Protective effects of amiodarone pretreatment on mitochondrial function and high energy phosphates in ischaemic rat heart

Nokin, Pierre; Jungbluth, L.; Mouton, J.

doi:10.1016/s0022-2828(87)80366-8

Cited by 15 publications

(7 citation statements)

References 40 publications

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“…The leakage of lysosomal enzymes, i.e., instability of lysosomal membranes, was observed in the ischaemic myocardium in the control group, whereas, mitochondrial function from the ischaemic area in the drug-treated groups was improved significantly compared with that in the control group. Nokin et al (1987) showed a protective effect of amiodarone against ischaemiainduced mitochondrial dysfunction. In the present study, stability of lysosomal membranes was also demonstrated by administration of amiodarone, sotalol or E-4031.…”

Section: Discussionmentioning

confidence: 94%

Effects of antiarrhythmic agents classified as class III group on ischaemia‐induced myocardial damage in canine hearts

Sano

Sugiyama

Taki

et al. 1990

British J Pharmacology

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The cardioprotective effects of antiarrhythmic agents classified as class III, amiodarone, sotalol and E‐4031, were investigated in anaesthetized dogs. The left anterior descending coronary artery was occluded for 2 h. Heart mitochondria were prepared from both the ischaemic and non‐ischaemic areas, and their function was estimated polarographically. Activities of the lysosmal enzymes, N‐acetyl‐β‐glucosaminidase and β‐glucuronidase, were measured in each fraction. Two hour occlusion induced ventricular arrhythmias, and amiodarone, sotalol and E‐4031 greatly suppressed the development of arrhythmias. Amiodarone, sotalol and E‐4031 significantly protected mitochondria against ischaemia, and prevented ischaemia‐induced leakage of lysosomal enzymes. Antiarrhythmic agents classified as class III show cardioprotective effects, which might participate in their antiarrhythmic effect.

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Section: Discussionmentioning

confidence: 94%

Effects of antiarrhythmic agents classified as class III group on ischaemia‐induced myocardial damage in canine hearts

Sano

Sugiyama

Taki

et al. 1990

British J Pharmacology

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“…Pretreatment with amiodarone or desethylamiodarone was done exactly as described previously (Nokin et al, 1987). Briefly, adult male Wistar rats (weighing 300 -350 g; n ϭ 4 in each group) were anesthetized with 200 mg/kg ketamine i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Some emphasized its beneficial effect on cardiac functions and arrhythmia after ischemia and reperfusion (Nokin et al, 1987;Vander-Elst et al, 1990); however, other reports found it worsened the damage to the mitochondrial energy metabolism caused by ischemia-reperfusion (Moreau et al, 1999). Moreover, there are only limited data about the effect of desethylamiodarone on ischemic heart.…”

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confidence: 99%

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Varbiro¹,

Tóth²,

Tapodi³

et al. 2003

J Pharmacol Exp Ther

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Amiodarone is a widely used and potent antiarrhythmic agent that is metabolized to desethylamiodarone. Both amiodarone and its metabolite possess antiarrhythmic effect, and both compounds can contribute to toxic side effects. Here, we compare the effect of amiodarone and desethylamiodarone on mitochondrial energy metabolism, membrane potential, and permeability transition and on mitochondria-related apoptotic events. Amiodarone but not desethylamiodarone protects the mitochondrial energy metabolism of the perfused heart during ischemia in perfused hearts. At low concentrations, amiodarone stimulated state 4 respiration due to an uncoupling effect, inhibited the Ca 2ϩ -induced mitochondrial swelling, whereas it dissipated the mitochondrial membrane potential (⌬⌿), and prevented the ischemia-reperfusion-induced release of apoptosis-inducing factor (AIF). At higher concentrations, amiodarone inhibited the mitochondrial respiration and simulated a cyclosporin A (CsA)-independent mitochondrial swelling. In contrast to these, desethylamiodarone did not stimulate state 4 respiration, did not inhibit the Ca 2ϩ -induced mitochondrial permeability transition, did not induce the collapse of ⌬⌿ in low concentrations, and did not prevent the nuclear translocation of AIF in perfused rat hearts, but it induced a CsA-independent mitochondrial swelling at higher concentration, like amiodarone. That is, desethylamiodarone lacks the protective effect of amiodarone seen at low concentrations, such as the inhibition of calcium-induced mitochondrial permeability transition and inhibition of the nuclear translocation of the proapoptotic AIF. On the other hand, both amiodarone and desethylamiodarone at higher concentration induced a CsA-independent mitochondrial swelling, resulting in apoptotic death that explains their extracardiac toxic effect.Amiodarone (2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl-ketone hydrochloride) is one of the most effective antiarrhythmic drugs and is frequently used in the clinical practice for treating ventricular and supraventricular arrhythmias. It is a class III antiarrhythmic agent, prolonging action potential duration whose effect may involve blocking of ␤-adrenergic receptors, sodium channels, and L-type calcium channels (Singh and Vaughan Williams, 1970;Nokin et al., 1983;Nattel et al., 1987;Varro et al., 1996). It may also have a role in preventing mortality after myocardial infarction (Julian et al., 1997). Despite its effective antiarrhythmical properties, the use of amiodarone is often limited by its toxic side effects, including thyroid dysfunction, liver, and pancreas fibrosis (Amico et al., 1984;Martin and Howard, 1985). However, the most severe adverse effect of the drug is pulmonary fibrosis, occurring in up to 13% of the patients receiving the amiodarone in doses higher than 400 mg day Ϫ1 (Martin and Rosenow, 1988). The etiology of the amiodarone-induced pulmonary toxicity is unknown.Desethylamiodarone, the major metabolite of amiodarone, also has antiarrhyth...

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“…Amiodarone acts as a class III antiarrhythmic drug [17,18], and has been shown to inhibit ATP-sensitive potassium channels [19], to interact with myocardial Na + K + -ATPase in guinea pig microsomal preparations [20] and to protect the ischemic rat heart by inhibiting oxidative phosphorylation [21]. Intramuscular or intravenous amiodarone treatment has been used in controlling tachyarryhthmia in children [22] and young adults [23], and results in sustained bradycardia clinically.…”

Section: Discussionmentioning

confidence: 99%

Regulation of A1 adenosine receptors by amiodarone and electrical stimulation in rat myocardial cells in vitro

El-Ani

Shainberg

1997

Biochemical Pharmacology

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The effects of conditions that either increase or decrease heart rate on the pharmacological properties of adenosine receptors in cultured rat myocytes were examined. Levels of A 1 adenosine receptors, following prolonged treatment with electrical stimulation (ES) or the antiarrhythmic drug amiodarone, were determined using radioligand binding with the specific A 1 receptor antagonist [ 3 H]1,3-dipropyl-8-cyclopentylxanthine (CPX). The effects of lowering temperature were also explored. Exposure to amiodarone for 4 days reduced the density of A 1 receptors by 19% (from 24.7 ± 0.4 to 20.09 ± 0.3 fmol/dish) and inhibited the rate of contraction by 60% (from 188 ± 16 to 76 ± 30 beats/min), without changing the receptor affinity, protein content, creatine kinase (CK) activity or cell number. Electrical stimulation at 25°C elevated the density of A 1 adenosine receptors by 185% (from 4.1 ± 0.4 to 11.69 ± 2.1 fmol/dish). Four days of reduced temperature (from 37°C to either 30 or 25°C) lowered the density of A 1 adenosine receptors by 69 or 86%, respectively (from 24.1 ± 1.2 to 7.4 ± 0.4 or 3.4 ± 0.3 fmol/dish), with no significant change in the receptor affinity, activity of CK, or lactate dehydrogenase (LDH), protein content or cell number. The observed up-and down-regulation of A 1 adenosine receptors in primary myocyte cultures in response to conditions that exogenously alter the rate of contraction, is indicative of the role of adenosine receptors in adaptation of heart cells to stress.Keywords adenosine receptor; heart rate; amiodarone; electrical stimulation; temperature; cardiocytes Adenosine and amiodarone are antiarrhythmic agents that slow conduction, suppress premature heart beats, are used for the emergency treatment of supraventricular tachycardia [1][2][3], and are used for long-term treatment of atrioventricular tachycardia [4]. Both drugs decrease heart rate as a result of direct effects on the sinoatrial (SA) § node [5,6].The A 1 adenosine receptor is upregulated in hyperthyroidism [7], an effect accompanied by stimulation of myocardial contractility and a biochemical transition of slow-twitch ("red") ‡ Corresponding author: Prof. Asher Shainberg, Department of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. TEL: 972-3-5318265; FAX: 972-3-5351824; shaina@ashur.cc.biu.ac.il. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript muscle to the fast-twitch ("white") muscle type [8]. Treatment with amiodarone, which bears a structural similarity to thyroxin, decreased the serum level of T 3 [9] and caused similar symptoms of hypothyroidism [10]. Amiodarone decreased sensitivity of the heart to catecholamines via a noncompetitive inhibition of catecholamine receptors and decreased the number of β-adrenoceptors in the myocardium [10,11].Electrical stimulation (ES) inhibited the synthesis of nicotinic acetylcholine receptors [12] and increased the density of L-type Ca 2+ channels [13] in cultured muscle cells. ES also reduced the levels of muscarinic ac...

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Protective effects of amiodarone pretreatment on mitochondrial function and high energy phosphates in ischaemic rat heart

Cited by 15 publications

References 40 publications

Effects of antiarrhythmic agents classified as class III group on ischaemia‐induced myocardial damage in canine hearts

Effects of antiarrhythmic agents classified as class III group on ischaemia‐induced myocardial damage in canine hearts

Protective Effect of Amiodarone but NotN-Desethylamiodarone on Postischemic Hearts through the Inhibition of Mitochondrial Permeability Transition

Regulation of A1 adenosine receptors by amiodarone and electrical stimulation in rat myocardial cells in vitro

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