Stimulation of Suicidal Erythrocyte Death by Ipratropium Bromide

Shaik, Nazneen; Alhourani, Eyad; Bosc, Anastasia; Liu, Guilai; Towhid, Syeda Tasneem; Lupescu, Adrian; Läng, Florian

doi:10.1159/000343339

Cited by 7 publications

(5 citation statements)

References 58 publications

(58 reference statements)

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“…A recent clinical study also correlated the use of anti-muscarinics with adverse cardiovascular outcomes in patient trials (Liou et al, 2018), therefore indicating adverse cardiovascular effects with drug use. In particular, Ipratropium bromide, a short acting anti-muscarinic has been shown to exacerbate myocardial ischaemia/reperfusion injury in an in vitro whole heart model (Harvey et al, 2014) and initiate calcium mediated suicidal cell death of erythrocytes (Shaik et al, 2012), indicating the occurrence of intercellular signalling otherwise not ascribed to antagonists.…”

Section: Introductionmentioning

confidence: 99%

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart

Cassambai

Mee

Renshaw

et al. 2019

Toxicology and Applied Pharmacology

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Section: Introductionmentioning

confidence: 99%

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart

Cassambai

Mee

Renshaw

et al. 2019

Toxicology and Applied Pharmacology

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“…However, despite the known co-morbidities, to our knowledge there have been no non-clinical investigations to date to assess the effects of anticholinergic compounds, such as ipratropium, in the setting of simulated IHD or MI. Further to this, Shaik et al (2012) have recently demonstrated that ipratropium is capable of eliciting suicidal erythrocyte death (eryptosis) via a mechanism due to stimulation of increased cytosolic Ca 2+…”

Section: Ipratropium Bromide Mediated Myocardial Injury In In Vitro Mmentioning

confidence: 93%

“…activity (Shaik et al, 2012). Despite differences between eryptosis and apoptosis, which only occurs in nucleated cells, both of these processes can be initiated by increases in Ca 2+ concentration, indicating that ipratropium may have the ability to also trigger apoptosis.…”

Section: Ipratropium Bromide Mediated Myocardial Injury In In Vitro Mmentioning

confidence: 99%

Ipratropium Bromide-Mediated Myocardial Injury in In Vitro Models of Myocardial Ischaemia/Reperfusion

Harvey

Hussain

Maddock

2014

Toxicological Sciences

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Ipratropium bromide, a nonselective muscarinic antagonist, is widely prescribed for the treatment of chronic obstructive pulmonary disease (COPD). Analyses of COPD patients, with underlying ischaemic heart disease, receiving anticholinergics, have indicated increased risk of severity and occurrence of cardiovascular events (including myocardial infarction). The present study explored whether ipratropium bromide induces myocardial injury in nonclinical models of simulated myocardial ischaemia/reperfusion injury. Adult Sprague Dawley rat hearts/primary ventricular myocytes were exposed to simulated ischaemia/hypoxia prior to administration of ipratropium at the onset of reperfusion/reoxygenation. Infarct to risk ratio and cell viability was measured via triphenyl tetrazolium chloride staining and thiazolyl blue tetrazolium bromide (MTT) assay. The involvement of apoptosis and necrosis was evaluated by flow cytometry. Mitochondrial-associated responses were detected by tetramethylrhodamine methyl ester fluorescence and myocyte contracture. Ipratropium (1 × 10⁻¹¹ M - 1 × 10⁻⁴ M) significantly increased infarct/risk ratio and decreased cell viability in a dose-dependent manner. Increased levels of necrosis and apoptosis were observed via flow cytometry, accompanied by increased levels of cleaved caspase-3 following ipratropium treatment. Levels of endogenous myocardial acetylcholine were verified via use of an acetylcholine assay. In these experimental models, exogenous acetylcholine (1 × 10⁻⁷ M) showed protective properties, when administered alone, as well as abrogating the exacerbation of myocardial injury during ischaemia/reperfusion following ipratropium coadministration. In parallel experiments, under conditions of myocardial ischaemia/reperfusion, a similar injury was observed following atropine (1 × 10⁻⁷ M) administration. These data demonstrate for the first time in a nonclinical setting that ipratropium exacerbates ischaemia/reperfusion injury via apoptotic- and necrotic-associated pathways.

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“…Triggers of eryptosis may include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ) [34], formation of ceramide [35], energy depletion [34], activated caspases [36,37,38,39,40], activation of casein kinase 1α [41,42], Janus-activated kinase JAK3 [43], protein kinase C [44], or p38 kinase [45], as well as impaired activity of AMP activated kinase AMPK [46], cGMP-dependent protein kinase [37], PAK2 kinase [47], sorafenib sensitive kinases [48], and sunitinib sensitive kinases [49]. Moreover, eryptosis is stimulated by a wide variety of xenobiotics [35,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79] including several natural substances [34] including gambogic acid [80], tannic acid [81], ipratropium [82], withaferin [83], tanshinone [58], thymoquinone [84], ursolic acid [85], honokiol [86], saponin [87], apigenin [88], oridonin [89], and alpha-lipoic acid [36]. …”

Section: Introductionmentioning

confidence: 99%

Stimulation of Suicidal Erythrocyte Death by Artesunate

Alzoubi

Calabrò

Bissinger

et al. 2014

Cell Physiol Biochem

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Background: The artemisinin derivative artesunate is effective in the treatment of severe malaria and is considered for the treatment of malignancy. Artesunate triggers tumor cell apoptosis, an effect at least in part mediated by mitochondria. Even though lacking mitochondria, erythrocytes may similarly enter suicidal death or eryptosis, which is characterized by cell shrinkage and breakdown of the phospholipid asymmetry of the cell membrane with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), ceramide formation, and oxidative stress. The present study explored whether artesunate stimulates eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ceramide abundance from binding of specific antibodies, and oxidative stress from 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence. Results: A 48 h exposure of human erythrocytes to artesunate significantly increased the percentage of annexin-V-binding cells (≥ 9 µg/ml) without significantly influencing forward scatter. Artesunate significantly increased [Ca²⁺]_i. The stimulation of annexin-V-binding by artesunate (15 µg/ml) was significantly blunted but not abolished by removal of extracellular Ca²⁺. Artesunate increased the ceramide abundance at the cell surface and the 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence. Conclusions: Artesunate stimulates phosphatidylserine translocation at the erythrocyte cell membrane, an effect at least partially due to increase of [Ca²⁺]_i, stimulation of ceramide formation and generation of oxidative stress.

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Stimulation of Suicidal Erythrocyte Death by Ipratropium Bromide

Cited by 7 publications

References 58 publications

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart

Tiotropium bromide, a long acting muscarinic receptor antagonist triggers intracellular calcium signalling in the heart

Ipratropium Bromide-Mediated Myocardial Injury in In Vitro Models of Myocardial Ischaemia/Reperfusion

Stimulation of Suicidal Erythrocyte Death by Artesunate

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