Apomorphine prevents myocardial ischemia/reperfusion-induced oxidative stress in the rat heart

Khaliulin, Igor; Schneider, Aviva; Houminer, Esther; Borman, Joseph B.; Schwalb, Herzl

doi:10.1016/j.freeradbiomed.2004.06.029

Cited by 23 publications

(14 citation statements)

References 40 publications

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“…This could readily account for their reduced sensitivity to Ca 2+ -induced MPTP opening. Furthermore, we and others have shown that three other preconditioning protocols, treatment with urocortin [231], apomorphine [232] or exposure to several intermittent brief hypothermic episodes before index ischaemia (temperature preconditioning) [227], are also associated with mitochondria that develop less oxidative stress during ischaemia/reperfusion and are less sensitive to Ca 2+ -induced MPTP opening. Our discovery that temperature preconditioning is even more potent than IP in reducing oxidative stress, MPTP opening, necrotic damage and arrhythmias suggests this protocol may have considerable clinical implications if it can be mimicked pharmacologically [227].…”

Section: Preconditioningmentioning

confidence: 84%

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Halestrap

2010

Biochemical Society Transactions

270

239

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In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca(2+) overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca(2+) load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.

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Section: Preconditioningmentioning

confidence: 84%

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Halestrap

2010

Biochemical Society Transactions

270

239

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“…It has also been shown that apomorphineinduced myocardial protection is attributable to its antioxidant effect and not via dopamine receptors (17,18). Therefore, it seems that the antioxidant properties of apomorphine might be responsible for its protective effect against ROS-induced injury.…”

Section: Discussionmentioning

confidence: 99%

“…Bromocriptine, a D 2 -like receptor agonist, protects kidney cells against I/R-induced injury in rats (15). It has also been demonstrated that apomorphine, a non-selective dopamine-receptor agonist (16), prevents myocardial I/R-induced oxidative stress in rat heart and that this protective effect is due to an anti-oxidation mechanism (17,18). In addition, our previous study demonstrated that apomorphine protected HT22 cells, originally derived from mouse hippocampal neurons, against oxidative stress-induced cell death through the activation of dopamine D 4 receptors (19).…”

Section: Introductionmentioning

confidence: 98%

Activation of Dopamine D4 Receptors Is Protective Against Hypoxia/Reoxygenation-Induced Cell Death in HT22 Cells

et al. 2010

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Abstract. Several reports have shown that some dopamine receptor ligands modulate the ischemia-reperfusion injury in animal models; however, its underling mechanisms are still unclear. In this study, we sought to establish an in vitro experimental model of hypoxia/reoxygenation (H/R) using HT22 cells that originated from mouse hippocampal neurons and to examine protective the effect of dopamine-receptor ligands against H/R-induced cell injury. The treatment with hypoxia for 18 h followed by reoxygenation for 6 h induced the elevation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential; however, lactate dehydrogenase (LDH) release was not changed at this time point. LDH release was increased after reoxygenation for 18 h and longer, and this increase in LDH release was suppressed by dopamine receptor agonists such as apomorphine and apocodeine. The suppressive effects of these agonists were reversibly inhibited by L750667, a D 4 -receptor antagonist but not by D 2 -or D 3 -receptor antagonists. In addition, PD168077, a selective dopamine D 4 -receptor agonist, also protected against H/Rinduced cell death. These results suggest that H/R causes oxidative stress-induced cell death and that the activation of dopamine D 4 receptors protects against H/R-induced cell death in HT22 cells.

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“…Protein carbonylation Frozen heart samples were homogenized in buffer containing (m m ) 10 Hepes, 137 NaCl, 4.6 KCl, 1.1 KH 2 PO 4 , 0.6 MgSO 4 , 1 EDTA, and complete protease inhibitor cocktail (Roche Diagnostics, Lewis, UK) and centrifuged (10 000 g for 10 min) to obtain the soluble proteins. Protein carbonyls were determined following derivatization with dinitrophenylhydrazine (Chemicon International, Chandlers Ford, UK) exactly as previously described (Khaliulin et al 2004 a ). Derivatized proteins (10 μg) were separated by 10% SDS‐PAGE and subjected to Western blotting with antidinitrophenyl antibodies (Sigma, diluted 1 : 1000).…”

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confidence: 99%

Temperature preconditioning of isolated rat hearts – a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore

Khaliulin

Clarke

Lin

et al. 2007

The Journal of Physiology

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We investigate whether temperature preconditioning (TP), induced by short-term hypothermic perfusion and rewarming, may protect hearts against ischaemic/reperfusion injury like ischaemic preconditioning (IP). Isolated rat hearts were perfused for 40 min, followed by 25 min global ischaemia and 60 min reperfusion (37 • C). During pre-ischaemia, IP hearts underwent three cycles of 2 min global ischaemia and 3 min reperfusion at 37• C, whereas TP hearts received three cycles of 2 min hypothermic perfusion (26 • C) interspersed by 3 min normothermic perfusion. Other hearts received a single 6 min hypothermic perfusion (SHP) before ischaemia. Both IP and TP protocols increased levels of high energy phosphates in the pre-ischaemic heart. During reperfusion, TP improved haemodynamic recovery, decreased arrhythmias and reduced necrotic damage (lactate dehydrogenase release) more than IP or SHP. Measurements of tissue NAD + levels and calcium-induced swelling of mitochondria isolated at 3 min reperfusion were consistent with greater inhibition of the mitochondrial permeability transition at reperfusion by TP than IP; this correlated with decreased protein carbonylation, a surrogate marker for oxidative stress. TP increased protein kinase Cε (PKCε) translocation to the particulate fraction and pretreatment with chelerythrine (PKC inhibitor) blocked the protective effect of TP. TP also increased phosphorylation of AMP-activated protein kinase (AMPK) after 5 min index ischaemia, but not before ischaemia. Compound C (AMPK inhibitor) partially blocked cardioprotection by TP, suggesting that both PKC and AMPK may mediate the effects of TP. The presence of N -(2-mercaptopropionyl) glycine during TP also abolished cardioprotection, indicating an involvement of free radicals in the signalling mechanism.

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Apomorphine prevents myocardial ischemia/reperfusion-induced oxidative stress in the rat heart

Cited by 23 publications

References 40 publications

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection

Activation of Dopamine D4 Receptors Is Protective Against Hypoxia/Reoxygenation-Induced Cell Death in HT22 Cells

Temperature preconditioning of isolated rat hearts – a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore

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