Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. METHODS: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18-40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. RESULTS: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min-1 kg-1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 µmol/l; interaction 'exercise' × 'group', p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma L-arginine (p < 0.05)-in particular when HbA1c was high (mean estimation: -4.0, p < 0.05)-and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. Graphical abstract CONCLUSIONS/INTERPRETATION: Participants with uncomplicated type 1 diabetes displayed reduced availability of L-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. TRIAL REGISTRATION: clinicaltrials.gov NCT02051504.

In Amateur Athletes With Type 1 Diabetes, a 9-Day Period of Cycling at Moderate-to-Vigorous Intensity Unexpectedly Increased the Time Spent in Hyperglycemia, Which Was Associated With Impairment in Heart Rate Variability.

OBJECTIVE: In type 1 diabetes, autonomic dysfunction may occur early as a decrease in heart rate variability (HRV). In populations without diabetes, the positive effects of exercise training on HRV are well-documented. However, exercise in individuals with type 1 diabetes, particularly if strenuous and prolonged, can lead to sharp glycemic variations, which can negatively impact HRV. This study explores the impact of a 9-day cycling tour on HRV in this population, with a focus on exercise-induced glycemic excursions. RESEARCH DESIGN AND METHODS: Twenty amateur athletes with uncomplicated type 1 diabetes cycled 1,500 km. HRV and glycemic variability were measured by heart rate and continuous glucose monitoring. Linear mixed models were used to test the effects of exercise on HRV, with concomitant glycemic excursions and subject characteristics considered as covariates. RESULTS: Nighttime HRV tended to decrease with the daily distance traveled. The more time the subjects spent in hyperglycemia, the lower the parasympathetic tone was. This result is striking given that hyperglycemic excursions progressively increased throughout the 9 days of the tour, and to a greater degree on the days a longer distance was traveled, while time spent in hypoglycemia surprisingly decreased. This phenomenon occurred despite no changes in insulin administration and a decrease in carbohydrate intake from snacks. CONCLUSIONS: In sports enthusiasts with type 1 diabetes, multiday prolonged exercise at moderate-to-vigorous intensity worsened hyperglycemia, with hyperglycemia negatively associated with parasympathetic cardiac tone. Considering the putative deleterious consequences on cardiac risks, future work should focus on understanding and managing exercise-induced hyperglycemia.

Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis.

Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress. The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology. This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes. Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019. We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls. Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included. Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: -0.61 (95% CI: -0.79, -0.44) but also of VSM SMD: -0.32 (95% CI: -0.57, -0.07). The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity. Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds. The latter was particularly altered in cases of poor glycemic control [HbA1c > 67 mmol/mol (8.3%)]. Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes. Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.

Beetroot Juice Does Not Enhance Supramaximal Intermittent Exercise Performance in Elite Endurance Athletes.

Objective: Nitrate (NO3-)-rich beetroot juice (BR) is recognized as an ergogenic supplement that improves exercise tolerance during submaximal to maximal intensity exercise in recreational and competitive athletes. A recent study has investigated the effectiveness of BR on exercise performance during supramaximal intensity intermittent exercise (SIE) in Olympic-level track cyclists, but studies conducted in elite endurance athletes are scarce. The present study aimed to determine whether BR supplementation enhances the tolerance to SIE in elite endurance athletes.Methods: Eleven elite endurance athletes (age: 21.7 ± 3.7 years, maximal oxygen uptake [Formula: see text] 71.1 ± 5.2 mL·kg-1·min-1) performed an SIE test until exhaustion following either a 3-day BR supplementation (340 mg/d) or a placebo (PL) supplementation (<2.5 mg/d) in a randomized, single blind, placebo-controlled, and crossover study. The exercise test consisted of 15-second cycling exercise bouts at 170% of the maximal aerobic power interspersed with 30-second passive recovery periods. Gas exchange was measured during SIE tests as local muscle O2 delivery and extraction were assessed by near infrared spectroscopy.Results: The number of repetitions completed was not significantly different between BR (13.9 ± 4.0 reps) and PL conditions (14.2 ± 4.5 reps). BR supplementation did not affect oxygen uptake ([Formula: see text]) during SIE tests (BR: 3378.5 ± 681.8 mL·min-1, PL: 3466.1 ± 505.3 mL·min-1). No significant change in the areas under curves was found for local muscle total hemoglobin (BR: 6816.9 ± 1463.1 arbitrary units (a.u.), PL: 6771.5 ± 3004.5 a.u.) and deoxygenated hemoglobin (BR: 6619.7 ± 875.8 a.u., PL: 6332.7 ± 1336.8 a.u.) during time-matched work + recovery periods from SIE tests following BR supplementation.Conclusions: BR supplementation does not enhance the tolerance to SIE in elite endurance athletes and affects neither [Formula: see text] nor local muscle O2 delivery and extraction.

Plasma asymmetric dimethylarginine concentrations are not related to differences in maximal oxygen uptake in endurance trained and untrained men.

NEW FINDINGS: What is the central question of this study? Is there an association of plasma concentration of asymmetric dimethylarginine, which is related to exercise capacity in patients with cardiovascular diseases, with oxygen delivery and subsequently exercise capacity in healthy subjects in the absence of the potentially confounding influence of inflammation and oxidative stress? What is the main finding and its importance? Plasma asymmetric dimethylarginine concentrations are not related to exercise capacity in healthy subjects, while O2 delivery in the working skeletal muscle during the maximal graded-exercise test is not associated with any of the l-arginine analogues. ADMA alone does not play a crucial role in local muscle perfusion and in maintaining exercise capacity. ABSTRACT: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis that could limit oxygen (O2 ) delivery in the working skeletal muscles by altering endothelium-dependent vasodilatation. Exercise capacity is associated with plasma ADMA concentrations in patients with cardiovascular diseases, but this issue has still not been investigated in healthy subjects. We aimed to determine whether plasma ADMA concentrations were negatively associated with exercise capacity in young healthy male subjects. Ten men with maximal oxygen uptake ( V ̇ O 2 max ) > 65 mL kg-1  min-1 were included in the high exercise capacity group (HI-FIT), and 10 men with V ̇ O 2 max  < 45 mL kg-1  min-1 were included in the low exercise capacity group (LO-FIT). Plasma ADMA and other l-arginine analogue concentrations were measured before and after a maximal graded-exercise test by liquid chromatography-tandem mass spectrometry. Microvascular O2 delivery during exercise was estimated through the pattern from the sigmoid model of muscle deoxygenation in the vastus lateralis measured by near infrared spectroscopy. V ̇ O 2 max was 60% higher in the HI-FIT group (median: 70.2 mL kg-1  min-1 ; IQR: 68.0-71.9 mL kg-1  min-1 ) than in the LO-FIT group (median: 43.8 mL kg-1  min-1 ; IQR: 34.8-45.3 mL kg-1  min-1 ). Plasma ADMA concentrations did not differ between the LO-FIT and HI-FIT groups before (0.50 ± 0.06 vs. 0.54 ± 0.07 µmol L-1 , respectively) and after the maximal incremental exercise test (0.49 ± 0.08 vs. 0.55 ± 0.03 µmol L-1 , respectively). There was no significant association of plasma ADMA concentrations with the pattern of local muscle deoxygenation and exercise capacity. Exercise capacity and microvascular O2 delivery are not related to plasma ADMA concentrations in young healthy male subjects. Our findings show that ADMA does not play a crucial role in local muscle perfusion and in maintaining exercise capacity without pathological conditions.

Carbon monoxide pollution aggravates ischemic heart failure through oxidative stress pathway.

Risk of hospital readmission and cardiac mortality increases with atmospheric pollution for patients with heart failure. The underlying mechanisms are unclear. Carbon monoxide (CO) a ubiquitous environmental pollutant could be involved. We explored the effect of daily exposure of CO relevant to urban pollution on post-myocardial infarcted animals. Rats with ischemic heart failure were exposed 4 weeks to daily peaks of CO mimicking urban exposure or to standard filtered air. CO exposure worsened cardiac contractile dysfunction evaluated by echocardiography and at the cardiomyocyte level. In line with clinical reports, the animals exposed to CO also exhibited a severe arrhythmogenic phenotype with numerous sustained ventricular tachycardias as monitored by surface telemetric electrocardiograms. CO did not affect cardiac ß-adrenergic responsiveness. Instead, mitochondrial dysfunction was exacerbated leading to additional oxidative stress and Ca2+ cycling alterations. This was reversed following acute antioxidant treatment of cardiomyocytes with N-acetylcysteine confirming involvement of CO-induced oxidative stress. Exposure to daily peaks of CO pollution aggravated cardiac dysfunction in rats with ischemic heart failure by specifically targeting mitochondria and generating ROS-dependent alterations. This pathway may contribute to the high sensibility and vulnerability of individuals with cardiac disease to environmental outdoor air quality.

Effect of dietary nitrate supplementation on metabolic rate during rest and exercise in human: A systematic review and a meta-analysis.

BACKGROUND: Recent randomized controlled trials have suggested that dietary nitrate (NO3(-)), found in beetroot and other vegetables, and inorganic NO3(-) salts decrease metabolic rate under resting and exercise conditions. OBJECTIVE: Our aim was therefore to determine from a systematic review and meta-analysis whether dietary NO3(-) supplementation significantly reduces metabolic rate, expressed as oxygen uptake (VO2), under resting and exercise conditions in healthy humans and those with cardiorespiratory diseases. DESIGN: A systematic article search was performed on electronic databases (PubMed, Scopus and Web of Science) from February to March 2015. The inclusion criteria included 1) randomized controlled trials; 2) studies reporting the effect of NO3(-) on VO2 under resting and/or exercise conditions; 3) comparison between dietary NO3(-) supplementation and placebo. Random-effects models were used to calculate the pooled effect size. RESULTS: Twenty nine randomized placebo-controlled trials were included in the systematic review, and 26 of which were included in the meta-analysis. Dietary NO3(-) supplementation significantly decreases VO2 during submaximal intensity exercise [-0.26 (95% IC: -0.38, -0.15), p < 0.01], but not in the sub-analysis of subjects with chronic diseases [-0.09 (95% IC: -0.50, 0.32), p = 0.67]. When data were separately analyzed by submaximal intensity domains, NO3(-) supplementation reduces VO2 during moderate [-0.29 (95% IC: -0.48,-0.10), p < 0.01] and heavy [-0.33 (95% IC: -0.54,-0.12), p < 0.01] intensity exercise. When the studies with the largest effects were excluded from the meta-analysis, there is a trend for a VO2 decrease under resting condition in dietary NO3(-) supplementation [-0.28 (95% IC: -0.62, 0.05), p = 0.10]. CONCLUSION: Dietary NO3(-) supplementation decreases VO2 during exercise performed in the moderate and heavy intensity domains in healthy subjects. The present meta-analysis did not show any significant effect of dietary NO3(-) supplementation on metabolic rate in subjects with chronic diseases, despite enhanced exercise tolerance.

Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise.

Dietary nitrate (NO3(-)) supplementation has been shown to increase exercise tolerance and improve oxidative efficiency during aerobic exercise in healthy subjects. We tested the hypothesis that a 3-day supplementation in beetroot juice (BJ) rich in NO3(-) would improve the tolerance to supramaximal intensity intermittent exercise consisting of 15-s exercise periods at 170% of the maximal aerobic power interspersed with 30-s passive recovery periods. The number of repetitions completed before reaching volitional exhaustion was significantly higher in the BJ than in the placebo condition (26.1 ± 10.7 versus 21.8 ± 8.0 respectively, P < 0.05). In contrast to previous findings during exercise performed at intensity below the peak oxygen uptake (VO2peak), oxygen uptake (VO2) was unaffected (BJ: 2735 ± 345 mL kg(-1) min(-1) vs. placebo: 2787 ± 346 mL kg(-1) min(-1), NS). However, the Area Under the Curve for microvascular total hemoglobin (AUC-THb) in the vastus lateralis muscle assessed by near infrared spectroscopy during 3 time-matched repetitions was significantly increased with NO3(-) supplementation (BJ: 9662 ± 1228 a.u. vs. placebo:8178 ± 1589 a.u.; P < 0.05). Thus, increased NO3(-) (BJ: 421.5 ± 107.4 µM vs placebo:39.4 ± 18.0 µM) and NO2(-) (BJ: 441 ± 184 nM vs placebo: 212 ± 119 nM) plasma levels (P < 0.001 for both) are associated with improved muscle microvascular Red Blood Cell (RBC) concentration and O2 delivery during intense exercise, despite no effect on resting femoral artery blood flow, and vascular conductance. Maximal voluntary force during an isometric leg extensor exercise, and blood lactate levels were also unaffected by NO3(-) supplementation. To conclude, dietary NO3(-) supplementation enhances tolerance to exercise at supramaximal intensity, with increased microvascular total RBC concentration in the working muscle, in the absence of effect on contractile function and resting hemodynamic parameters.

Specific left ventricular twist-untwist mechanics during exercise in children.

BACKGROUND: In adults, left ventricular (LV) systolic twist is an important factor that determines LV filling, both at rest and during exercise. In children, lower LV twist has been demonstrated at rest, but its adaptation during exercise and its functional consequences on LV filling are unknown. METHODS: Using speckle-tracking echocardiography, LV twist-untwist mechanics were studied in 25 children (aged 10-12 years) and 20 young adults (aged 18-44 years) at rest and during three exercise workloads performed at 20%, 30%, and 40% of their maximal aerobic power. RESULTS: At rest, LV twist was lower in children, because of a higher temporal dispersion of peak rotation between base and apex. During exercise, the increase of basal rotation was blunted in children compared with adults (-6.7 ± 2.7° vs -9.0 ± 2.0° at 40% of maximal aerobic power, P < .05). Consequently, LV twist increased to a lesser extent (13.0 ± 5.0° vs 15.8 ± 4.5° at 40% of maximal aerobic power, P < .05). The increase in LV untwisting rates during exercise was also lower in children, leading to a lower percentage of untwisting during early diastole (8 ± 8% vs 29 ± 20% at 40% of maximal aerobic power, P < .001). Consequently, during early diastole, the normal timing of diastolic events observed in young adults, with untwist occurring before radial displacement, was blunted in children. Nevertheless, children exhibited normal LV filling due to higher diastolic radial and longitudinal strain rates. CONCLUSIONS: Twist-untwist mechanics may evolve with advancing age. In children, early diastolic LV untwisting appears to be less important than in adults. Their better LV intrinsic myocardial relaxation may ensure adequate LV filling during exercise without dependence on the additional effect of suction resulting from LV energy recoil.

Carbon monoxide exposure enhances arrhythmia after cardiac stress: involvement of oxidative stress.

Arrhythmias following cardiac stress are a key predictor of death in healthy population. Carbon monoxide (CO) is a ubiquitous pollutant promoting oxidative stress and associated with hospitalization for cardiovascular disease and cardiac mortality. We investigated the effect of chronic CO exposure on the occurrence of arrhythmic events after a cardiac stress test and the possible involvement of related oxidative stress. Wistar rats exposed chronically (4 weeks) to sustained urban CO pollution presented more arrhythmic events than controls during recovery after cardiac challenge with isoprenaline in vivo. Sudden death occurred in 22% of CO-exposed rats versus 0% for controls. Malondialdehyde (MDA), an end-product of lipid peroxidation, was increased in left ventricular tissue of CO-exposed rats. Cardiomyocytes isolated from CO-exposed rats showed higher reactive oxygen species (ROS) production (measured with MitoSox Red dye), higher diastolic Ca(2+) resulting from SR calcium leak and an higher occurrence of irregular Ca(2+) transients (measured with Indo-1) in comparison to control cells after a high pacing sequence. Acute treatment with a ROS scavenger (N-acetylcysteine, 20 mmol/L, 1 h) prevented this sequence of alterations and decreased the number of arrhythmic cells following high pacing. Chronic CO exposure promotes oxidative stress that alters Ca(2+) homeostasis (through RYR2 and SERCA defects) and thereby mediates the triggering of ventricular arrhythmia after cardiac stress that can lead to sudden death.

ß-Adrenergic receptors desensitization is not involved in exercise-induced cardiac fatigue: NADPH oxidase-induced oxidative stress as a new trigger.

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that ß-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the ß-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to ß-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

Carbon monoxide pollution promotes cardiac remodeling and ventricular arrhythmia in healthy rats.

RATIONALE: Epidemiologic studies associate atmospheric carbon monoxide (CO) pollution with adverse cardiovascular outcomes and increased cardiac mortality risk. However, there is a lack of data regarding cellular mechanisms in healthy individuals. OBJECTIVES: To investigate the chronic effects of environmentally relevant CO levels on cardiac function in a well-standardized healthy animal model. METHODS: Wistar rats were exposed for 4 weeks to filtered air (CO < 1 ppm) or air enriched with CO (30 ppm with five peaks of 100 ppm per 24-h period), consistent with urban pollution. Myocardial function was assessed by echocardiography and analysis of surface ECG and in vitro by measuring the excitation-contraction coupling of single left ventricular cardiomyocytes. MEASUREMENTS AND MAIN RESULTS: Chronic CO pollution promoted left ventricular interstitial and perivascular fibrosis, with no change in cardiomyocyte size, and had weak, yet significant, effects on in vivo cardiac function. However, both contraction and relaxation of single cardiomyocytes were markedly altered. Several changes occurred, including decreased Ca(2+) transient amplitude and Ca(2+) sensitivity of myofilaments and increased diastolic intracellular Ca(2+) subsequent to decreased SERCA-2a expression and impaired Ca(2+) reuptake. CO pollution increased the number of arrhythmic events. Hyperphosphorylation of Ca(2+)-handling and sarcomeric proteins, and reduced responses to beta-adrenergic challenge were obtained, suggestive of moderate CO-induced hyperadrenergic state. CONCLUSIONS: Chronic CO exposure promotes a pathological phenotype of cardiomyocytes in the absence of underlying cardiomyopathy. The less severe phenotype in vivo suggests a role for compensatory mechanisms. Arrhythmia propensity may derive from intracellular Ca(2+) overload.

Moderate exercise training does not worsen left ventricle remodeling and function in untreated severe hypertensive rats.

Exercise training and hypertension induced cardiac hypertrophy but modulate differently left ventricle (LV) function. This study set out to evaluate cardiac adaptations induced by moderate exercise training in normotensive and untreated severe hypertensive rats. Four groups of animals were studied: normotensive (Ctl) and severe hypertensive (HT) Wistar rats were assigned to be sedentary (Sed) or perform a moderate exercise training (Ex) over a 10-wk period. Severe hypertension was induced in rat by a two-kidney, one-clip model. At the end of the training period, hemodynamic parameters and LV morphology and function were assessed using catheterism and conventional pulsed Doppler echocardiography. LV histology was performed to study fibrosis infiltrations. Severe hypertension increased systolic blood pressure to 202 +/- 9 mmHg and induced pathological hypertrophy (LV hypertrophy index was 0.34 +/- 0.02 vs. 0.44 +/- 0.02 in Ctl-Sed and HT-Sed groups, respectively) with LV relaxation alteration (early-to-atrial wave ratio = 2.02 +/- 0.11 vs. 1.63 +/- 0.12). Blood pressure was not altered by exercise training, but arterial stiffness was reduced in trained hypertensive rats (pulse pressure was 75 +/- 7 vs. 62 +/- 3 mmHg in HT-Sed and HT-Ex groups, respectively). Exercise training induced eccentric hypertrophy in both Ex groups by increasing LV cavity without alteration of LV systolic function. However, LV hypertrophy index was significantly decreased in normotensive rats only (0.34 +/- 0.02 vs. 0.30 +/- 0.02 in Ctl-Sed and Ctl-Ex groups, respectively). Moreover, exercise training improved LV passive filling in Ctl-Ex rats but not in Ht-Ex rats. In this study, exercise training did not reduce blood pressure and induced an additional physiological hypertrophy in untreated HT rats, which was slightly blunted when compared with Ctl rats. However, cardiac function was not worsened by exercise training.

Exercise and vasorelaxing effects of CO-releasing molecules in hypertensive rats.

PURPOSE: Because carbon monoxide (CO) has been reported able to induce relaxation, we aimed to investigate the effects of exercise training on the rat thoracic aorta responsiveness to a CO-releasing molecule (CORM), tricarbonyldichlororuthenium ([Ru(CO)3Cl2]2). METHODS: Male Wistar rats (N = 32) were divided in hypertensive and normotensive groups using the two-kidney, one-clip model of Goldblatt or SHAM surgery. Hypertensive and normotensive groups were assigned to an exercise training protocol on a level treadmill over a 10-wk period or were assigned to remain sedentary. After the exercise training protocol, blood pressure and cardiac tissue weight were assessed. The responsiveness of endothelium-denuded thoracic aortic rings to [Ru(CO)3Cl2]2 was evaluated by isometric contractions recordings. RESULTS: Systolic, diastolic, and mean blood pressures were significantly increased in hypertensive rats compared with control rats. Exercise training did not significantly alter blood pressure but decreased pulse pressure in hypertensive animals compared with sedentary hypertensive rats. In all groups, application of [Ru(CO)3Cl2]2 induced relaxation in precontracted aortic rings. Compared with normotensive rats, CO-induced relaxation was significantly decreased in hypertensive rats. Nevertheless, training exercise increased relaxation markedly in response to [Ru(CO)3Cl2]2 application in hypertensive rats, whereas it remained without effect in control rings. Pretreatment with TEA, a nonselective K+ channel inhibitor, decreased [Ru(CO)3Cl2]2-induced relaxation in all groups that became similar. In trained hypertensive rats, iberiotoxin had effects similar to those of TEA. CONCLUSIONS: This finding supports the concept that the CORM [Ru(CO)3Cl2]2 can induce relaxation in both normotensive and hypertensive rats with an impairment of the CO-induced relaxation during hypertension. However, exercise training improves the aorta's ability to relax in response to [Ru(CO)3Cl2]2 during hypertension, probably by increasing K+ channel activity.

Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction.

We aimed to assess the accuracy of Doppler tissue imaging (DTI) in detecting right ventricle (RV) dysfunction and electromechanical coupling alteration following pulmonary hypertension (PHT) in rat. PHT was induced by chronic hypoxia exposure (hypoxic PHT) or monocrotaline treatment (monocrotaline PHT). In both PHT models, we observed transparietal RV pressure increase and remodeling, including hypertrophy and dilation. Conventional echocardiography provided evidence for pulmonary outflow impairment with midsystolic notch and acceleration time decrease in PHT groups (21.7 +/- 1.6 and 13.2 +/- 2.9 ms in hypoxic and monocrotaline PHT groups vs. 28.1 +/- 1.0 ms in control). RV shortening fraction was decreased in the monocrotaline PHT group compared with the hypoxic PHT and control groups. Combining conventional Doppler and DTI was more helpful to detect RV diastolic dysfunction in the monocrotaline PHT group (E/Ea ratio = 17.0 +/- 1.4) compared with the hypoxic PHT and control groups (11.5 +/- 0.7 and 10.2 +/- 0.4, respectively). Tei index measured using DTI highlighted global RV dysfunction in the monocrotaline PHT group (1.36 +/- 0.24 vs. 0.92 +/- 0.05 and 0.86 +/- 0.05 in the hypoxic PHT and control groups, respectively). Q-Sm time measured from the onset of Q wave to the onset of DTI Sm wave was increased in both PHT groups. PHT-induced electromechanical coupling alteration was confirmed by in vitro activation-contraction delay measurements on isolated RV papillary muscle, and both Q-Sm time and activation-contraction delay were correlated with PHT severity. We demonstrated that Q-Sm time measured in DTI was an easily and convenient index to detect early RV electromechanical coupling alteration in both moderate and severe PHT.

Gamma irradiation induces acetylcholine-evoked, endothelium-independent relaxation and activates K-channels of isolated pulmonary artery of rats.

PURPOSE: To test the effects of irradiation (R*) on the pulmonary artery (PA). METHODS AND MATERIALS: Isolated PA rings were submitted to gamma irradiation (cesium, 8 Gy/min(-1)) at doses of 20 Gy-140 Gy. Rings were placed in an organ chamber, contracted with serotonin (10(-4) M 5-hydroxytryptamine [5-HT]), then exposed to acetylcholine (ACh) in incremental concentrations. Smooth muscle cell (SMC) membrane potential was measured with microelectrodes. RESULTS: A high dose of irradiation (60 Gy) increased 5HT contraction by 20%, whereas lower (20 Gy) doses slightly decreased it compared with control. In the absence of the endothelium, 5-HT precontracted rings exposed to 20 Gy irradiation developed a dose-dependent relaxation induced by acetylcholine (EI-ACh) with maximal relaxation of 60 +/- 17% (n = 13). This was totally blocked by L-NAME (10(-4) M), partly by 7-nitro indazole; it was abolished by hypoxia and iberiotoxin, decreased by tetra-ethyl-ammonium, and not affected by free radical scavengers. In irradiated rings, hypoxia induced a slight contraction which was never observed in control rings. No differences in SMC membrane potential were observed between irradiated and nonirradiated PA rings. CONCLUSION: Irradiation mediates endothelium independent relaxation by a mechanism involving the nitric oxide pathway and K-channels.

Chronic hypoxia induces nonreversible right ventricle dysfunction and dysplasia in rats.

The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 +/- 2 mmHg in the C group, 35 +/- 2 mmHg in the CH group, and 14 +/- 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 +/- 1 vs. 34 +/- 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 +/- 0.40 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 +/- 0.08 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 +/- 4.2% vs. 36 +/- 2.8%) but decreased in the N-RE group [20 +/- 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 +/- 0.8 and 0.72 +/- 0.1 vs. 0.88 +/- 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia.