AIMS: Aerobic exercise is indicated for prevention and treatment of obesity-induced cardiovascular disorders. Although the resistance training (RT) may also produce effects similar to aerobic exercise, this is not completely clear yet. In the present study, we tested if RT in moderate intensity might prevent alterations in blood pressure (BP), sympathetic modulation of systolic blood pressure (SBP), baroreflex function and the changes in renin-angiotensin system (RAS) and cytokines mRNA expression within the nucleus of the tract solitary (NTS) in rats fed with high-fat diet (HFD). MAIN METHODS: Male Holtzman rats (300-320 g) were divided into 4 groups: sedentary with standard chow diet (SED-SD); sedentary with high-fat diet (SED-HFD); RT with standard chow diet (RT-SD); and RT with high-fat diet (RT-HFD). The trained groups performed a total of 10 weeks of moderate intensity RT in a vertical ladder. In the first 3 weeks all experimental groups were fed with SD. In the next 7 weeks, the SED-HFD and RT-HFD groups were fed with HFD. KEY FINDINGS: In SED-HFD, BP and sympathetic modulation of SBP increased, whereas baroreflex bradycardic responses were attenuated. RT prevented the cardiovascular and inflammatory responses (increases in tumoral necrosis factor-α and interleukin-1ß) produced by HFD in SED rats. The anti-inflammatory interleukin-10, angiotensin type 2 receptor, Mas receptor and angiotensin converting enzyme 2 mRNA expressions in the NTS increased in the RT-HFD compared to SED-HFD. SIGNIFICANCE: The data demonstrated that moderate intensity RT prevented obesity-induced cardiovascular disorders simultaneously with reduced inflammatory responses and modifications of RAS in the NTS.

Heart rate variability and plasma biomarkers in patients with type 1 diabetes mellitus: Effect of a bout of aerobic exercise.

OBJECTIVE: The aim of this study was to evaluate: (1) the cardiovascular parameters and plasma biomarkers in people with type 1 diabetes mellitus (T1DM) at baseline; and (2) the heart rate variability (HRV) and blood glucose in response to a session of aerobic exercise (AE) and during recovery period. RESEARCH DESIGN AND METHODS: Adults (18-35 years) were divided into two groups: control (CT, n=10) and T1DM (n=9). Anthropometric, cardiovascular, and biochemical parameters, and aerobic capacity (indirect peak oxygen uptake, VO2peak) were evaluated at baseline. Thirty minutes of AE (40-60% intensity) was performed on a treadmill. Blood glucose and HRV were determined at rest, during AE, and during the recovery period. RESULTS: Anthropometric measurements, cardiovascular parameters, aerobic capacity, and biochemical parameters were similar between the groups at baseline. In the T1DM group, blood glucose, glycated hemoglobin, and thiobarbituric acid reactive substances concentrations were increased while nitrite/nitrate (NOx(-)) levels were reduced. During AE, the magnitude of the reduction of blood glucose was greater than that during the recovery period in the T1DM group. The RR intervals and SDNN were reduced at rest as well as in the recovery period in T1DM subjects, whereas the RMSSD and pNN50 were only reduced during the recovery period. No changes were observed in low frequency (LF), high frequency (HF), and LF/HF ratio. CONCLUSION: Our study shows that T1DM patients on insulin therapy have poor blood glucose control with greater lipid peroxidation and lower NOx(-) levels, accompanied by an imbalance in autonomic function detected by the challenge of AE.

Taurine supplementation reduces blood pressure and prevents endothelial dysfunction and oxidative stress in post-weaning protein-restricted rats.

INTRODUCTION: Taurine is a sulfur-containing amino acid that exerts protective effects on vascular function and structure in several models of cardiovascular diseases through its antioxidant and anti-inflammatory properties. Early protein malnutrition reprograms the cardiovascular system and is linked to hypertension in adulthood. This study assessed the effects of taurine supplementation in vascular alterations induced by protein restriction in post-weaning rats. METHODS AND RESULTS: Weaned male Wistar rats were fed normal- (12%, NP) or low-protein (6%, LP) diets for 90 days. Half of the NP and LP rats concomitantly received 2.5% taurine supplementation in the drinking water (NPT and LPT, respectively). LP rats showed elevated systolic, diastolic and mean arterial blood pressure versus NP rats; taurine supplementation partially prevented this increase. There was a reduced relaxation response to acetylcholine in isolated thoracic aortic rings from the LP group that was reversed by superoxide dismutase (SOD) or apocynin incubation. Protein expression of p47phox NADPH oxidase subunit was enhanced, whereas extracellular (EC)-SOD and endothelial nitric oxide synthase phosphorylation at Ser 1177 (p-eNOS) were reduced in aortas from LP rats. Furthermore, ROS production was enhanced while acetylcholine-induced NO release was reduced in aortas from the LP group. Taurine supplementation improved the relaxation response to acetylcholine and eNOS-derived NO production, increased EC-SOD and p-eNOS protein expression, as well as reduced ROS generation and p47phox expression in the aortas from LPT rats. LP rats showed an increased aortic wall/lumen ratio and taurine prevented this remodeling through a reduction in wall media thickness. CONCLUSION: Our data indicate a protective role of taurine supplementation on the high blood pressure, endothelial dysfunction and vascular remodeling induced by post-weaning protein restriction. The beneficial vascular effect of taurine was associated with restoration of vascular redox homeostasis and improvement of NO bioavailability.

Influence of aerobic exercise training on cardiovascular and endocrine-inflammatory biomarkers in hypertensive postmenopausal women.

Given that few studies have examined the interaction between endocrine-inflammatory mediators and aerobic exercise training in hypertensive postmenopausal women, the aim of this study was to investigate whether aerobic exercise training (AET) for twenty-four sessions would alter cortisol, leptin and interleukin-1ß (IL-1ß) levels. To further analyze endothelium function in response to AET, we also examined redox state as well as NO/cGMP pathway in this population. Eighteen hypertensive postmenopausal women finished this study. AET program consisted of 24 sessions in treadmill, 3 times per week, duration of 30 up to 40 min for each session, for 8 weeks at intensity of 100% of the MLSS according to previous incremental test. Heart rate was monitored in all studied time (resting and during exercise sessions). After 48 h of the last exercise session, blood samples were collected for biochemical analyses (levels of cortisol, leptin, IL-1ß, nitrite/nitrate (NOx-), cGMP, malondialdehyde (MDA) and asymmetric dimethylarginine (ADMA); superoxide and catalase activity). We also measured systolic and diastolic blood pressure. A significant reduction in body mass was observed. As expected, systolic and diastolic blood pressure values were significantly reduced after AET in hypertensive women. We also found a marked increase in NOx- levels as well as cGMP concentration in trained women, approximately 37.7 and 30.8%, respectively. No changes in cortisol, leptin, ADMA and IL-1ß levels were observed after AET. Similarly, MDA levels and catalase activity were not affected by AET. In contrast, a marked increase in SOD activity was found (86.6%). In conclusion, our findings show that aerobic exercise training for twenty-four sessions promoted a significant reduction in blood pressure by activating NO/cGMP pathway as well as by promoting an up-regulation of SOD activity without changing in cortisol/leptin levels in postmenopausal hypertensive women.

Platelet hyperaggregability in high-fat fed rats: a role for intraplatelet reactive-oxygen species production.

BACKGROUND: Adiposity greatly increases the risk of atherothrombotic events, a pathological condition where a chronic state of oxidative stress is reported to play a major role. This study aimed to investigate the involvement of (NO)-soluble guanylyl cyclase (sGC) signaling pathway in the platelet dysfunction from high fat-fed (HFF) rats. METHODS: Male Wistar rats were fed for 10 weeks with standard chow (SCD) or high-fat diet (HFD). ADP (10 µM)- and thrombin (100 mU/ml)-induced washed platelet aggregation were evaluated. Measurement of intracellular levels of ROS levels was carried out using flow cytometry. Cyclic GMP levels were evaluated using ELISA kits. RESULTS: High-fat fed rats exhibited significant increases in body weight, epididymal fat, fasting glucose levels and glucose intolerance compared with SCD group. Platelet aggregation induced by ADP (n = 8) and thrombin from HFD rats (n = 8) were significantly greater (P < 0.05) compared with SCD group. Platelet activation with ADP increased by 54% the intraplatelet ROS production in HFD group, as measured by flow cytometry (n = 6). N-acetylcysteine (NAC; 1 mM) and PEG-catalase (1000 U/ml) fully prevented the increased ROS production and platelet hyperaggregability in HFD group. The NO donors sodium nitroprusside (SNP; 10 µM) and SNAP (10 µM), as well as the NO-independent soluble guanylyl cyclase stimulator BAY 41-2272 (10 µM) inhibited the platelet aggregation in HFD group with lower efficacy (P < 0.05) compared with SCD group. The cGMP levels in response to these agents were also markedly lower in HFD group (P < 0.05). The prostacyclin analogue iloprost (1 µM) reduced platelet aggregation in HFD and SCD rats in a similar fashion (n = 4). CONCLUSIONS: Metabolic abnormalities as consequence of HFD cause platelet hyperaggregability involving enhanced intraplatelet ROS production and decreased NO bioavailability that appear to be accompanied by potential defects in the prosthetic haem group of soluble guanylyl cyclase.

Interaction between advanced glycation end products formation and vascular responses in femoral and coronary arteries from exercised diabetic rats.

BACKGROUND: The majority of studies have investigated the effect of exercise training (TR) on vascular responses in diabetic animals (DB), but none evaluated nitric oxide (NO) and advanced glycation end products (AGEs) formation associated with oxidant and antioxidant activities in femoral and coronary arteries from trained diabetic rats. Our hypothesis was that 8-week TR would alter AGEs levels in type 1 diabetic rats ameliorating vascular responsiveness. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats were divided into control sedentary (C/SD), sedentary diabetic (SD/DB), and trained diabetic (TR/DB). DB was induced by streptozotocin (i.p.: 60 mg/kg). TR was performed for 60 min per day, 5 days/week, during 8 weeks. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (PHE) and tromboxane analog (U46619) were obtained. The protein expressions of eNOS, receptor for AGEs (RAGE), Cu/Zn-SOD and Mn-SOD were analyzed. Tissues NO production and reactive oxygen species (ROS) generation were evaluated. Plasma nitrate/nitrite (NO(x)⁻), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS) and N(ε)-(carboxymethyl) lysine (CML, AGE biomarker). A rightward shift in the concentration-response curves to ACh was observed in femoral and coronary arteries from SD/DB that was accompanied by an increase in TBARS and CML levels. Decreased in the eNOS expression, tissues NO production and NO(x)⁻ levels were associated with increased ROS generation. A positive interaction between the beneficial effect of TR on the relaxing responses to ACh and the reduction in TBARS and CML levels were observed without changing in antioxidant activities. The eNOS protein expression, tissues NO production and ROS generation were fully re-established in TR/DB, but plasma NO(x)⁻ levels were partially restored. CONCLUSION: Shear stress induced by TR fully restores the eNOS/NO pathway in both preparations from non-treated diabetic rats, however, a massive production of AGEs still affecting relaxing responses possibly involving other endothelium-dependent vasodilator agents, mainly in coronary artery.

Exercise training ameliorates the impairment of endothelial and nitrergic corpus cavernosum responses in diabetic rats.

AIMS: The effect of exercise training (ET) on vascular responsiveness in diabetes mellitus has been largely well studied. However, limited studies have investigated the effects of ET on functional responses of the corpus cavernosum (CC) in diabetic animals. Therefore, the aim of this study was to investigate whether prior ET prevents the impairment of erectile function in streptozotocin-induced diabetic rats. MAIN METHODS: Rats were exercised for four weeks prior to the induction of diabetes, and then again for another 4 weeks thereafter. Concentration-response curves to acetylcholine, sodium nitroprusside, Y-27632, BAY 412272 and phenylephrine (PE) were obtained in CC. The excitatory and inhibitory effects of electrical-field stimulation were also evaluated. KEY FINDINGS: Plasma SOD levels were markedly decreased in the sedentary diabetic group (D-SD) as compared to control sedentary animals (C-SD), approximately 53% (P<0.05) and this reduction was restored in trained diabetic animals. Physical training restored the impairment of endothelium-dependent and -independent relaxation responses seen in the D-SD group. The potency values for Y-27632 in the CC were significantly reduced in the D-SD group, which was reversed by physical training. The impairment of electrical-field stimulation (EFS)-induced relaxation seen in the D-SD group was restored by physical training. On the other hand, both EFS-induced contractions and concentration-response curves to PE in cavernosal strips were not modified by either diabetes or physical training. SIGNIFICANCE: Practice of regular physical exercise may be an important approach in preventing erectile dysfunction associated with diabetes mellitus by re-establishment of the balance between NO production and its inactivation.