Direct measurement of free radical generation in isolated rat heart by electron paramagnetic resonance spectroscopy: effect of trimetazidine.
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Animals↗
Biomedical subjects
L Rochette
Publications and source records attributed to L Rochette.
Evolution of free radical formation during low-flow ischemia and reperfusion in isolated rat heart.
Free radicals have been implicated in several aspects of cellular injury, both during ischemia and reperfusion of the myocardium. In this study, formation of free radicals in the isolated rat heart was measured a) directly using electron paramagnetic resonance (EPR) spectroscopy and b) indirectly using the generation of thiobarbituric acid reactants as an index of lipid peroxidation. EPR spectra of frozen heart powder recorded at 100 degrees K show several lines and consist of different components separated by temperature studies: signal C disappears after warming the sample 1 minute at 190 degrees K and is suggestive of a triplet signal g = 2.001, aN = 25 Gauss; signal B g parallel = 2.034, g perpendicular = 2.007, disappears after 1 min at 240 degrees K, and is similar to those previously reported for oxygen alkylperoxyl free radical; the remaining signal, signal A with g = 2.004 is identical to that of a carbon-centered ubiquinone free radical. The total free radical concentration in isolated rat heart perfused at a constant flow rate of 12 ml/min was increased by 44% compared with control (p less than 0.05) after 10 minutes of normothermic global ischemia with a 10% residual flow, and by only 31% compared with control after 20 seconds of reflow with oxygenated perfusate (p less than 0.05). Compared with the reperfused group, trimetazidine 10(-5) M administered 15 minutes before the ischemic period decreased the free radical concentration (-20%). However, this free radical generation in heart was not associated with a concomitant increase of lipid peroxides.
Animals↗
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.
Amiodarone↗
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.
Action Potentials↗
Effects of increased heart work on release of norepinephrine and ventricular arrhythmias following reperfusion in the isolated rat heart.
The influence of increasing left atrial pressures (0.5, 1.0, and 2.0 kPa) on the incidence of ventricular arrhythmias and the liberation of prelabeled norepinephrine (3H-NE) was investigated in the isolated working rat heart. Acute regional myocardial ischemia (30 min) was produced by ligature of the left main coronary artery with subsequent release of the ligature to achieve reperfusion, which consistently provoked ventricular arrhythmias. The magnitude of regional ischemia was measured by microspheres, and the efflux of 3H-labeled NE compounds was measured in the coronary effluent. Our data show that an increase in atrial pressure enhanced reperfusion arrhythmias, but the magnitude of NE release was not directly related to the occurrence of arrhythmias. It is proposed that increased heart work has an arrhythmogenic effect by enhancing the severity of regional ischemia.
Animals↗
Prevention of reperfusion-induced ventricular arrhythmias in isolated rat heart with magnesium.
The effects of magnesium (from 1.2 to 7.2 mM) were investigated in isolated perfused rat heart subjected to coronary artery ligation and reperfusion. Increasing magnesium concentrations, of the medium containing 3.00 mM of calcium, induced a significant bradycardia and a protective effect towards reperfusion arrhythmias. A significant correlation was found between the heart rate and the antiarrhythmic activity of increasing magnesium concentrations. The effects of high magnesium concentration (4.8 mM) were also investigated after labelling of internal stores of noradrenaline with [3H]noradrenaline. Without any marked change in the pattern of release of radioactivity, a significant reduction of the sudden release of radioactivity was observed during the reperfusion. However, magnesium did not change the uptake of noradrenaline by the heart. Our results suggest that the antiarrhythmic effect of magnesium might be of importance in the clinical treatment of myocardial ischemia.
Animals↗
Beneficial effect of perindopril, an angiotensin-converting enzyme inhibitor, on left ventricular performance and noradrenaline myocardial content during cardiac failure development in the rat.
The left coronary artery in rats was ligated for a period of 15 days to induce hypertrophy of the non-infarcted myocardium. Left ventricular performances were evaluated in the working heart model. In addition, cardiac hypertrophic indices and noradrenaline content were measured. Variables were determined in the absence or presence of the angiotensin-converting enzyme inhibitor, perindopril. A 35 and 60% decrease in the coronary and cardiac output, respectively, and a 57% decrease in the noradrenaline content of the non-infarcted left ventricular free wall were seen. Furthermore, a 15% increase in the heart/body weight ratio was observed in the infarcted group. After chronic treatment of the animals with perindopril (2 mg.kg-1 body weight, per os), coronary and cardiac output were impaired to a lesser extent: 8 and 35% respectively, with only a 15% decrease in the noradrenaline content of the non-infarcted left ventricular free wall. Furthermore, the increase in heart/body weight ratio was significantly less than in the nontreated infarct group (7%). We conclude that the beneficial effects of converting enzyme inhibition, during the development of myocardial infarction, on left ventricular performances are associated with a decrease in the hypertrophic indices and a normalization of sympathetic activity.
Angiotensin-Converting Enzyme Inhibitors↗
Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.
We assessed the effect of 1,3-butanediol on cerebral energy metabolism and edema after inducing multifocal brain infarcts in 108 rats by the intracarotid injection of 50-microns carbonized microspheres. An ethanol dimer that induces systemic ketosis, 25 mmol/kg i.p. butanediol was injected every 3 hours to produce a sustained increase in the plasma level of beta-hydroxybutyrate. Treatment significantly attenuated ischemia-induced metabolic changes by increasing the concentrations of phosphocreatine, adenosine triphosphate, and glycogen and by reducing the concentrations of pyruvate and lactate. Lactate concentration 2, 6, and 12 hours after embolization decreased by 13%, 44%, and 46%, respectively. Brain water content increased from 78.63% in six unembolized rats to 80.93% in 12 saline-treated and 79.57% in seven butanediol-treated rats 12 hours after embolization. (p less than 0.05). The decrease in water content was associated with significant decreases in the concentrations of sodium and chloride. The antiedema effect of butanediol could not be explained by an osmotic mechanism since equimolar doses of urea or ethanol were ineffective. Our results support the hypothesis that the beneficial effect of butanediol is mediated through cerebral utilization of ketone bodies arising from butanediol metabolism, reducing the rate of glycolysis and the deleterious accumulation of lactic acid during ischemia.
3-Hydroxybutyric Acid↗
Effect of sotalol against reperfusion-induced arrhythmias in Sprague-Dawley and Wistar rats.
The effect of (+/-)-sotalol (a beta-blocker with class III antiarrhythmic activity) against reperfusion-induced arrhythmias was studied in artificially ventilated, open-chest, Sprague-Dawley and Wistar rats. Coronary artery occlusion was produced for 5 min and reperfusion allowed for 10 min. A somewhat different arrhythmic profile was observed between saline-treated rats of the 2 strains studied, with more Sprague-Dawley rats experiencing an irreversible ventricular fibrillation (VF) upon reperfusion, compared to Wistar rats, in whom a combination of reversible ventricular tachycardia (VT) and VF was more frequently observed. No difference in action potential characteristics and ventricular effective refractory period determined in vitro, nor in myocardial noradrenaline content, was found between the 2 strains of rats. (+/-)-Sotalol (5 and 10 mg/kg, IV) showed marked beta-blocking activity and reduced the mean duration of VT-VF in both strains studied. It also produced similar increases in action potential duration and refractory period in vitro in these 2 strains. In a different series of experiments, the antiarrhythmic action of the racemic form was compared to that of (+)-sotalol using Wistar rats. (+)-Sotalol had much less beta-blocking activity, and was found to be similarly effective against reperfusion-induced VT-VF. It is concluded that the antiarrhythmic effect of sotalol against reperfusion-induced arrhythmias may not be related to beta-adrenergic blockade but probably to class III type activity. Despite differences in the profile of reperfusion-induced arrhythmias between Sprague-Dawley and Wistar rats, both strains were sensitive to the antiarrhythmic action of (+/-)-sotalol.
Animals↗
[In vitro study of functional parameters and cardiac arrhythmia in localized ischemia followed by reperfusion in two rat strains (Sprague Dawley and Wistar)].
The cardiac parameters of two rat strains [Wistar (W) and Sprague Dawley (SD)] were compared during Langendorff perfusion. The values of coronary flow, heart rate, amplitude of contraction and the incidence of arrhythmias were studied during three 10 minutes periods: perfusion, ischemia by coronary artery occlusion and reperfusion. The values of heart rate and coronary flow of SD hearts are always higher than those of W hearts whatever the potassium (K+) concentration of perfusate (5.9 or 3 mM). Furthermore, with a high K+ perfusate (5.9 mM) and during ischemia. W rat hearts showed ventricular tachycardia periods which are never observed in SD rat hearts. It is concluded that W rat hearts present a higher sensitivity to the development of dysfunction than SD rat hearts.
Analysis of Variance↗
PAF-acether-induced mortality in mice: protection by benzodiazepines.
Intraperitoneal injection to mice of platelet-activating factor (PAF) induces severe shock symptoms, leading to death. The effects of various drugs which are potential specific or non-specific PAF inhibitors were tested. Salbutamol, a beta 2-agonist, showed a partial protection, whereas the specific PAF antagonists CV 3988 or BN 52021 induced an important beneficial action against PAF-induced lethal effects. The effects of drugs related to benzodiazepines were also studied: alprazolam administered p.o. prior to PAF challenge provides almost complete protection against PAF toxicity. Thus PAF-induced death in mice represents a useful model of systemic anaphylaxis; moreover, studies of benzodiazepine-related compounds may be interesting for investigating the mechanisms of the biological actions of PAF.
Adrenergic beta-Agonists↗
Evaluation of free radical and lipid peroxide formation during global ischemia and reperfusion in isolated perfused rat heart.
Free radical species have been implicated as important agents involved in myocardial ischemic and reperfusion injuries. In our study, formation of free radicals was measured directly with electron paramagnetic resonance spectroscopy before ischemia, during 10 minutes of global ischemia, and 20 seconds after reperfusion in the rat heart. We also investigated the formation of thiobarbituric acid-reactive material as index of lipoperoxidation induced by free radicals and measured arrhythmias. Production of free radicals takes place during ischemia since the signal intensity with a g value of 2.004 attributed to free radical species was increased by 50% after 10 minutes of global ischemia. In hearts reperfused with oxygenated perfusate for 20 seconds, the signal doubled. These experiments supply evidence that free radicals are generated in isolated rat heart during a short period of global ischemia and reperfusion. However, this increase was not associated with a concomitant increase of lipid peroxides in the myocardium nor with the development of reperfusion arrhythmias.
Animals↗
Effects of promethazine on ischemic and reperfusion arrhythmias in rat heart.
The effects of the H1-receptor antagonists promethazine, mepyramine, and chlorpheniramine on ischemic and reperfusion arrhythmias were studied in the isolated perfused rat heart. Promethazine reduced both ischemic and reperfusion arrhythmias (2 x 10(-6)M-7.5 x 10(-6)M). Mepyramine and chlorpheniramine decreased these arrhythmias but at concentrations about 10 times higher. The H2-blockers cimetidine and ranitidine had no antiarrhythmic effect. Promethazine also: (i) increased release of noradrenaline by the heart; and (ii) increased coronary flow in the reperfusion period and in some mildly ischemic zones. It is proposed that promethazine exerts most of its antiarrhythmic effects by a nonspecific mechanism, possibly membrane stabilization; in addition, enhanced coronary flow may play a role.
Animals↗
Antiarrhythmic properties of antidepressant drugs after coronary artery occlusion and reperfusion in rats.
The effects of the intravenously administered antidepressant drugs mianserin, imipramine, metapramine, nomifensine and amineptine against ischaemia and reperfusion arrhythmias were investigated in anaesthetized rats. Imipramine, metapramine, mianserin and high doses of nomifensine (0.5 mg.kg-1) reduced the mortality and the duration of ventricular fibrillation observed following coronary artery ligation. Amineptine was ineffective in preventing early postligation arrhythmias. With the tricyclic antidepressant drugs imipramine and metapramine, the arrhythmias were practically suppressed after 15 min following coronary artery ligation. The incidence of reperfusion arrhythmias was significantly reduced by tricyclic antidepressant drugs. In contrast, amineptine was not effective and did not alter cardiac function. It was suggested that nonspecific effects of these drugs account for their antiarrhythmic action. The most plausible explanation for their antiarrhythmic action may be a quinidine-like cardiac depressant activity.
Animals↗
[Direct cardiac effects of angiotensins I and II and 2 converting enzyme inhibitors (captopril and perindopril). Indirect demonstration of a converting enzyme in the rat heart].
In order to establish the possible existence of a cardiac converting enzyme and its role in the pathophysiology of the myocardial ischemia, the direct cardiac effects of IEC and AI or AII were studied on the isolated rat heart perfused through the left atria. Three series of seven hypertensive rats (SHR) were used. The reduction of the aortic flow (QAO) due to ischemia (produced by a left coronary artery ligation of 10 mn) was brought into line with the reduction of the coronary flow (QCORO) and the weight of the heart. This reduction was 2.06 +/- 1.8 for the control, 1.96 +/- 1.27 when captopril (CAP) (10(-5) M) was added to the perfusion liquid and 1 +/- 0.42 when perindopril (PER) (1.2 x 10(-5) M) was added to the perfusion liquid (p less than 0.05 vs CAP). Four series of 10 rat hearts (Sprague Dawley) were used to study the changes on the working heart caused by short perfusions of AI or AII (10(-7) M) in the presence of IEC or saralasin (SAR 10(-7) M). AII caused a reduction of the QCORO of 2.1 +/- 0.26 ml/mn, an increase of the QAO of 2.5 +/- 0.9 ml/mn and an increase of the heart rate (HR) of 9 +/- 3.24 beats/mn. In the presence of CAP or PER the effects of AII were the same, however in the presence of SAR these effects were prevented. AI caused a reduction of the QCOR of 2.5 +/- 0.4 ml/mn, an increase of the QAO of 2.5 +/- 0.8 ml/mn and an increase of the HR of 18 +/- 4 beats/mn.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin I↗
Converting enzyme inhibitors (captopril, enalapril, perindopril) prevent early-post infarction ventricular fibrillation in the anaesthetized rat.
The angiotensin-converting enzyme inhibitors, captopril, enalapril and perindopril, exert antiarrhythmic effects on early post-infarction arrhythmias in anaesthetized rats. These studies support the hypothesis that converting enzyme inhibitors could have a "cardioprotective" effect, but the doses used are probably "high" in relation to those therapeutically applicable to man.
Anesthesia↗
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.
Action Potentials↗
Effects of alterations in sympathetic nervous activity on the severity of reperfusion-induced arrhythmias in anaesthetised rats.
The effects of a number of interventions influencing sympathetic nervous activity on the severity of coronary artery reperfusion-induced arrhythmias in anaesthetised rats have been examined. Noradrenaline (0.1 microgram kg-1 min-1) reduced the mortality that usually occurred as a consequence of ventricular fibrillation. Isoprenaline (5 micrograms kg-1) did not significantly affect the severity of reperfusion-induced arrhythmias, although arrhythmias occurring during the 5-min period of ischaemia were exacerbated. The alpha-adrenoceptor antagonist nicergoline (0.25 and 0.5 mg kg-1 min-1) markedly suppressed both the ventricular tachycardia and fibrillation occurring upon release of the occlusion, whereas prazosin (1.0 mg kg-1) only slightly reduced the incidence of ventricular tachycardia. The beta-adrenoceptor antagonists atenolol and timolol did not significantly modify the severity of these reperfusion-induced arrhythmias. Pretreatment with reserpine (0.1 mg kg-1) or 6-hydroxydopamine (20 mg kg-1), which depleted myocardial catecholamine concentrations by 90%, had no effect on the indices of arrhythmic activity. Similarly, administration of L-thyroxine (1 mg kg-1) or propylthiouracil (50 mg kg-1) on 7 consecutive days prior to coronary artery occlusion did not alter the incidence of arrhythmias occurring upon reperfusion. Taken as a whole, these results do not suggest an important role for sympathetic nervous activity in the genesis of reperfusion-induced arrhythmias in anaesthetised rats.
Adrenergic alpha-Antagonists↗