Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

Drug Research ◽  
2020 ◽  
Vol 70 (04) ◽  
pp. 151-157 ◽  
Author(s):  
Enayatollah Seydi ◽  
Yasaman Tabbati ◽  
Jalal Pourahmad
Keyword(s):  
Mitochondrial Membrane ◽  
Heart Diseases ◽  
Isolated Heart ◽  
Chain Complex ◽  
Heart Mitochondria ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Rat Heart Mitochondria ◽  
Β Receptor ◽  
Underlying Mechanisms

AbstractPropranolol and atenolol are known as β receptor blocker drugs. These drugs are used to treat some heart diseases. There are controversies in the relationship between the use of beta-blocker drugs and the level of reactive oxygen species (ROS). Mitochondria as one of the most important sources of ROS are considered as one of the targets of drug-induced cardiotoxicity. The aim of this study was to evaluate the effects of propranolol and atenolol on mitochondria isolated from the heart. To achieve this aim, several markers of mitochondrial and cellular toxicity were evaluated. The key results of this study are the increased ROS level, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release as well as disruption of respiratory chain complex II in mitochondria in isolated heart mitochondria after exposure to propranolol and atenolol. The results indicate an increase in caspase-3 activity and a decrease in the ATP level in cardiomyocytes after exposure to propranolol and atenolol. The underlying mechanisms of propranolol and atenolol induced cardiotoxicity may be associated with alterations in mitochondrial function, oxidative stress, and changes in the mitochondrial membrane.

scholarly journals Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

Drug Research ◽  
2020 ◽  
Vol 70 (02/03) ◽  
pp. 112-118 ◽  
Author(s):  
Enaytollah Seydi ◽  
Tina Servati ◽  
Fatemeh Samiei ◽  
Parvaneh Naserzadeh ◽  
Jalal Pourahmad
Keyword(s):  
Cytochrome C ◽  
Mitochondrial Membrane ◽  
Mitochondrial Swelling ◽  
Ros Generation ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Peroxisome Proliferator Activated Receptor ◽  
Underlying Mechanisms

AbstractPioglitazone (PG) is one of the thiazolidinedione (TZDs) drugs used in diabetic patients. TZDs are known as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Mitochondria are considered as one of the targets of these drugs. The mechanisms of the effect of PG on mitochondria are not well understood. In this study, we investigated the effect of PG on mitochondria isolated from brain and heart. Mitochondrial parameters such as succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) generation, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release were evaluated. The results showed that PG at concentrations of 12.5, 25 and 50 µg/ml increased the generation of ROS, the collapse of MMP, mitochondrial swelling and the release of cytochrome c in mitochondria isolated from both brain and heart tissues. The underlying mechanisms of PG induced neuro-toxicity and cardio-toxicity may be associated with changes in mitochondrial function, ROS generation (oxidative stress), and changes in the mitochondrial membrane.

Abstract 104: Effects of Pinacidil and Ca 2 + on Sodium-loaded Rat Heart Mitochondria

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sergey M Korotkov ◽  
Vladimir P Nesterov ◽  
Irina V Brailovskaya ◽  
Larisa V Emelyanova ◽  
Svetlana A Konovalova ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Rat Heart ◽  
Mitochondrial Membrane ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Potassium Acetate ◽  
Heart Mitochondria ◽  
Inner Mitochondrial Membrane ◽  
Rat Heart Mitochondria ◽  
Acetate Medium

Deterioration of the contractile parameters of the heart muscle caused by ischemia and followed reperfusion is known as the main postoperative complication which is related to Ca 2+ and Na + overload in cardiomyocytes and mitochondria. Pinacidil reduced the overload in ischemia/reperfusion experiments. The mechanism of this phenomenon is still not clear. We hypothesized that increased ion permeability of the inner mitochondrial membrane (IMM) followed drop of electrochemical potential (ΔΨ mito ) can reduce the calcium. The aim of the study was to elucidate the effect of pinacidil (100 μM) and Ca 2+ (100 μM ) on swelling, oxygen consumption and ΔΨ mito of isolated sodium-loaded rat heart mitochondria (RHM(Na)) energized glutamate and malate. Pinacidil significantly enchanced the permeability of IMM to protons in ammonium nitrate medium. Also increased swelling of RHM(Na) energized with substrates in potassium acetate medium revealed that pinacidil increased potassium transport into matrix. Pinacidil stimulated oxygen consumption of RHM(Na) in State 4 and detained Ca 2+ -induced dissipation of ΔΨ mito . Under condition of Ca 2+ and Na + overload simulating ischemia/reperfusion, RHM(Na) oxygen consumption was not affected with pinacidil in State 3 and in the presence of 2,4-dinitrophenol. Cyclosporin A and ADP, the inhibitors of mitochondrial permeability transition pore (MPTP), markedly decreased Ca 2+ - induced swelling of RHM(Na) in nitrate ammonium or potassium acetate medium in the presence of pinacidil. Carboxyatractyloside, an inhibitor of cytosolic side-specific adenine nucleotide translocase, eliminated a pinacidil-stimulated oxygen consumption of succinate-energized RHMNa in State 4 regardless of the presence of Ca 2+ . Pinacidil was also concluded to accelerat potassium flux into energized RHM(Na) and promot MPTP opening in the low conduction state. Based on our data we suggested that the effect of pharmacological preconditioning induced by pinacidil could be due to it’s direct effect on mitochondria which is connected with above stimulation of the potassium permeability of the inner mitochondrial membrane and following reduce of the ΔΨ mito that thus prevent calcium overload of cardiomyocytes after ischemia/reperfusion in turn.

scholarly journals Mesalazine Induces Oxidative Stress and Cytochrome c Release in Isolated Rat Heart Mitochondria: An Analysis of Cardiotoxic Effects

2020 ◽  
Vol 39 (3) ◽  
pp. 241-247
Author(s):  
Ahmad Salimi ◽  
Farnaz Bahreini ◽  
Zhaleh Jamali ◽  
Jalal Pourahmad
Keyword(s):  
Cytochrome C ◽  
Rat Heart ◽  
Isolated Rat Heart ◽  
Mitochondrial Swelling ◽  
Heart Mitochondria ◽  
Cytochrome C Release ◽  
Mitochondrial Ros ◽  
Ros Formation ◽  
Rat Heart Mitochondria ◽  
Inflammatory Bowel

Mesalazine is widely used in the management of inflammatory bowel disease. Previous studies reported that mesalazine-induced cardiotoxicity is a rare, potentially fatal complication. Mitochondria play an important role in myocardial tissue homeostasis. Deterioration in mitochondrial function will eventually lead to cardiomyocyte death and consequently cardiovascular dysfunction. The aim of the current study was to investigate the effects of mesalazine on rat heart mitochondria. Rat heart mitochondria were isolated by mechanical lysis and differential centrifugation. Parameters of mitochondrial toxicity including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release were evaluated. Results revealed that mesalazine induced a concentration- and time-dependent rise in mitochondrial ROS formation, inhibition of SDH, MMP collapse, mitochondrial swelling, and cytochrome c release in rat heart mitochondria. These results indicate that the cardiotoxic effects of mesalazine are most likely associated with mitochondrial dysfunction and ROS formation, which finally ends in cytochrome c release signaling and induction of apoptosis.

scholarly journals Ca2+ stimulates both the respiratory and phosphorylation subsystems in rat heart mitochondria

1996 ◽  
Vol 320 (1) ◽  
pp. 329-334 ◽  
Author(s):  
Vida MILDAZIENE ◽  
Rasa BANIENE ◽  
Zita NAUCIENE ◽  
Ausra MARCINKEVICIUTE ◽  
Ramune MORKUNIENE ◽  
...  
Keyword(s):  
Rat Heart ◽  
Mitochondrial Membrane ◽  
Isolated Rat Heart ◽  
Heart Mitochondria ◽  
Proton Leak ◽  
Succinate Oxidation ◽  
Kinetic Dependence ◽  
Intermediate States ◽  
Rat Heart Mitochondria ◽  
Stimulation Of

Stimulation of mitochondrial respiration by physiological concentrations of Ca2+ was studied to determine which components of oxidative phosphorylation are affected by Ca2+. The kinetic dependence of the respiratory chain, phosphorylation subsystem and proton leak on the mitochondrial membrane potential in isolated rat heart mitochondria respiring on 2-oxoglutarate or succinate was measured at two different concentrations of external free Ca2+. The results show that proton leak is not directly affected by Ca2+, but that both the respiratory and phosphorylation systems can be directly stimulated by Ca2+ depending on conditions. Although Ca2+ directly stimulates the phosphorylation system, this has relatively little effect on respiration rate with 2-oxoglutarate in States 3 and 4 because the subsystem has little control over respiration. However, in intermediate states, the phosphorylation system has greater control and Ca2+ stimulation of this system contributes substantially to the stimulation of respiration and phosphorylation. In the case of succinate oxidation neither the respiratory subsystem nor the phosphorylation system is stimulated by Ca2+.

scholarly journals Polyamines directly induce release of cytochrome c from heart mitochondria

2000 ◽  
Vol 347 (3) ◽  
pp. 875-880 ◽  
Author(s):  
Claudio STEFANELLI ◽  
Ivana STANIC' ◽  
Maddalena ZINI ◽  
Francesca BONAVITA ◽  
Flavio FLAMIGNI ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Permeability Transition ◽  
Isolated Rat Heart ◽  
Heart Mitochondria ◽  
Cardiac Cell ◽  
Cytochrome C Release ◽  
Free Model ◽  
Discrete Amount ◽  
Rat Heart Mitochondria ◽  
Selective Process

Cytochrome c release from mitochondria to the cytosol represents a critical step in apoptosis, correlated to the activation of the caspase cascade. In this report, we show that addition of micromolar concentrations of polyamines to isolated rat heart mitochondria induces the release of cytochrome c. Spermine, which is effective at concentrations of 10-100 μM, is more potent than spermidine, whereas putrescine has no effect up to 1 mM. The release of cytochrome c caused by spermine is a rapid, saturable and selective process that is independent of mitochondria damage. Spermine, unlike polylysine, is able to release a discrete amount of cytochrome c from intact, functional mitochondria. The cytochrome c-releasing power of spermine is not affected by cyclosporin A, differently from the effect of permeability transition inducers. In a cardiac cell-free model of apoptosis, the latent caspase activity of cytosolic extracts from cardiomyocytes could be activated by cytochrome c released from spermine-treated heart mitochondria. These data indicate a novel mechanism of cytochrome c release from the mitochondrion, and suggest that prolonged and sustained elevation of polyamines, characteristic of some pathologies such as heart hypertrophy, could be involved in the development of apoptosis.

Combined assays on isolated heart mitochondria and Cor.4U hiPS-derived cardiomyocytes to predict drug-induced cardiotoxicity

2018 ◽  
Vol 295 ◽  
pp. S200-S201
Author(s):  
C. Martel ◽  
C. Pertuiset ◽  
B. Aubry ◽  
M. Porceddu ◽  
N. Buron ◽  
...  
Keyword(s):  
Isolated Heart ◽  
Heart Mitochondria ◽  
Drug Induced

scholarly journals Diabetes-associated dysregulation ofO-GlcNAcylation in rat cardiac mitochondria

2015 ◽  
Vol 112 (19) ◽  
pp. 6050-6055 ◽  
Author(s):  
Partha S. Banerjee ◽  
Junfeng Ma ◽  
Gerald W. Hart
Keyword(s):  
Mitochondrial Dysfunction ◽  
Rat Heart ◽  
Mitochondrial Membrane ◽  
Diabetic Rats ◽  
Neonatal Rat ◽  
Heart Mitochondria ◽  
Cardiac Mitochondria ◽  
Rat Cardiomyocytes ◽  
Pyrimidine Nucleotide ◽  
Rat Heart Mitochondria

Elevated mitochondrialO-GlcNAcylation caused by hyperglycemia, as occurs in diabetes, significantly contributes to mitochondrial dysfunction and to diabetic cardiomyopathy. However, little is known about the enzymology of mitochondrialO-GlcNAcylation. Herein, we investigated the enzymes responsible for cyclingO-GlcNAc on mitochondrial proteins and studied the mitochondrial transport of UDP-GlcNAc. Analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats show increased mitochondrialO-GlcNAc transferase (OGT) and a concomitant decrease in the mito-specific O-GlcNAcase (OGA). Strikingly, OGT is mislocalized in cardiac mitochondria from diabetic rats. Interaction of OGT and complex IV observed in normal rat heart mitochondria is visibly reduced in diabetic samples, where OGT is mislocalized to the matrix. Live cell OGA activity assays establish the presence of O-GlcNAcase within the mitochondria. Furthermore, we establish that the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transports UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowers mitochondrialO-GlcNAcylation. Inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affects energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption. These data suggest that cardiac mitochondria not only have robustO-GlcNAc cycling, but also that dysregulation ofO-GlcNAcylation likely plays a key role in mitochondrial dysfunction associated with diabetes.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

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