Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia.

The aim of our work was to study (1) the antioxidant properties of lipoic acid (LA) and its reduced metabolite dihydrolipoic acid (DHLA) formed by reduction of LA and (2) the effects of treatment with LA and DHLA on (a) K(+) efflux from human red blood cells and (b) post-ischemic recovery and oxidative stress in isolated perfused rat hearts challenged with an ischemia-reperfusion (IR) sequence. In vitro, we used xanthine and xanthine oxidase to generate superoxide anion, which is not directly measurable by electron paramagnetic resonance (EPR), but specifically oxidizes the spin probe CPH into an EPR-detectable long lasting CP(*) nitroxide radical. While 5 mM of LA was ineffective in reducing the kinetics of CP(*) nitroxide formation, DHLA was shown to lessen this rate in a dose-dependent manner and at 30 mM was even more efficient than 300 UI/ml SOD. These results are in agreement with the fact that DHLA is able to directly scavenge superoxide anion. Red cells are a good model to investigate oxidative damage in biological membranes; hence, we used a suspension of erythrocytes incubated with 2,2(')-azobis(2-amidinopropane) hydrochloride (AAPH) which generates in vitro free radicals. DHLA provided more effective protection of red cells membranes than LA; DHLA was comparable to Trolox for its antioxidant potency. In vivo, treatment of rats (50 mg/kg/day i.p. for 7 days) with LA induced a slight increase in coronary flow (CF) in isolated perfused hearts, after 30 min of global total ischemia. This effect was not associated with an improvement in contractile function and reduction of myocardial oxidative stress. In conclusion, because of their ability to scavenge free radicals, LA and to an even greater degree DHLA were able to protect the membranes of red blood cells. This finding suggests that LA and DHLA might be useful in the treatment of diseases associated with oxidative stress such as diabetes.

[Hydrogen sulfide (H2S), an endogenous gas with odor of rotten eggs might be a cardiovascular function regulator]. / Le sulfure d'hydrogène (H2S), un gaz endogène à l'odeur d'oeuf pourri, pourrait être un régulateur des fonctions cardiovasculaires.

A novel concept of "gasotransmitter" arrived recently. They are small molecules of endogenous gases. Hydrogene sulfide (H2S) is qualified as the third gasotransmitter beside nitric oxide (NO) and carbon monoxide (CO). The physiological functions of endogenous H2S are not well-known. The location of the H2S synthetizing enzymes as well as the detector of endogenous levels of H2S in the tissues suggests that the cardiovascular system is a source of H2S generation. This gas relaxes vascular smooth muscle both in vitro and in vivo probably by opening smooth K+ATP channels. Being a reducing agent, H2S may alter cellular redox status. It is able to produce thiyls free radicals: SH degrees and S degrees . The advances in H2S researchs may revolutionize many conventional doctrines in the cardiovascular area.

[Oxidative stress is exacerbated in diabetic patients during cardiopulmonary bypass]. / Exacerbation du stress oxydatif chez les patients diabétiques durant une circulation extracorporelle.

UNLABELLED: Circulation on blood extracorporeally through plastic tubing activates several pathways including systemic inflammation and oxidative stress. These phenomena are suspected to participate to neurological and cardiovascular side effects observed in the patients under cardiopulmonary bypass (CPB). A direct relationship, in diabetic patients, between hyperglycemia and morbidity and mortality has been established. However, it is still unclear whether perioperative hyperglycemia has a direct effect on adverse events in cardiac surgery. The purpose of this study was to determine the influence of hyperglycemia on inflammation and oxidative stress in patients under CPB during cardiac surgery. MATERIAL AND METHODS: Control patients (n=17) and diabetic (type 2) patients (n=13) were included in this study. Blood samples were drawn before, during and after the CPB. Oxidative stress was evaluated in the plasma by direct and indirect approaches. Direct detection of ascorbyl radicals was assessed by electron spin resonance spectroscopy. An index: ascorbyl radical/vitamin C ratio is an indicator of the degree of oxidative stress taking place in the plasma. Oxygen radical absorbing capacity (ORAC) values were used as measurement of antioxidant capacity of the plasma. To determine inflammation profile of patients, we measure the evolution of plasma concentration of interleukin 8 (IL-8). RESULTS: During cross clamping and post-CPB, the index ascorbyl radical/vitamin C is increased; the value of the index is more significant in diabetic patients. Concomitantly, ORAC values decreased in all the patients during cross clamping (p<0.05). Results concerning inflammatory index showed that IL-8 levels increased during the CPB. CONCLUSION: In conclusion, the current study indicates that a systemic oxidative stress occurs during CPB and post-CPB periods and that in patients with type 2 diabetes mellitus, the systemic oxidative stress was increased.

Influence of rosuvastatin on the NAD(P)H oxidase activity in the retina and electroretinographic response of spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Retinal complications may be encountered during the development of hypertension as a response to oxidative stress. Statins may reduce the risk of developing hypertension and ocular diseases. We evaluate the effects of rosuvastatin (ROSU) on retinal functionality and oxidative stress levels in normotensive and spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH: Wistar Kyoto (WKY) and SHR were treated for 3 weeks with rosuvastatin (10 mg kg(-1) day(-1)). Electroretinograms (ERG) were recorded before and after rosuvastatin treatment. Reactive oxygen species (ROS) were determined in the retina with dihydroethidium staining and NAD(P)H oxidase activity was evaluated. KEY RESULTS: Retinal ganglion cell ROS and retinal NAD(P)H oxidase activity were higher in SHR than in WKY rats, respectively (17.1+/-1.1 vs 10.2+/-1.2 AU, P<0.01; 38095+/-8900 vs 14081+/-5820 RLU mg(-1); P<0.05). The ERG b-wave amplitude in SHR was significantly lower than that in WKY rats. Rosuvastatin reduced SBP in SHR but did not change plasma lipid levels. Rosuvastatin treatment in SHR significantly decreased ROS levels (11.2+/-1.3, P<0.01), NAD(P)H activity in retinal ganglion cells (9889+/-4290; P<0.05), and increased retinal plasmalogen content in SHR, but did not modify the ERG response. CONCLUSIONS AND IMPLICATIONS: Rosuvastatin, beyond lowering cholesterol levels, was able to lower ROS in the retina induced by hypertension, but without improving retinal function in SHR. These findings point to a complex relationship between ROS in the pathogenesis of retinal disease and hypertension.

Delayed 24 hours Nomega-nitro-L-arginine methyl ester injection induces pharmacological cardioprotection against reperfusion injury.

Previous studies indicate that adenosine supplementation or nitric oxide synthase (NOS) inhibition during reperfusion exert protective effects against myocardial ischemia-reperfusion (I/R) injury. We wanted to test the hypothesis that NOS inhibition before I/R also protects the myocardium against further injury and aimed to determine the involvement of adenosine receptors in a perfused rat heart model. Rats were injected with 10 mg/kg of L-NAME (N(omega)-nitro-L-arginine methyl ester) or L-NAME + SPT (8-(p-sulfophenyl)-theophylline)--an adenosine antagonist - at 2 x 25 mg/kg or with a saline buffer, 24 hrs prior to heart excision. The hearts, perfused retrogradely were subjected to 60 min of global ischemia followed by 120 min reperfusion. L-NAME decreased NOx (nitrite and nitrate) production (16.2 +/- 3.2 vs. 7.0 +/- 1.8 micromol/L; P<0.05) in vivo and increased the release of troponin I (0.04 +/- 0.01 vs. 0.02 +/- 0.01 microg/L; P<0.05) in the plasma, compared to controls. After 120 min of reperfusion, there was a higher release of adenosine (26.1 +/- 2.2 vs. 2.4 +/- 1.2 nmol/min; P<0.01) and a decrease in troponin I levels (0.19 +/-0.07 vs. 0.59 +/- 0.16 ng/min; P<0.05) in the L-NAME group compared to controls. These results were accompanied by a higher proportion of recovery of left ventricular developed pressure (72.0 +/- 4.0 vs. 60.0 +/- 4.0%; P<0.05) and coronary flow (72.0 +/- 5.0 vs. 51.0 +/- 4.0%; P<0.05) in the L-NAME group. These beneficial effects were not blocked by the adenosine receptor antagonist. The present study reveals that L-NAME protects against I/R injury when the inhibitor is administered 24 hrs before ischemia. The beneficial effects observed in this model appear to be independent of adenosine receptor stimulation.

[Development of cardiac physiopathological models from cultured cardiomyocytes]. / Développement de modèles physiopathologiques cardiaques a partir des cultures de cardiomyocytes.

The cultures of neonatal rat cardiomyocytes represent a very useful tool for the observation and the understanding of the cellular aspects of the electrophysiological, contractile, morphological, metabolic and molecular properties of the myocardium. This model is characterized by a homogeneous population of cardiac muscular cells and by vast possibilities of control of the chemical and physical environment of the cells, allowing the in vitro mimicry of a wide range of cardiac pathological situations. The cardiomyocyte cultures are thus suited to very varied experimental protocols, allowing multiparametric analysis of the cardiocellular effects of different stress such as hypoxia-reoxygenation, of ischemia-reperfusion, of the free radical attack and of thermal shock. These investigations can be combined with the study of the effects and of the cytotoxicity of pharmacological agents, not limited to the putatively cardioactive drugs. The present review proposes an outline of the procedures for the isolation, the culture and the use of neonatal cardiomyocytes. To illustrate the potentialities of this preparation, we describe more specifically the protocols and the various consequences at the cellular scale of an in vitro model of myocardial ischemia reperfusion.

[Preventing the cardiotoxic effects of anthracyclins. From basic concepts to clinical data]. / Prévention de la cardiotoxicité des anthracyclines: approche fondamentale des mécanismes mis en jeu; relations avec les données cliniques.

The chronic cardiotoxicity of the cytotoxic agents such as anthracyclines is one of the main factors, which limits their prolonged use. Clinically, this cardiotoxicity results in a cardiomyopathy with irreversible congestive heart failure, with high mortality. The molecular mechanisms, which could explain this cardiac toxicity, are complex but it seems distinct from the anticancer mechanism. Several hypotheses were advanced but it appears that the induction of an oxidative stress within myocardial tissue constitutes the common denominator. The prevention of this cardiotoxicity lies on:--a rigorous cardiac monitoring--the use of anthracyclines analogues with lower cardiotoxicity,--modifications of the protocols of administration. The myocardial protection, with cardioprotective agents targeting oxidative stress during chemotherapy would be of great interest for an optimal use of the anthracyclines.

Calcitonin gene-related peptide partly protects cultured smooth muscle cells from apoptosis induced by an oxidative stress via activation of ERK1/2 MAPK.

Oxidative stress induced by a glucose/glucose oxidase (G/GO) generator system dose-dependently decreased the viability of cultured vascular smooth muscle cells (VSMC) as estimated by MTT assay. Cell death was induced in 40% of cells exposed to 0.2 IU/ml of the free radical generating mixture. Annexin-V labeling, Hoechst staining together with DNA laddering demonstrated that apoptosis was responsible for this cell loss. Pretreatment of the cells with 10(-8) M calcitonin gene-related peptide (CGRP) significantly attenuated the damaging effect of the oxidative stress. Indeed, cell viability was estimated to be 80% in CGRP-treated group, instead of 60% in absence of CGRP treatment. This protective effect of CGRP was antagonized by 8-37 CGRP, an antagonist of CGRP-1 receptors, whereas it was not reproduced by amylin, a CGRP analogue. As indicated by the reduction in Hoechst staining and in DNA laddering, CGRP prevented the onset of apoptosis. We also demonstrated that the peptide significantly up-regulated the activation of ERK1/2 and P38 kinases. Inhibitors of the kinases prevented the protective effect of CGRP. We conclude that CGRP antagonizes oxidative stress-induced apoptosis by up-regulating MAP kinase activation and that activation of these kinases was necessary to protection.

Stage-dependent activation of cell cycle and apoptosis mechanisms in the right ventricle by pressure overload.

The molecular basis of the intrinsic vulnerability of the compliant right ventricle to chronic pressure overload is poorly understood. Extensive apoptosis, possibly coupled with aberrant cell cycle reentry, in response to unrestrained biomechanical stress may account for this phenotypic flaw. To address this issue we have studied changes in expression of the cell cycle and apoptosis regulators in the right ventricle following induction of pulmonary hypertension in the rat by injection of monocrotaline. Hypertrophy, apoptosis and cell cycle events, as well as expression of their regulator genes were documented during a period of 31 days. The hypertrophy index reached 127% at day 31. At the early stage both apoptosis and cell proliferation pathways were coincidentally activated. The level of cyclin A and E transcripts steadily increased, the labeling index was 4.8% at day 31, and expression of the caspase-3 gene peaked at day 14. Until day 21 execution of apoptosis was prevented, probably by a high level of Bcl-2. At this time point Bcl-2 collapsed, cyclin D1 was upregulated, the differentiation gatekeeper p27Kip1 was downregulated, pro-caspase-3 was activated and extensive apoptosis developed. These results indicate that the right ventricle is especially vulnerable to apoptotic pressure-dependent stimuli, and that the cell cycle and apoptosis pathways were co-activated in this experimental model.

Potential role of the neuropeptide CGRP in the induction of differentiation of rat hepatic portal vein wall.

The media of the rat hepatic portal vein is composed of an internal circular muscular layer (CL) and an external longitudinal muscular layer (LL). These two perpendicular layers differentiate progressively from mesenchymal cells within the first month after birth. In this paper, we studied the development of calcitonin gene-related peptide (CGRP) innervation during post-natal differentiation of the vessel. We show that CGRP innervation is already present around the vessel at birth in the future adventitia but far from the lumen of the vessel. Progressively, CGRP immunoreactive fibers reached first LL then CL. CL by itself become only innervated at day 14 after birth. This corresponds to the time at which thick filaments (myosin) are visible in electron microscopy and desmin visualisable by immunocytochemistry. Furthermore, we provide evidence by autoradiography, that binding sites for CGRP are transiently expressed on the portal vein media at day 1 and 14 after birth. Vascular smooth muscle cells were transfected with constructs containing promoters for desmin or smooth muscle myosin heavy chain (smMHC). CGRP treatment of the cells significantly increased the expression of smMHC. Overall these results suggest that CGRP can potentially influence the differentiation of smooth muscle cells from the vessel wall.

[A treatment with rosuvastatin induced a reduction of arterial pressure and a decrease of oxidative stress in spontaneously hypertensive rats]. / Un traitement par la rosuvastatine induit une réduction de la pression artérielle et une diminution du niveau du stress oxydatif chez le rat spontanément hypertendu.

The aim of this study was to appreciate consequences of rosuvastatin administration on hemodynamic function, vascular oxidative stress and ischemia/reperfusion disorders in normotensive and hypertensive rats. At 10 weeks of age, spontaneously hypertensive rats (SHR, n=20) and normotensive Wistar Kyoto male rats (WKY, n=20) were divided into four groups and given, either vehicle or 10 mg/kg/day of rosuvastatin by gavage for 3 weeks. Systolic blood pressure was assessed every week. At the end of these treatments, vascular NADPH oxidase activity was evaluated by chemiluminescence (lucigenin 0.5 microM). Hearts were isolated and perfused according to the Langendorff method and were subjected to 30 min of global ischemia. Reactive oxygen species (ROS) produced during reperfusion were quantified by electron spin resonance (ESR) spectroscopy using a spin probe (CP-H, 1 mM). After one week of treatment, rosuvastatin reduced the arterial pressure in SHR rats (180.3 +/- 2.1, SHR vs 169.7 +/- 2.3 mmHg, SHR+rosuvastatin; p < 0.01), without lowering plasma cholesterol levels; these effects were not observed in WKY. NADPH activity was 25% higher in control SHR rat aortas compared to control WKY, and was reduced by rosuvastatin in SHR rats. In isolated rat hearts subjected to ischemia/reperfusion sequences, there was a deterioration in functional parameters in control SHR compared to control WKY hearts. Rosuvastatin decreased post-ischemic contracture in WKY hearts by 50% (41.5 +/- 7.5, WKY control vs 18.4 +/- 4.6 mmHg, WKY+rosuvastatin; p < 0.01) and increased left ventricular developed pressure. This beneficial effect was accompanied by a decrease in ROS detected by ESR during reperfusion (312.5 +/- 45.3, WKY control; vs 219.3 +/- 22.9 AUC/mL, WKY+rosuvastatin; p < 0.05). In conclusion, these results are in accordance with the hypothesis that oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases including hypertension, and demonstrate the beneficial effects of rosuvastatin.

Electrophysiological effects of some antidepressant drugs on canine cardiac Purkinje fibres.

The electrophysiological effects of several antidepressant drugs, imipramine, metapramine, minanserin, nomifensine, and amineptine, were studied in canine cardiac Purkinje fibres at concentrations between 10(-6) mol.litre-1 and 10(-4) mol.litre-1. Metapramine (10(-5) mol.litre-1) decreased the action potential amplitude, the action potential duration, and Vmax. In addition, imipramine or metapramine induced a pronounced increase of conduction time and conduction block at 10(-4) mol.litre-1, whereas with mianserin and nomifensine a 10(-4) mol.litre-1 concentration was necessary to induce a decrease of Vmax and conduction velocity. With the exception of conduction time and action potential duration, amineptine was not able significantly to change the electrophysiological indices of canine Purkinje fibres. The decrease of Vmax observed with imipramine, metapramine, and with high concentration of mianserin and nomifensine confirms that the antiarrhythmic action of these agents might be related principally to their class I antiarrhythmic effects. The fact that amineptine, which is not antiarrhythmic, does not decrease Vmax reinforces this suggestion.

Temporal relationships between levels of circulating NO derivatives, vascular NO production and hyporeactivity to noradrenaline induced by endotoxin in rats.

OBJECTIVE: Lipopolysaccharide (LPS) induces early (within 1 h) and delayed (after several hours) impairment of vascular reactivity to catecholamines whose mechanisms are different, although they probably both involve nitric oxide (NO). Temporal and quantitative relationships between hyporeactivity to noradrenaline and NO production were investigated in a rat model of endotoxaemia allowing to clearly distinguish the two phases of hyporeactivity. METHODS: Anaesthetised rats were infused with LPS (14 mg kg-1 h-1) for 1 h. Pressure responses to noradrenaline (NA) and circulating NO derivatives (nitrosyl haemoglobin, NO2-, NO3-) were monitored for 5 h after the onset of infusion. Reactivity to NA and tissue cyclic GMP level were also assessed ex vivo, in aortic rings taken at different experimental times. RESULTS: LPS-induced early hyporeactivity to NA was associated with a moderate but significant increase in plasma NO3- level, without any significant change in concentration of the other circulating NO derivatives. Neither reactivity ex vivo nor cyclic GMP content were modified in aortae taken after 1 h of LPS infusion. By contrast, delayed hyporeactivity (5 h after the onset of LPS infusion) was associated with a large increase in all circulating NO derivatives (up to 2.5 fold), enhanced aortic cyclic GMP level and aortic hyporeactivity ex vivo. Pre-treatment of rats with NG-nitro-L-arginine methyl ester (1 mg kg-1 i.v.) entirely prevented early hyporeactivity and rise in NO3- concentration. In addition it attenuated in comparable proportion both delayed hyporeactivity to NA in vivo and circulating levels of NO derivatives. CONCLUSION: The results confirm the involvement of NO in the two phases of hyporeactivity to NA induced by LPS. They strongly support the view that a circulating factor is involved in triggering endothelial NO release during the early phase, whereas the delayed phase is associated with a high production of NO in vascular smooth muscle resulting from the induction of NO synthase.

Antiarrhythmic effect of amiodarone on doxorubicin acute toxicity in working rat hearts.

STUDY OBJECTIVE: The clinical application of doxorubicin, a potent cytotoxic agent, is limited by a dose dependent cardiotoxicity and by the acquired resistance of the neoplastic cells. Recently, the sensitivity of resistant cancer cells to doxorubicin has been enhanced by the acute administration of amiodarone. The aim of this study was to investigate whether or not this potentiates the cardiotoxicity of doxorubicin. DESIGN: Hearts from rats pretreated or not with amiodarone 50 mg.kg-1.d-1 for 5 d were perfused via the left atrium with a Krebs-Henseleit solution containing, or not, doxorubicin 6 mg.litre-1. After 40 min of perfusion, the left main coronary artery was ligated and the ligature was maintained for 10 min. It was then cut and reperfusion continued for 10 min. The cardiac output, heart rate, and mean fibrillation duration induced by the reperfusion were measured by timed collections and ECG recordings. SUBJECTS: 32 adult male Sprague-Dawley rats (250-300 g) were used throughout the study. MEASUREMENTS AND RESULTS: After 40 min of perfusion, the cardiac output in the control and amiodarone groups was constant, but significant decreases of 25.5 and 30.4% were noted in both doxorubicin groups. The mean fibrillation durations observed during reperfusion were 331(73), 66(22), 444(86), and 22(9) s for the control, amiodarone, doxorubicin and amiodarone-doxorubicin groups respectively. CONCLUSION: Amiodarone, while maintaining its antiarrhythmic effect, did not potentiate the negative inotropic effect of doxorubicin. These results suggest that the cardiotoxicity produced by the clinically acute administration of amiodarone with doxorubicin is not greater than that caused by doxorubicin given alone.

Alteration in plasma antioxidant capacities in chronic renal failure and hemodialysis patients: a possible explanation for the increased cardiovascular risk in these patients.

OBJECTIVE: The high incidence of cardiovascular diseases in chronic renal failure (CRF) and hemodialyzed (HD) patients is now well established and the involvement of oxidative stress has been hypothesized in these phenomena. The aim of our study was to evaluate the level of oxidative stress in healthy controls (CTL) compared with CRF and HD patients before (pre-HD) and after (post-HD) the dialysis session, carried out on a high biocompatible polyacrylonitrile membrane AN69. METHODS: Several indicators of the extracellular redox status were evaluated in plasma. The ascorbyl free radical (AFR) was directly measured using electron spin resonance spectroscopy (ESR) and expressed with respect to the vitamin C level to obtain a direct index of oxidative stress. Indirect plasma parameters such as vitamin E, thiol and uric acid levels were also quantified. The plasma antioxidant status (PAS) was evaluated by the allophycocyanin test. Nitric oxide (NO) stable-end metabolites: nitrites and nitrates (NO(x)), were measured in plasma. RESULTS: In CRF patients, vitamin C and thiol levels were low, and the AFR/vitamin C ratio high compared with the CTL. On the other hand, PAS and uric acid levels were shown to be higher in CRF patients. After the dialysis session, vitamin C level decreased and AFR/vitamin C ratio increased. The thiol levels were shown to be increased, in return PAS and uric acid levels were significantly lower after the dialysis session. NO(x) levels rose during CRF, but were significantly decreased after the dialysis procedure. No differences in vitamin E status were observed between CTL, CRF and HD patients. CONCLUSION: Our study demonstrates that profound disturbances in the extracellular redox system occur during the course of chronic renal failure and hemodialysis, and may provide an explanation for the cardiovascular complications in these patients.

Effects of the free radical generating system FeCl3/ADP on reperfusion arrhythmias of rat hearts and electrical activity of canine Purkinje fibres.

STUDY OBJECTIVE: The aim was to evaluate the arrhythmogenic effect of a free radical generating system, FeCl3/ADP using two different approaches. DESIGN: Ventricular arrhythmias were studied in isolated rat hearts subjected to regional ischaemia and reperfusion without or with simultaneous treatment with nicergoline (0.4 mg.litre-1). In the second part of this study the electrophysiological effects of FeCl3/ADP (0.1/1.0 microM) were investigated in normal Purkinje fibres and in Purkinje fibres from dog surviving infarction, by using conventional microelectrode method. EXPERIMENTAL MATERIALS: Hearts were obtained from male Sprague-Dawley rats, weight 250-300 g. Purkinje fibres were dissected from hearts of mongrel dogs of either sex (10-15 kg) with or without prior myocardial infarction. MEASUREMENTS AND RESULTS: FeCl3/ADP (0.1/1.0 microM and 1.0/1.0 microM respectively) weakly changed the incidence of reperfusion induced arrhythmias. In nicergoline pretreated hearts, in which the incidence of reperfusion arrhythmias was reduced, FeCl3/ADP (0.1/1.0 microM and 1.0/1.0 microM) did not change the incidence and the duration of reperfusion arrhythmias. In normal Purkinje fibres, FeCl3/ADP (0.1/1.0 microM) induced a decrease in action potential duration without any pronounced effect on Vmax, diastolic potential, and activation potential. In Purkinje fibres from post infarct myocardium, FeCl3/ADP decreased action potential duration, diastolic potential, and activation potential. CONCLUSIONS: Free radical generation did not antagonise the antiarrhythmic activity of alpha adrenergic blockade. Free radical generation induced slow and minor changes in electrophysiological activity of Purkinje fibres both from normal and ischaemic hearts. Our data suggest that free radical generation may not be the only mechanism involved in the genesis of reperfusion arrhythmias.

Postischemic myocardial recovery and oxidative stress status of vitamin C deficient rat hearts.

OBJECTIVE: To investigate the role of vitamin C tissue content as a protective agent during myocardial ischemia-reperfusion injury, we have evaluated the postischemic functional recovery and free radical release of osteogenic disorder Shionogi (ODS) inherently scorbutic rat hearts and compared them to healthy Wistar rat hearts. METHODS: Isolated perfused hearts of ODS or Wistar rats underwent 30 min of a global total normothermic ischemia followed by 30 min of reperfusion. The lipid-soluble spin trap alpha-phenyl N-tert-butylnitrone (3 mM) was perfused upstream of the coronary bed. Functional parameters were recorded and samples of coronary effluents were analysed using electron spin resonance spectroscopy to characterise and quantify the amount of radical species released. RESULTS: From the onset of reperfusion, a large and long-lasting release of alkyl/alkoxyl radicals was detected, with a peak value of 29.0+/-3.2 nM obtained after 13 min, which was associated with a persistent contractile dysfunction. However, ODS rat hearts showed a higher myocardial recovery with lower left ventricular end diastolic pressure (44.34+/-1.74 vs. 55.03+/-1.57 mmHg for Wistar), higher recovery of rate pressure product (12.3+/-1.4 vs. 1.9+/-1.7x10(3) mmHg beats/min for Wistar) and shorter duration of contractile abnormalities during reperfusion (3.7+/-1.0 vs. 20.8+/-5.3 min for Wistar). Moreover, free radical release was identical in ODS rat hearts as compared to control Wistar rats. Ascorbic acid tissue content was significantly altered in ODS rats (31.9+/-3.3 vs. 591.0+/-54.9 mmol/g of tissue for Wistar) but superoxide dismutases, glutathion peroxidases and inducible heat shock protein 70 genes were up-regulated. CONCLUSIONS: This study shows that ascorbic-acid-deficient ODS rat hearts are more resistant to an ischemic insult than control Wistar rats, probably through the development of alternative protective defences, like the induction of heat shock proteins. These paradoxical results raise the question of the relative importance of each endogenous antioxidant in the cardiac resistance to ischemia-reperfusion injury.

Prolongation by captopril of action potential duration in the normal and hypertrophied rat ventricle: direct action or inhibition of the local angiotensin converting enzyme?

OBJECTIVE: The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy. METHODS: Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction. RESULTS: In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction. CONCLUSIONS: In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.

Trends in prevalence, incidence and mortality of diagnosed and silent coronary heart disease in Quebec.

INTRODUCTION: Of all cardiovascular causes of mortality, coronary heart disease (CHD) remains the leading cause of death. Our objectives were to establish trends in the prevalence and incidence of CHD in the province of Quebec, and to determine the proportion of CHD mortality that had no previous CHD diagnosis. METHODS: Trends in prevalence, incidence and mortality were examined with a population-based study using the Quebec Integrated Chronic Disease Surveillance System, which links several health administrative databases. Data are presented using two case definitions for Quebecers aged 20 years and over: 1) a validated definition, and 2) CHD causes of death codes added to estimate the proportion of deaths that occurred without any previous CHD diagnosis as a proxy for sudden cardiac death (SCD). RESULTS: In 2012/2013, the crude prevalence of CHD was 9.4% with the first definition (593 000 people). Between 2000/2001 and 2012/2013, the age-standardized prevalence increased by 14%, although it has been decreasing slightly since 2009/2010. Age-standardized incidence and mortality rates decreased by 46% and 26% respectively, and represented a crude rate of 6.9 per 1000 and 5.2% in 2012/2013. The proportion identified only by CHD mortality, our SCD proxy, was only significant for the incident cases (0.38 per 1000 in 2009/2010) and declined over the study period. CONCLUSION: The prevalence of CHD has tended to decrease in recent years, and incidence and mortality have been declining in Quebec. Most CHD mortality occurs in previously diagnosed patients and only a small proportion of incident cases were not previously identified.

TITRE: Tendances de la prévalence, de l'incidence et de la mortalité des cardiopathies ischémiques diagnostiquées et silencieuses au Québec. INTRODUCTION: Parmi toutes les causes de décès d'origine cardiovasculaire, les cardiopathies ischémiques (CI) demeurent les plus importantes. Notre étude visait à définir les tendances de la prévalence et de l'incidence des CI au Québec ainsi qu'à déterminer la proportion de décès par CI qui n'avait aucun diagnostic antérieur de CI. MÉTHODOLOGIE: Les tendances de la prévalence, de l'incidence et de la mortalité ont été examinées avec une étude populationnelle utilisant le Système intégré de surveillance des maladies chroniques du Québec, qui jumelle plusieurs fichiers médico-administratifs. Les données, recueillies auprès des Québécois de 20 ans et plus, sont présentées selon deux définitions de cas : 1) une définition validée et 2) une définition reposant sur l'addition des codes de décès liés aux CI afin d'estimer la proportion des décès sans diagnostic antérieur de CI comme indicateur de mort cardiaque subite (MCS). RÉSULTATS: En 2012-2013, la prévalence brute des CI selon la première définition était de 9,4 % (593 000 personnes). Entre 2000-2001 et 2012-2013, la prévalence ajustée selon l'âge a augmenté de 14 %, avec une légère diminution depuis 2009-2010. Les taux d'incidence et de mortalité ajustés selon l'âge ont diminué de respectivement 46 % et 26 %, les taux bruts s'établissant à 6,9 pour 1 000 et à 5,2 % en 2012-2013. La proportion de décès identifiés uniquement grâce au décès par CI, soit l'indicateur de MCS, n'était significative que pour les cas incidents (0,38 pour 1 000 en 2009-2010) et elle a diminué au cours de la période à l'étude. CONCLUSION: La prévalence des CI a eu tendance à diminuer au cours des dernières années et l'incidence comme la mortalité ont également diminué au Québec. La majorité des décès par CI touchent des patients ayant déjà reçu un diagnostic, seule une faible proportion des cas incidents n'ayant pas été préalablement identifiée.