Claire Abadie

Vitamin E analogues reduce the incidence of ventricular fibrillations and scavenge free radicals

Summary— The aim of our study was to analyse the protective effects of different α‐tocopherol analogues 1) against fibrillations induced by an ischemia‐reperfusion sequence, and 2) to further investigate in vitro the radical scavenging properties of these analogues by two sensitive methods. Concerning 1: isolated rat hearts underwent 10 min of coronary ligation followed by reperfusion and the α‐tocopherol analogues were infused IS min before occlusion. Functional parameters including heart rate and fibrillations were recorded. Concerning 2: the β‐phycoerythrin assay was utilised to determine the oxygen radical absorbing capacity (ORAC) of these vitamin E analogues against peroxyl radicals. Electron paramagnetic resonance (EPR) was used to measure their scavenger abilities on hydroxyl radical and superoxide anion production. Concerning 1: ventricular fibrillation times were reduced for all analogues treated hearts at concentrations of 1 μM and 5 μM, with Trolox being the most efficacious. Concerning 2: in our experimental conditions of intense production of free radicals, scavenging IC50 values for hydroxyl radical were 1.15, 2.17 and 4.04 mM for Trolox, MDL 74270 and MDL 74366 respectively. Superoxide anion IC50 values were 1.0 and 6.75 mM for Trolox and MDL 74270.

Interleukin-1β and tumor necrosis factor-α inhibit the release of [3H]-noradrenaline from mice isolated atria

In the present study, we have investigated the ability of four cytokines, interleukin-1β, interleukin-2, interleukin-6 and tumor necrosis factor-α, to modulate the stimulation-induced outflow of radioactivity from isolated superfused mouse atria which where pre-incubated with [3H]-noradrenaline. The tissues were subjected twice to field stimulation (5 Hz frequency, 50 mA intensity, 2 ms pulses for 60 s) and the drugs were added prior to the second stimulation in order to assess their modulatory effects.The results show that mouse recombinant interleukin-1β and tumor necrosis factor-α inhibited the stimulation-induced release of radioactivity from the isolated mouse atria. The effect of interleukin-1β was blocked by a human recombinant interleukin-1 receptor antagonist. The inhibitory effect of interleukin-1β was also abolished by the cyclooxygenase inhibitor, diclofenac (1 μmol/1) suggesting that the action of interleukin-1β might be mediated through the formation of prostaglandins. The effect of interleukin-1β appears to be time-dependent, since a stronger inhibition of radioactivity release was observed when the incubation time was increased from 20 to 65 minutes before the second stimulation. Interleukin-2 and interleukin-6 were ineffective in modulating release under these experimental conditions.The ability of interleukin-1β and tumor necrosis factor-α to inhibit noradrenaline release suggests that mediators of the immune system produced locally may modulate the activity of the sympathetic nervous system.

An α-tocopherol analogue with antioxydant activity improves myocardial function during ischemia reperfusion in isolated working rat hearts

Abstract Recently, it has been reported that α-tocopherol analogues reduce infarct size in vivo in the rat and improve contractility upon reperfusion following global ischemia in isolated rat hearts. In the present study, we have thus investigated the effects of the hydrophilic α-tocopherol analogue MDL 74366 on nonenzymatic lipid peroxidation using a tissue homogenate method and reperfusion-induced arrhythmias following a local ischemia in isolated working rat hearts. Lipoperoxide (LPO) production was inhibited in a concentration-dependent manner in spontaneous as well as in induced peroxydations. The concentration resulting in a 50% inhibition (IC50) was around 2 μM. MDL 74366 treatment had no significant effect on baseline heart rate and cardiac output values. However, MDL 74366 decreased the incidence of reperfusion arrhythmias (ventricular tachycardia, VT; ventricular fibrilllation, VF). The coincidence observed between the protective effect of MDL 74366 against tissue LPO formation and the preventive effect of this α-tocopherol analogue in the heart during the ischemia-reperfusion sequence confirms that vitamin E has beneficial effects against induced oxidative damage.

Effect of in vivo heart irradiation on the development of antioxidant defenses and cardiac functions in the rat

During radiotherapy of thoracic tumors, the heart is often included in the primary treatment volume, and chronic impairment of myocardial function occurs. The cellular biomolecules are altered directly by radiation or damaged indirectly by free radical production. The purpose of this investigation was to evaluate the biochemical and functional responses of the rat heart to a single high dose of radiation. The effect of 20 Gy local X irradiation was determined in the heart of Wistar rats under general anesthesia. Mechanical performances were measured in vitro using an isolated perfused working heart model, and cardiac antioxidant defenses were also evaluated. Hearts were studied at 1 and 4 months after irradiation. This single dose of radiation induced a marked drop in the mechanical activity of the rat heart: aortic output was significantly reduced (18% less than control values) at 1 month postirradiation and remained depressed for the rest of the experimental period (21% less than control 4 months after treatment). This suggests the development of myocardial failure after irradiation. The decline of functional parameters was associated with changes in antioxidant defenses. The decrease in cardiac levels of vitamin E (-30%) was associated with an increase in the levels of Mn-SOD and glutathione peroxidase (+45.5% and +32%, respectively, at 4 months postirradiation). However, cardiac vitamin C and catalase levels remained constant. Since these antioxidant defenses were activated relatively long after irradiation, it is suggested that this was probably due to the production of free radical species associated with the development of inflammation.

Interleukin-1β and tumor necrosis factor-α inhibit the release of [3H]-Noradrenaline from isolated human atrial appendages

Abstract In the present study, we have investigated the ability of human recombinant interleukin-1β (hIL-1β) and human recombinant tumor necrosis factor-α (hTNF-α) to modulate the stimulation-induced (S-I) outflow of [3H]-noradrenaline ([3H]-NA) from isolated superfused human atria. Pieces of human right atrial appendages were excised during routine cardiac surgery. Tissues were incubated with [3H]-NA (0.2 μmol/l) for 30 min at 37°C, then inserted in a Brandel suprafusion system where the radioactivity was washed for 75 min with a Krebs-Henseleit solution at a rate of 0.4 ml/min. Thereafter, the effluent was collected for the remainder of the protocol during which two trains of electrical stimulation (50 mA intensity, 5 Hz frequency, 60 s duration, 2 ms pulses) were delivered at 10 min and 45 min (short protocol) or 85 min (long protocol). The effect of drugs on the S-I outflow of [3H]-NA was determined by adding drugs 20 min (short protocol) or 60 min (long protocol) before the second stimulation. Experiments were carried out in the continuous presence of desipramine (1 μmol/l) to prevent neuronal NA reuptake. The results showed that in human atrium, hIL-1β (3 ng/ml) and hTNF-α (0.5 ng/ml) significantly inhibited the S-I release of [3H]-NA. The inhibitory effect of hIL-1β was blocked by human recombinant IL-1 receptor antagonist (50 ng/ml), and by the cyclooxygenase inhibitor, diclofenac (1 μmol/l), suggesting that hIL-1β inhibited NA release through the formation of prostaglandins. The ability of hIL-1β and hTNF-α to inhibit NA release suggest that mediators of the immune system produced locally may modulate the activity of the sympathetic nervous system in human atrial appendages.

An α-tocopherol analogue with antioxidant activity improves myocardial function during ischemia-reperfusion in isolated working rat hearts

Recently, it has been reported that alpha-tocopherol analogues reduce infarct size in vivo in the rat and improve contractility upon reperfusion following global ischemia in isolated rat hearts. In the present study, we have thus investigated the effects of the hydrophilic alpha-tocopherol analogue MDL 74366 on nonenzymatic lipid peroxidation using a tissue homogenate method and reperfusion-induced arrhythmias following a local ischemia in isolated working rat hearts. Lipoperoxide (LPO) production was inhibited in a concentration-dependent manner in spontaneous as well as in induced peroxidations. The concentration resulting in a 50% inhibition (IC50) was around 2 microM. MDL 74366 treatment had no significant effect on baseline heart rate and cardiac output values. However, MDL 74366 decreased the incidence of reperfusion arrhythmias (ventricular tachycardia, VT; ventricular fibrillation, VF). The coincidence observed between the protective effect of MDL 74366 against tissue LPO formation and the preventive effect of this alpha-tocopherol analogue in the heart during the ischemia-reperfusion sequence confirms that vitamin E has beneficial effects against induced oxidative damage.

Absence of Relationship between Antiarrhythmic Effects of Antidepressant Drugs and Lipid Peroxidation

Tricyclic antidepressant drugs may affect the cardiovascular system, principally in patients with preexisting cardiac disease. The present study was undertaken to compare the effects of amitriptyline and mianserin with those of tianeptine, an atypical tricyclic antidepressant drug, in rat isolated working heart subjected to a local myocardial ischemia. Coronary, aortic and cardiac flows, and heart rate remained stable during the whole preischemic period in control hearts. Ligation of the left main coronary artery induced a 50% decrease in coronary, aortic and cardiac flow without any change in heart rate. Reperfusion was characterized by the occurrence of ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) and by a marked reduction in cardiodynamic parameters. Amitriptyline (1 and 10 mumol/l) and mianserin (1 and 10 mumol/l) exhibited an antiarrhythmic activity against reperfusion arrhythmias. Tianeptine (1 and 10 mumol/l) was not able to reduce the incidence of reperfusion arrhythmias. Although tianeptine did not change heart rate, mianserin and amitriptyline induced a bradycardia. Mianserin and amitriptyline improved the cardiac recovery of cardiac function during reperfusion. The cardiodynamic parameters (coronary, aortic and cardiac flows) were not altered by tianeptine during the preischemic period. Furthermore, these parameters were similar to those observed in the control group both during ischemia and reperfusion. The beneficial effects of amitriptyline and mianserin observed in the setting of myocardial reperfusion were not associated with a reduced lipoperoxidation investigated by using an in vitro model in the presence or absence of a free-radical-generating system. The results of the present study indicate that the pronounced antiarrhythmic activities of mianserin and amitriptyline cannot be explained by an antiperoxidative action of these drugs.